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. 2020 Dec 28;15(12):e0244521. doi: 10.1371/journal.pone.0244521

The first national survey of antimicrobial use among dentists in Japan from 2015 to 2017 based on the national database of health insurance claims and specific health checkups of Japan

Akane Ono 1,#, Masahiro Ishikane 1,2,#, Yoshiki Kusama 1,*, Chika Tanaka 1,2, Sachiko Ono 3, Shinya Tsuzuki 1, Yuichi Muraki 4, Daisuke Yamasaki 5, Masaki Tanabe 5, Norio Ohmagari 1,2
Editor: Simon Clegg6
PMCID: PMC7769482  PMID: 33370390

Abstract

Purpose

To counter the global health threat of antimicrobial resistance, effective antimicrobial stewardship programs are needed to improve antimicrobial use (AMU) among dentists in addition to physicians. This study aimed to investigate the nationwide epidemiology of AMU among Japanese dentists to facilitate the development of dentist-centered programs.

Methods

We conducted a retrospective population-based study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan to analyze the AMU among Japanese dentists between 2015 and 2017. AMU was quantified as the defined daily doses per 1,000 inhabitants per day (DID). The trends in dentist-prescribed AMU were examined according to antimicrobial category and administration route. We also compared outpatient oral AMU between dentists and physicians as well as between on-site and off-site dispensing.

Results

The DID values of dentist-prescribed AMU were 1.23 in 2015, 1.22 in 2016, and 1.21 in 2017. During this study period, outpatient oral antimicrobials comprