TRENDS IN SYSTEMIC ANTIBIOTIC THERAPY OF ENDODONTIC INFECTIONS: A SURVEY AMONG DENTAL PRACTITIONERS IN LITHUANIA

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Alexander Mende

2019, group 11

TRENDS IN SYSTEMIC ANTIBIOTIC THERAPY

OF ENDODONTIC INFECTIONS:

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cause. Inadequate prescribing practices of systemic antibiotics in endodontic therapy have been thoroughly described in present studies and the available literature. Prescription trends to certain antibiotic classes in Lithuania have been observed. Given the potential contribution to antimicrobial resistance and the evidence of inappropriate prescriptions highlights, that the periodical assessment of antibiotic consumption trends is required.

Aim: The aim of this work was to provide a study on prescription behavior of Lithuanian general

dental practitioners concerning systemic antibiotic therapy of endodontic infections.

Tasks: To compare the results of this study with recommendations presented in the position

statement of the European Society of Endodontics and to evaluate changes between obtained results and previous studies of similar type.

Material and methods: 213 Lithuanian dentists have been asked to provide anonymous

information of their clinical work by means of an online questionnaire.

Results: Antibiotics were prescribed in approximately less than 20% of endodontic cases. Most

common diagnosis for the prescription was symptomatic apical periodontitis with periostitis and apical abscesses with systemic involvement. Amoxicillin and co-amoxiclav were the preferred choices for the antimicrobial therapy. Clindamycin is prescribed in cases of allergy to beta-lactams.

Conclusions: Within the limitations of this study it can be concluded, that in this sample

discrepancies between the practice of Lithuanian general dental practitioners and the literature exist. The majority of practitioners were aware of the clinical recommendations. Especially young dentists performed better than in earlier studies of similar type. Clinicians of higher age were found to be more likely to prescribe antibiotic combinations with broad spectrum than their younger associates.

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INTRODUCTION

Antibiotic resistance is one of the greatest global threats to human health. In particular, the spread of drug resistant bacteria into the community is a problematic development and one principal causer of this emerging resistance is the inappropriate usage of antibiotics [1]. Concerns that overprescribing antibiotics is leading to drug resistant infections are not new and beside the problem of resistance, antibiotic therapy may also be associated with serious complications, involving drug-related adverse effects and allergic reactions. This puts patients unnecessarily at risk if prescribed inconsiderately.

In dentistry the indications for the use of systemic antibiotics are limited [2]. Nevertheless, every year a comparatively high amount of antibiotic prescriptions is issued in the dental sector.

In Europe between 6,5% and 9,1% of all dispensed antibiotics in the primary care are prescribed by general dental practitioners (GDPs) [1].

In comparison with other European countries, Lithuania demonstrates an overall decline in numbers of antibiotic usage in the primary care sector. Data published by the European Centre for Disease Control and Prevention on outpatient antibiotic use in Lithuania shows a decrease in total antibiotic consumption during the last years. Nonetheless, prescription trends to certain antibiotic classes can be observed [3]. The antibiotic therapy in dentistry is typically empirical without aid of microbiologic sampling. Therefore the antimicrobial treatment regularly involves the utilization of systemic broad-spectrum agents, against recommendations of guidelines and on basis of clinical symptoms, which do not justify the use of it. This applies also for the therapy of endodontic infections. Infections of endodontic origin, in the absence of systemic symptoms or indications for spreading infections, usually do not require adjunctive systemic antibiotic therapy and are preferably managed by operative intervention [4].

As an approach to reverse the trend in resistance, it is important to reduce the inappropriate use of antibiotics in the sector of dental public health. Consequently the in the literature provided evidence of inadequate prescribing practices in endodontic patients highlights, that further investigation of GDPs prescription patterns for antibiotic agents is required [5].

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Aim

To analyze the prescription behavior of Lithuanian GDPs, concerning systemic antibiotic therapy of endodontic infections and to evaluate the overall benefits and risks of their usage, to restrain overuse and creation of resistant bacteria, not susceptible to antibiotics.

Tasks

1. To compare the results of this study with recommendations presented in the statement of the European Society of Endodontology.

2. To investigate if broad-spectrum antibiotics are preferred by dentists of younger age, relatively to their older associates.

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1 REVIEW OF LITERATURE

1.1 Background

Antimicrobial resistance

The emerging problem of antibiotic resistance is an international concern for public health and patient safety, both on the individual and community level. Common bacterial infections once easy to treat are becoming increasingly resistant to antibiotics. This evolving problem affects global medical progress and poses a continuous challenge for physicians worldwide [7, 8].

A study by the European Antimicrobial Resistance Surveillance Network on attributable deaths related to antibiotic resistant infections estimates, that annually about 33000 people in the EU died as consequence of an infection with drug-resistant bacteria. This number is comparable to the combined burden of infections with influenza, tuberculosis and HIV/ Aids all together. It also shows that the received numbers continue to rise [8]. Despite persistent efforts of control, antibiotic misuse and increasing counts of prescriptions are primarily responsible for this development.

Reducing unnecessary antibiotic use has been a focus for many years already.

As an approach to reverse the trend in resistance, it is important to reduce the inappropriate use of antibiotics and its purpose must be reserved only for those who can benefit from it. This problem concurs with the current situations in dentistry [1, 9]. Even though the percentage of dental prescriptions represents only a minor part of the total amount of issued antibiotics, its potential contribution to the problem of resistance cannot be underestimated.

Epidemiology of endodontic microbiology

Most pathogens, which are identified within endodontic infections, are microorganisms of the own microbiota of the oral cavity. If oral conditions change, some strains predominate within the microbiota and the homeostasis is disrupted. However due to the aseptic nature of the root canal system in its intact state, any microorganism can be described as potential pathogen regardless, once it finds its way into the root canal. In any case, the variations of host responses are significant. Possible consequences may vary from reversible inflammatory reactions of the pulp to necrosis and the development of periapical lesions [11]. In certain circumstances microorganisms can overcome the barriers of the canal system and establish an extraradicular infection which may lead to apical abscess formation with purulent inflammation in the periapical tissue [12].

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In root canal samples taken from endodontic patients, diagnosed with apical periodontitis, streptococci and obligate anaerobic bacteria are found to be the predominant forms in primary infections. Whereas in secondary infections after root canal manipulation, facultative anaerobic strains of Enterococcus faecalis dominate [13]. Anerobic bacteria are the most prevalent type of microorganisms in extraradicular infections [12]. Although these forms are among the most abundant types associated with apical periodontitis, also fungi, viruses and archae can be detected within the infected root canal. Despite their low concentration, these forms still have significant effect on virulence, persistence and symptomology of the infection. Some microorganisms, including gram negative anaerobic rods and gram positive bacteria are able to persist the intracanal disinfection procedures of endodontic therapy and remain active after biomechanical preparation of canals [11, 12].

The limits of antimicrobial therapy

Despite the abundant character of microorganisms within the oral cavity, the indications for usage of systemic antibiotics for endodontic pathology remain very limited. Most acute dental conditions are preferably managed by operative intervention where adjunctive utilization of antibiotics is not indicated. This includes for example cases of symptomatic pulpitis, necrotic pulps, localized acute apical abscesses and other odontogenic pathologies in the absence of signs of spreading infection or symptoms of systemic involvement, such as cellulitis, malaise, lymphadenopathy and fever [4, 6, 14]. Clinical trials and reviews provide evidence, that antibiotics do not relief pain or swelling in the therapy of these apical pathologies without systemic involvement. A Cochrane review focused on two studies comparing the results of therapy for apical periodontitis and acute apical abscesses with either adjunctive antibiotics or surgical measures only, could find no significant difference in outcomes reported by the participants with oral antibiotics and those which received placebos [15]. In fact due to the restricted blood flow within infected root canals, systemic antibiotics cannot effectively reach the therapeutic area to erase microorganisms [4, 14, 16].

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1.2 Antibiotic prescription practices by dentists in Europe

In Europe, the increasing numbers of prescriptions in the light of emerging antimicrobial resistance encouraged several observational studies to investigate the patterns of antibiotic therapy in dentistry [2]. Hereby surveys have been successful instruments over the past years to obtain data on the clinical practice, including prescription habits and preferred types of antibiotics [Table 1].

Concerning first choice antimicrobial agents, in most of these studies amoxicillin, solely or in combination with clavulanate, has been the preferred type of antibiotics in the initial therapy of odontogenic infections [5, 18 - 21, 23 - 25]. Only in Norway the preferred first choice agent was penicillin VK. In the majority of cases compounds for second choice therapy have been clindamycin and co-amoxiclav (AMC). Preferred usage of the so-called Van-Winkelhoff Cocktail, amoxicillin in combination with metronidazole, was found in Norway [22]. High rates of prescriptions for metronidazole were solely documented by practitioners in Wales, the United Kingdom [25]. Favored types for the therapy of patients with allergy to beta-lactams were clindamycin and macrolides without exception [5, 18 - 25]. The rate of prescriptions issued by dental practitioners varied within the presented studies not only in numbers, but also in methods of calculation and could therefore not be effectively compared. Further significant variations between the studies can be seen in the selection of diagnoses, validating the usage of antibiotics.

With regards to prescriptions patterns, periapical abscesses were described as the most common diagnosis for the antibiotic usage in the UK, Belgium, Croatia and Turkey. Yet in 92,2% of cases in Belgium, antibiotics were found to be prescribed in the absence of systemic infections [18].

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Table 1. Studies on antibiotic prescriptions issued by European dentists

Author Year Country

Primary indicated diagnosis First choice antibiotic Second choice antibiotic Mainjot A et al. [18] Peric M et al. [19] Pipalova R et al [20] Halling F et al. [21] Skucaite N et al. [5] Preus HR et al. [22] Ezpeleta O et al. [23] Kaptan RF et al. [24] Cope AL et al. [25] 2009 2015 2014 2017 2010 2017 2018 2013 2016 Belgium Croatia Czech Republic Germany Lithuania Norway Spain Turkey UK, Wales PAA PAA - - SAPP PAA SAP PAA PAA Amoxicillin Amc Amc Amoxicillin Amoxicillin Penicillin V Amc Amc Amoxicillin Amc Clindamycin Clindamycin Clindamycin Amc Amx + Mtz Amoxicillin Clindamycin Metronidazole PAA, Periapical abscess; SAP, Symptomatic apical periodontitis; SAPP, Symptomatic apical periodontitis with periostitis; Amc, Amoxicillin clavulanate; Amx + Mtz, Amoxicillin – metronidazole combination;

1.3 Guidelines for antibiotic therapy in endodontic patients

Adjunctive Antibiotics

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specific cases to stop infections from spreading via interstitial and tissue spaces. Therefore special care must be taken on symptoms such as diffuse swellings, cellulitis or signs of osteomyelitis. Patients with systemic infection may express symptoms such as elevated body temperature above 38°C, lymphadenopathy, malaise or trismus. The combination of local drainage and antibiotic therapy for spreading infections, allows aside from the evacuation of pus and relief also deeper diffusion of antibiotics into the affected area [2]. For scenarios where firsthand local therapy cannot be achieved, the literature gives not sufficient evidence whether antibiotic aid is beneficial or not [6]. As the majority of antibiotic prescriptions are made empirical, infections must be monitored carefully as antimicrobial agents may be ineffective or insufficient for the treatment.

Antibiotic prophylaxis

Compared to previous recommendations, there are currently only few cases in which the antibiotic prophylaxis may be indicated and changes in guidelines can be seen [28]. In the therapy of medically compromised or immunosuppressed patients, antimicrobial prophylaxis may be considered in the attempt to prevent postoperative infections. However risks of adverse effects often outweigh the benefits for most patients. Immunodeficiency can be the result of uncontrolled diabetes, various chronic diseases or due to medication and oncologic therapies.

In relation to conventional endodontic treatments, surgical endodontic interventions in such patients express higher risks of postoperative infection. Hence certain procedures with higher risk of bacterial exposure and bacteremia are of higher priority in the consideration of antibiotic prophylaxis. For these groups of patients, together with the empiric therapy, microbiologic samples should be taken for the distinct identification and susceptibility testing. Moreover the dental clinician must practice in close collaboration with other responsible physicians [2].

Concerning antibiotic prophylaxis in terms of infective endocarditis, the European Society of Cardiology advises that the prophylaxis should only be considered for a small subset of

patients with underlying cardiac conditions, undergoing invasive dental procedures like root canal therapy and is not recommended in other situations [26]. Regardless, newest changes in NICE guidelines (National Institute for Health and Care Excellence) in the UK state, that the antibiotic prophylaxis is not recommended routinely for patients undergoing dental treatment and therefore emphasizes, that the usage is only appropriate in individual cases [27].

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infections [28]. A cohort study on this topic, found that the risk of infection is not increased following dental procedures in patients with prosthetic joint replacement and is unaffected by antibiotic prophylaxis. Nonetheless in cases of large oral infections or history of previous joint infections, an antibiotic prophylaxis should be considered for the patient [4, 28, 29].

1.4 Recommended selection of antibiotics effective in endodontic therapy

From the stretching list of available antibiotic agents, only few types have been approved in the therapy of endodontic infections [Table 2]. With that said, the choice of antibiotic agents has to be considered deliberately. On basis of the literature and present studies, penicillin and amoxicillin have been found suitable as first-line antimicrobial adjuncts for endodontic therapy, with amoxicillin alone or in combination with clavulanic acid as preferred choice among European dentists [Table 1]. The literature provides evidence of common susceptibility of endodontic microorganisms to penicillin, which makes it a suitable option for the first-line therapy [13]. In comparison to penicillin VK, amoxicillin shows improved absorption, lower risk of side effects and broader spectrum against gram-negative bacteria [2, 4, 13] This spectrum can be further increased by combination with beta-lactamase inhibitors such as clavulanic acid. Despite reported associations with Clostridium difficile infections, co-amoxiclav is one of the recommended choices for endodontic infections because of its sufficiently wide spectrum, low reports of bacterial resistance and efficacy against Staphylococcus aureus. Still its usage should be prioritized for high-risk patients, or second choice therapy after initial antimicrobials were inefficient as the high-risks of emerging bacterial resistance and adverse effects predominate, due to its broad antimicrobial spectrum [4, 6, 17]. A comparing study on therapy outcomes of dentoalveolar infections could find no differences in the therapy with penicillin, amoxicillin or co-amoxiclav [30].

One downside of aminopenicillins is its possibility of allergic reaction. In patients with confirmed allergy to beta lactams, therapy with clindamycin or macrolides like clarithromycin or azithromycin is advised. Beside therapy for allergic patients, lincosamides like clindamycin should not be considered routinely despite its large popularity in dentistry, as reports on microbial resistance showed association with methicillin-resistant Staphylococcus aureus (MRSA).

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Table 2. Antibiotics approved for the therapy of endodontic infections

Antibiotic Spectrum Microbial indication

Recommended usage Suscep- tibility** Penicillin VK Pen + Mtz Amoxicillin Co-amoxiclav Clindamycin Clarithromycin narrow moderate moderate broad broad moderate

aerobic gram-negative cocci facultative / anaerobes* * + anaerobes

* + Gram-negatives

* + Staphylococcus aureus

gram positive aerobes gram positive / negative facultative / anerobes aerobic / anerobic gram-positive / gram – negative bacteria First-line First-line First-line Secondary Allergies Allergies 85% 93% 91% 100% 96% -

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2 MATERIAL AND METHODS

Sample selection

The study was conducted in the period of one month, from January until February 2019.

For the collection of data, questionnaires regarding antimicrobial therapy in endodontics [Annex 1] were emailed to all Lithuanian dental practitioners, registered at the Lithuanian Dental Chamber, which gave their consent to the processing of personal data according to the new EU General Data Protection Regulation. In total 1269 invitations were electronically distributed by the Lithuanian Dental Chamber, of which 213 surveys were returned with a recall rate of 16,78%. From all received responses, only those of dentists, licensed as GDP (excluding dental specialists), were included in the statistical analysis. The sample size was determined using priori probability [Fig. 1].

Participants

In total 213 enrolled dentists accepted the invitation to participate in the study, of which 15 have been excluded because they were dental specialists and 198 GDPs complied with the given criteria. Out of the 198 respondents, 165 women and 33 men from all age groups provided anonymous information. Practitioners have also been asked to indicate if they are working in the private sector or community service [Table 3]. Considering the geographic distribution of the respondents, both dentists from rural and urban areas of Lithuania are represented within the sample.

Table 3: Demographics of the sample

Characteristic Frequency n=198 Practitioner gender (%) Male Female 33 (16,7) 165 (83,3) Practitioner age (%) < 29 30 – 39 40 – 49 > 50

Type of dental practice (%)

64 (32,3) 69 (24,7) 28 (14,1) 57 (28.8)

Private practice

Community dental service

Both, private and community service

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Data collection

Participants were introduced with a short summary and purpose of the study. The questionnaire consisted out of 14 questions in total of which 10 of them had single choice questions and the remaining 4 were multiple-choice questions. The survey was divided into two parts. The first part concentrated on personal information of participants age, gender, type of dental practice, time of clinical activity, average rate of endodontic procedures and overall average frequency of systemic antibiotic usage in endodontic treatments. In the second part of the questionnaire concerning methods of antibiotic usage, clinicians have been asked to indicate diagnostic findings and forms of pathology, validating the systemic antibiotic aid according to their clinical work. Other questions focused on patient groups with special need for adjunctive antibiotic prophylaxis and descriptive treatment methods chosen for a clinical scenario. Furthermore participants reported their favored first- and second choice antimicrobial agents as well as antibiotics chosen for patients with allergy to beta-lactams. The clinical part of the survey was prepared on basis of criteria, presented in the literature and guidelines of the European Society of Endodontology [6]. For improved comparison and association of variables, the sample has been sorted into smaller groups, according to experience (years of clinical activity) and working place (type of dental practice).

Statistical analysis of data

IBM SPSS 23 software package was used to perform quantitative statistical analysis. Relationships between two categorical (nominal or ordinal) variables were tested using Pearson’s chi-squared test of independence. The relation between variables was significant when p-value <0.05.

Due to limitations of categorical data, chi-squared test was performed. In general, chi-squared test of independence tests hypothesis about association between two categorical variables. If statistically significant relationship (association) is given, the two variables are dependent. If this association is not statistically significant, the two variables are independent and there is no association. When chi-square assumptions were not met, Fisher’s exact test was performed by 2x2 tables.

Ethics

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Power analysis and calculation of sample size

Required sample size was calculated using G*Power 3.1.9.4 software at α=0,05, statistica l power (1-β)=0,80 and expected medium effect size (Cohen's h =0,5). A sample size of 198 participants allows to detect medium effect size as low as Cohen`s h=0,4 at 0.8 power and α=0,05 [Fig.1]. However, in order to detect effect sizes lower than 0.4 (at 0.8 power and α=0,05), higher sample size would be required.

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3 RESULTS

The statistical analysis of data provided by GDPs showed, that the majority of clinicians tend to use antibiotics in less than 20% of treated endodontic cases.

6,6% indicated the usage in 30-50% of treatments and 6,1% of them stated to never prescribe systemic antibiotics at all [Fig.2]. There was no relationship between dentists frequency of prescriptions and their age or experience. Association of prescription rate and practitioners type of practice (comparison of private practice and community service) was not statistically significant (p=0,07). However we can observe a tendency that GDPs working in the community dental service prescribe antibiotic agents more frequently than their colleagues in the private sector [Table 4].

In the clinical part of the questionnaire, the participants were asked to identify diagnostic findings and forms of pathology, validating the systemic antibiotic aid according to their clinical work. Exact numbers of this part are presented in Table 5. Most of the respondents (90,4%) stated cases of symptomatic apical periodontitis with spreading infection to the periosteum (SAPP) as indication criteria for the usage of systemic antibiotics. 16,7% of all clinicians prescribing antibiotics to treat Symptomatic apical periodontitis (SAP) without further progression.

Fig.2. Percentual distribution of Lithuanian general dental practitioners indicating to

prescribe antibiotics in the following amount of endodontic cases:

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Table 4: Comparison of average antibiotic prescription rate and participants type of dental practice

Prescriptions

Type of dental practice:

Total P value Private practice Community dental service Average of antibiotic prescriptions for endodontic therapies Never or less than 20 % of cases Count 121 26 147 % within practice type 96,0% 86,7% 94,2% 30-50% of cases Count 5 4 9 % within practice type 4,0% 13,3% 5,8% Total Count 126 30 156 % within practice type 100,0% 100,0% 100,0% 0,070* * p=0,07 according to statistical analysis by Fisher’s exact test

More than half of all participating GDPs (55,1%) provide antibiotic aid for spreading infections and cellulitis. In regards of clinical experience, association of nominal values (p<0,001) estimated that those dentists with less years of clinical activity tend to prescribe antibiotics in this scenario rather than their associates with longer activity of more than 10 years [Table 6]. 60,1% of respondents indicated the use for localized acute apical abscesses, however 8,1% also in acute abscesses without signs of systemic involvement. Concerning the identification of clinical findings [Table 6], most of practitioners mentioned osteomyelitis (90,9%), as well as signs of systemic infection such as elevated body temperature (88,9%) and lymphadenopathy (51,5%). Followed by presence of inflammatory exudate after initial root canal treatment (46%).

Yet some participants would prescribe antibiotics in fluctuant swellings without other signs of systemic infection (6,5%).

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Table 5: Most common diagnosis for systemic antibiotic usage in endodontic therapy

Diagnosis Frequency

(%)

Pathology

Symptomatic apical periodontitis with periostitits 90,4

Cellulitis, spreading infection 55,1

Acute apical abscess with sign of systemic infection 54,0

Symptomatic apical periodontitis 16,7

Acute apical abscess without systemic involvement 8,1 Symptomatic pulpitis

Diagnostic finding Osteomyelitis

Elevated body temperature Localized Fluctuant swelling Lymphadenopathy

Repeated exudation after root canal treatment

Localized fluctuant swelling (in absence of systemic infection) Pain to percussion and biting

Non vital teeth

Periapical radiolucency

Widening of periodontal space

0,5 90,9 88,9 56,6 51,5 46,0 6,5 5,6 3,0 2,0 1,0

Table 6: Practitioners antibiotic prescriptions for spreading infection in relation to their experience

Diagnostic finding

Years of clinical activity:

Total P value 1-10 years more than 10 years Cellulitis, spreading infection No prescription Count 25 64 89 % 25,0% 65,3% 44,9% Antibiotic prescription Count 75 34 109 % 75,0% 34,7% 55,1% *0,001

Comparison between less experienced dentists and those with experience of more than 10 years, in their tendency to prescribe antibiotics for cases of spreading infection and cellulitis.

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Prescription of adjunctive antibiotic prophylaxis for patient groups of special need is demonstrated in Table 7. Vast majority of the respondents indicated immunological compromised patients, diagnosed with apical abscess (79,3%). Also patients with history of infective endocarditis, rheumatic heart diseases or present signs of systemic infection, such as elevated temperature were selected as sub-groups in demand of antibiotic prophylaxis during endodontic treatment [Fig.3]. Only 24,7% of practitioners identified patients, which received orthopedic implants in the period of two years, as more susceptible to the effects of systemic infection and therefore in higher need for antimicrobial therapy.

Fig. 3. Percentual distribution of high-risk conditions for antibiotic prophylaxis in endodontic

therapy according to GDPs assessment

Table 7: Patient groups with increased demand for antibiotic prophylaxis according to general

dental practitioners

Participants indication

Frequency n = 198

(%)

Any procedure in patients with a history of infective endocarditis 172 86,9 Apical abscess in immunologically compromised patient 157 79,3 Apical pathosis in febrile patient showing systemic symptoms 140 70,7 Any procedure in patients with rheumatic heart disease 106 53,5 Any endodontic pathology in immunologically compromised patient 58 29,3 Any endodontic pathology in patients with orthopedic implant

(in the last 2 years)

49 24,7

n - number

All respondents have been asked to theoretically specify the extent of their treatment for the therapy of an abscess with discrete localized swelling - patient shows no symptoms of spreading systemic infection”. In this part 47,5% indicated the empiric therapy with broad-spectrum antibiotics

86.9 79.3 70.7 53.5 24.7 0 10 20 30 40 50 60 70 80 90 100 Infective

endocarditis suppressionImmuno- symptomsSystemic heart diseasesRheumatic Orthopedicimplants

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as necessary step. 52,5% of GDPs have been found to exclusively perform incision and drainage of the abscess without further measures.

Alone 4,5% decided to take additional samples for microbiologic analysis. With regards to increasing practice duration, age or type of practice, more doctors with longer experience recommended the microbiologic sampling. However potential connections with preferred therapy plans were found to be not statistically significant [Annex 3].

Frequency of antibiotic agents chosen for endodontic therapy is shown in Figure 4. Hereby participants have been asked to indicate medication as first choice agents and second choice antimicrobial (prescribed after first choice agent has been proven to be ineffective). They also had to provide information on preferred antibiotic agent for patients with allergy to beta lactams. Questioning of all participants has shown, that 78,8% of clinicians using amoxicillin as preferred first choice agent, followed by co-amoxiclav, the combination of amoxicillin together with clavulanic acid (17,2%).

Statistic analysis of association [Table 8] revealed, that the preference of clavulanic acid combination over simple usage of amoxicillin is increasing relative to the participants age (p=0,016) and working experience (p=0,008). Thus older clinicians with more years of experience are more likely to prescribe the co-amoxiclav combination for initial antibiotic treatment. Just 2,5% of all in the study included dentists preferring the initial treatment with penicillin V over other antimicrobial agents.

Considering the second choice prescribed antibiotic, amoxicillin with clavulanic acid has been found to be the favored choice in 54% of cases. Exclusively 16% of dentists stated to prescribe clindamycin, uncorrelated to their time of clinical experience (p=0,4). Less frequently chosen antibiotic agents were: metronidazole and lincomycin, followed by macrolides and cephalosporins in the presented order [Table 9]. Hypothesis of favored usage of Penicillin over Amoxicillin in regards to increasing age or experience could not be confirmed (p=0.381) [Annex 3].

Fig. 4. Most frequently prescribed first-line antibiotics by Lithuanian general dental practitioners

0% 20% 40% 60% 80% 100%

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In the matter of antibiotic usage for patients with allergy to beta lactams such as penicillin and amoxicillin, about every second clinician (54,0%) stated clindamycin as therapeutic agent of choice. 30,8% of respondents indicated to prefer macrolides for this group of patients. Around 15% of practitioners prescribed cephalosporins in given cases [Table 10].

Table 8. Distribution of amoxicillin and amoxicillin clavulanate prescriptions as first choice

antibiotic relative to participants age (P=0,016) and years of clinical activity (P=0,008)

Study population Amx Amc P value n (%) n (%) Participants age below 40 years above 40 years

Time of clinical activitiy 1 – 10 years

more than 10 years

95 61 85 71 88,0 74,4 89,5 74,7 13 21 10 24 12,0 25,6 10,5 25,3 0,016 0,008 Amx, Amoxicillin; Amc, Amoxicillin clavulanate

Table 9: Most frequently prescribed second choice antibiotics Second choice antibiotics

Frequency (%)

Amoxicillin clavulanate 59,8

Clindamycin 18,4

Metronidazole (with penicilin V or amoxicillin) 6,1

Lincomycin 5,6 Erythromycin 3,9 Clarithromycin or azithromycin Cefuroxim Ampicillin 3,4 1,6 1,2

Table 10: Most frequently prescribed antibiotics for patients with allergy to beta-lactams Antibiotics in allergic patients

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4 DISCUSSION

In order to design effective interventions to optimize antimicrobial prescribing in the dental practice, analysis of causes for the inappropriate usage is needed and influencing factors have to be understood [1].

In accordance to guidelines and similar to results of other European studies [Table 1], the majority of practitioners named spreading infections to the periosteum or soft tissue, along with symptoms of systemic involvement as the principal factors for antibiotic prescription. Most popular diagnosis validating the prescription was symptomatic apical periodontitis with perostitis, as well as

osteomyelitis. These results are similar to previous ones, stated in earlier studies [5]. Furthermore 46% of clinicians correctly indicated the antibiotic usage after local measures failed [Table 5].

Setup of this study and lacking governmental statistics on the number of antimicrobial prescriptions, issued by dental practitioners in Lithuania, did not allow precise assessment of exact prescription rates by GDPs. Obtained averages however were found to be not significantly higher compared to other European countries. The mean of prescription numbers (less than 20% of cases) were relatively lower than those found in the UK or Turkey [1, 24, 25]. A tendency that GDPs working in the community dental service prescribe antibiotic agents more frequently than their colleagues in the private sector could be observed [Table 4].

Despite low prescription numbers, the received data on prescription criteria gives reason to assume, that the indications for antibiotic usage are not fully understood by all clinicians.

In healthy patients without signs of spreading infection, symptomatic apical periodontitis, does not require adjunctive antibiotics. Still 16,7% of all general dentists in this study, have been found to utilize systemic antimicrobials for the given diagnosis. However in comparison to earlier Lithuanian studies, obtained numbers are lower than those from previous results (19.4%) [5].

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empiric therapy with broad-spectrum antibiotics (47,5%). The other half of clinicians stated to perform local incision and drainage only.

Practitioners recognized the contraindication of antibiotics in cases of symptomatic pulpitis.

Not even 1% of all respondents suggested the antibiotic therapy in these cases, even less than previous Lithuanian studies showed [5]. Compared to other cases in the EU this is a big improvement, as for example the diagnosis of pulpitis still accounts for 22% and 7,4% of cases in which antibiotics are prescribed by dentists in Spain and Croatia respectively [19, 23].

In terms of antibiotic selection, vast majority of all GDPs uses amoxicillin for the initial therapy (78,8%), followed by amoxicillin clavulanate as second choice agent, in accordance to recommendations in the literature [2, 4, 13]. When compared to the results of earlier studies on Lithuanian GDPs, the total prescription of amoxicillin has increased. A decline in the use of narrow-spectrum penicillins (2,5%) compared to previous years was observed [5]. Hypothesis that younger dentists prescribing broad-spectrum antibiotics more frequently, compared to their older colleague was disproved.

The preference of co-amoxiclav over simple amoxicillin as first-line therapeutic was found to be in relation with increasing age of the practitioners [Table 8]. Even though the combination of amoxicillin with clavulanic acid is popular within Europe [Table 1], utilization should be prioritized for high-risk patients or as second choice agent only, due to its adverse associations [4, 6, 17]. Prescriptions of the controversial broad-spectrum lincosamide clindamycin affected Lithuanian practitioners to a lesser extent, than for example dentists working in Germany [21].

Responses concerning antibiotic selection for patients with allergy to beta-lactams highlight that clinicians knowledge about antibiotic composition and classification was not always in conformity with the requirements. For this sub-group of patients 13,6% and 1,5% of GDPs indicated to prescribe cefalexin or cefadroxil and cefazolin respectively, despite these antibiotic agents belong to the family of cephalosporins, which are penicillin derivatives. Due to potential cross-sensitivity, their usage in the therapy of allergic patients is not indicated.

Furthermore newest guidelines by the European Society of Cardiology present the opinion that routinely antibiotic prophylaxis for patients with rheumatic heart diseases or orthopedic implants [Fig. 3.] is no longer indicated and includes only individual cases of high-risk patients [26].

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About nine years have passed after the first study of GDPs antibiotic prescription behavior for endodontic infections in Lithuania was conducted due to its potential contribution to the problem of microbial resistance. Time has shown that the dilemma of emerging resistance is internationally ubiquitous and the situation has not significantly improved.

Still if we are taking a closer look at the development of Lithuanian dentists participation in this process, a raise in general awareness and precaution for antimicrobials was detectable.

Especially young GDPs are more aware of new guidelines and clinical criteria, compared to young graduates from previous years [5]. Nevertheless within limitation of this study it can be stated, that variations in clinicians knowledge are noticeable among the sample, especially in terms of antibiotic composition. This emphasizes, that further advanced training of GDPs may be required. Attained results of this research provide a foundation, on which future studies can be established, considering larger participation of Lithuanian dental practitioners. It is recommended to repeat future studies with bigger sample size, as some observed correlations were low.

4.1 Limitations

Patterns of prescription were assessed on basis of self-reported data and may not always coincide with the actual practice of clinicians. In the sample selection, only those dentists which gave their consent to the processing of personal data according to the EU General Data Protection Regulation were included in the study. Because of the small samples, obtained information may not be representative for the general dentist population of Lithuania. Yet due to its demographic variety, the sample can portray a representative cross section. For non-significant relations, due to limitations in sample size, further research with bigger samples would be necessary.

4.2 Acknowledgement

I wish to acknowledge the Lithuanian Dental Chamber for its help in distributing the survey and all Lithuanian dental practitioners, which participated in this study.

Furthermore I would like to thank my supervisor Dr. Tadas Venskutonis and Miglė Mackevičiūtė.

4.3 Conflict of interests

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CONCLUSIONS

1. Antibiotic prescription criteria of Lithuanian general dental practitioners of this sample do not always coincide with recommendations in the literature. Still rates of antibiotic usage are not relatively higher than in other European countries. Implementation of correct

antimicrobial agents is given in the majority of cases.

2. With increasing age and years of experience, dental practitioners are more likely to prescribe antibiotic combinations with broader spectrum, compared to their younger colleagues.

3. Prescription preferences from narrow-spectrum penicillin V to amoxicillin were observed.

Practical Recommendations

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REFERENCES

1. Cope AL, Francis NA, Wood F, Chestnutt IG. Antibiotic prescribing in UK general dental practice: a cross-sectional study. Community Dent Oral Epidemiol. 2016; 44 (2) :145–153

2. Dar-Odeh NS, Abu-Hammad OA, Al-Omiri MK, Khraisat AS, Shehabi AA: Antibiotic prescribing practices by dentists: a review. Ther Clin Risk Manag 2010; 6:301–306

3. Antimicrobial consumption database (ESAC-Net), Consumption of antibiotics for systemic use in the community, European Centre for Disease Prevention and Control. Available from URL: http://ecdc.europa.eu/

4. Segura-Egea JJ, Gould K, Sen BH, Jonasson P, Cotti E, Mazzoni A, Sunay H, Tjäderhane L, Dummer PMH. Antibiotics in Endodontics: a review. Int Endod J. 2017; 50(12):1169-1184

5. Skučaitė N, Pečiulienė V, Manelienė R, Mačiulskienė V. (2010). Antibiotic prescription for the treatment of endodontic pathology: a survey among Lithuanian dentists. Medicina. 2010; 46(12):806-13

6. Segura-Egea JJ, Gould K, Şen BH, Jonasson P, Cotti E, Mazzoni A, Sunay H, Tjäderhane L, Dummer PMH. European Society of Endodontology position statement: the use of

antibiotics in endodontics. Int Endod J. 2018;51(1):20-25

7. World Health Organization (WHO). Global action plan on antimicrobial resistance. WHO. 2015. Available from URL:

http://apps.who.int/gb/ebwha/pdf_files/WHA68/A68_ACONF1Rev1-en.pdf. Accessed March 11th 2019.

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9. Foucault C, Brouqui, P. How to fight antimicrobial resistance. FEMS Immunol Med Microbiol. 2007; 49(2):173-83

10. European Centre for Disease Prevention and Control, Summary of the latest data on antibiotic consumption in EU: 2017, Available from URL: http://ecdc.europa.eu/

11. Persoon, IF, Özok AR. Definitions and Epidemiology of Endodontic Infections. Curr Oral Health Rep. 2017; 4(4): 278–285

12. Narayanan L, Vaishnavi C. Endodontic microbiology. J Conserv Dent. 2010; 13(4): 233–239.

13. Skucaite N, Peciuliene V, Vitkauskiene A, Machiulskiene V. Susceptibility of Endodontic Pathogens to Antibiotics in Patients with Symptomatic Apical Periodontitis. J Endod. 2010; 36(10):1611-6

14. Cope AL, Chestnutt IG. Inappropriate prescribing of antibiotics in primary dental care: reasons and resolutions. Prim Dent J. 2014;3(4):33-7

15. Cope A, Francis N, Wood F, Mann MK, Chestnutt IG. Systemic antibiotics for symptomatic apical periodontitis and acute apical abscess in adults. Cochrane Database Syst Rev. 2018; 9:CD010136

16. Keenan J, Farman A, Fedorowicz Z, Newton JT. A Cochrane Systematic Review Finds No Evidence to Support the Use of Antibiotics for Pain Relief in Irreversible Pulpitis. J Endod. 2006; 32(2):87-92

17. Leffler DA, Lamont JT. Clostridium difficile Infection. N Engl J Med. 2015; 372(16):1539-48

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19. Peric M, Perković I, Romić M, Simeon P, Matijević J, Mehičić GP, Krmek SJ. The Pattern of Antibiotic Prescribing by Dental Practitioners in Zagreb, Croatia. Cent Eur J Public Health. 2015; 23(2):107-13

20. Pipalova, R, Vlcek, J, Slezak, R. The trends in antibiotic use by general dental practitioners in the Czech Republic (2006-2012). Int Dent J. 2014; 64(3):138-43

21. Halling F, Neff A, Heymann P, Ziebart T. Trends in antibiotic prescribing by dental practitioners in Germany. J Craniomaxillofac Surg. 2017; 45(11):1854-1859

22. Preus HR, Fredriksen KW, Vogsland AE, Sandvik L, Grytten JI. Antibiotic-prescribing habits among Norwegian dentists: a survey over 25 years (1990-2015). Eur J Oral Sci. 2017; 125(4):280-287

23. Alonso-Ezpeleta O, Martín-Jiménez M, Martín-Biedma B, López-López J, Forner-Navarro L, Martín-González J, Montero-Miralles P, Del Carmen Jiménez-Sánchez M, Velasco-Ortega E, Segura-Egea JJ. Use of antibiotics by Spanish dentists receiving postgraduate training in endodontics. J Clin Exp Dent. 2018; 10(7): e687–e695

24. Kaptan RF, Haznedaroglu F, Basturk FB, Kayahan MB. Treatment approaches and antibiotic use for emergency dental treatment in Turkey. Ther Clin Risk Manag. 2013; 9: 443–449.

25. Cope AL, Barnes E, Howells EP, Rockey AM, Karki AJ, Wilson MJ, Lewis MA, Cowpe JG. Antimicrobial prescribing by dentists in Wales, UK: findings of the first cycle of a clinical audit. Br Dent J. 2016; 221(1):25-30

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27. Thornhill, MH, Dayer M, Lockhart PB, McGurk M, Shanson D, Prendergast B, Chambers JB. A change in the NICE guidelines on antibiotic prophylaxis for dental procedures. Br Dent J. 2016; 221(3):112-4

28. Daly CG. Antibiotic prophylaxis for dental procedures. Aust Presc. 2017; 40(5): 184–188

29. Kao FC, Hsu YC, Chen WH, Lin JN, Lo YY, Tu YK. Prosthetic Joint Infection Following Invasive Dental Procedures and Antibiotic Prophylaxis in Patients With Hip or Knee Arthroplasty. Infect Control Hosp Epidemiol. 2017;38(2):154-161

30. Kuriyama T, Absi EG, Williams DW, Lewis MAO. An outcome audit of the treatment of acute dentoalveolar infection: impact of penicillin resistance. Br Dent J. 2005; 198(12):759-63

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ANNEXES

Annex 1: Questionnaire

Antibiotikų skyrimo tendencijos endodontinio gydymo metu

Puslapis 1/3

Prieš pradėdami pildyti anketą prašome pateikti bendrąją informaciją apie save. Jūsų konfidencialumas yra užtikrinamas, anketa ir tyrimas yra anoniminiai, jokia asmeninė informacija nebus skelbiama. Tyrimo rezultatai bus pateikiami tik apibendrintai.

Lytis: Jūsų darbovietė?

o

Vyras

o

Moteris

o

Privati klinika

o

Valstybinė gydymo įstaiga

o

Privati klinika ir Valstybinė gydymo įstaiga

Amžius: Darbo patirtis(metai):

o

< 29

o

30 - 39

o

40- 49

o

> 50

o

1-5

o

6-10

o

11-20

o

>20

Vidutinis endodontinių procedūrų skaičius per mėnesį: Kvalifikacijos rusis:

o

4-9

o

10-15

o

16-29

o

>30

o

Gydytojas odontologas

o

Gydytojas endodontologas

o

Kitas specialistas

Kaip dažnai endodontinio gydymo metu Jūs skiriate sisteminius antibiotikus?

o

Niekada

o

20% ar mažiau

o

30 - 50%

o

Daugiau nei 60%

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Puslapis 2/3

Nurodykite metodus, kuriuos naudojate savo klinikinėje praktikoje.

Savo atsakymus žymėkite: ⦻

Galimi keli atsakymų variantai

__________________________________________________________________________________________________________________________

1. Kuriais atvejais endodontinio gydymo metu Jūs skiriate sisteminius antibiotikus ?

o

Simptominis viršūninis periodontitas

o

Simptominis viršūninis periodontitas su periostitu

o

Simptominis pulpitas

o

Pulpos nekrozė

o

Ūminis lokalus viršūninis pūlinys

o

Celiulitas, plintanti infekciją.

2. Pažymėkite klinikinius požymius, kuriems esant, taikysite antibiotikų terapiją

o

Skausmas perkutuojant ar kandant

o

Negyvybingas dantis

o

Lokalus patinimas

o

Pakilusi kūno temperatūra

o

Rentgenologiškai stebimi pokyčiai viršūniniame periodonte

o

Limfadenopatija

o

Praplatėjęs periodonto plyšys

o

Osteomielitas

o

Išliekanti eksudacija iš kanalų pakartotinių vizitų metu

3. Kurioms klinikinėms būklėms esant gydymo metu papildomai skiriama antibiotikų terapija?

o

Imunodeficitinės būklės pacientams esant viršūniniui pūliniui

o

Imunodeficitinės būklės pacientams esant bet kuriai endodontinei būklei/ligai?

o

Pacientams, kuriems buvo atliktas sąnarių protezavimas (dviejų metų laikotarpyje ) esant bet kokiai endodontinei ligai

o

Pacientams, kurių anamnezėje atžymimas infekcinis endokarditas

o

Pacientams, kuriems diagnozuota reumatoidinė širdies liga

o

Pacientams, kuriems pasireiškė bendriniai simptomai (Pvz., karščiavimas), esatn viršūninio periodonto patologijai

4. Pūlinio gydymas esant lokaliam patinimui be būdingų bendrinių pokyčių apima:

o

Empirinę terapiją plataus veikimo spektro antibiotikais

o

Iniciziją ie drenavimą

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Puslapis 3/3

Nurodykite metodus, kuriuos naudojate savo klinikinėje praktikoje.

Savo atsakymus žymėkite: ⦻

Prašau pasirinkite tik vieną atsakymo variantą.

__________________________________________________________________________________________________________________________

5. Koks Jūsų pirmo pasirinkimo antibiotikas, kurį dažniausiai skiriate endodontinio gydymo metu? (1 atsakymas)

o

Penicilinas

o

Amoksicilinas

o

Amoksicilinas su klavulano rūgštimi

o

Klindamicinas

o

Eritromicinas

o

Klaritromicinas ar Azitromicinas

o

Ampicilinas

o

Linkomicinas

o

Metronidazolis

o

Cefuroksimas

6. Koks Jūsų antro pasirinkimo antibiotikas, kurį skiriate endodontinio gydymo metu?

(1atsakymas)

o

Amoksicilinas

o

Amoksicilinas su klavulano rūgštimi

o

Klindamicinas

o

Eritromicinas

o

Klaritromicinas ar Azitromicinas

o

Ampicilinas

o

Linkomicinas

o

Metronidazolis

o

Cefuroksimas

7. Kokį antibiotiką skiriate pacientams, kurie yra alergiški Penicilinui/Amoksicilinui? (1atsakymas)

o

Klindamiciną

o

Cefaleksiną ar Cefadroksilį

o

Klaritromiciną ar Azitromiciną

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Annex 3

Empiric broad-spectrum antibiotics as part of therapy for an apical abscess.

Study population

Empiric AB therapy

n *(%) P value

Time of clinical activity 1 – 10 years

more than 10 years

Type of dental practice Private practice

51 43 62 13 51,0 43,9 49,2 43,3 0,316 0,563

AB, Antibiotic; n, number *(%), Percent within total answers of the responding question not the total sample.

Microbiologic sampling of endodontic pathogens as part of therapy for an apical abscess.

Microbiologic sampling

n *(%) P value

more than 10 years

Type of dental practice Private practice

3 6 6 1 3,0 6,1 4,8 3,3 0,329 1,000

n, number; *(%), Percent within total answers of the responding question not the total sample.

Choice of first-line antibiotic in regards of participants clinical activity and age

Penicillin Amoxicillin

P value

n *(%) n *(%)

more than 10 years

Participants age below 40 above 40 4 1 4 1 4,5 1,4 4,0 1,6 85 71 95 61 95,5 98,6 96 98,4 0,381 0,650 Comparison of preference for penicillin over amoxicillin in relation to participants age

TRENDS IN SYSTEMIC ANTIBIOTIC THERAPY OF ENDODONTIC INFECTIONS: A SURVEY AMONG DENTAL PRACTITIONERS IN LITHUANIA

Alexander Mende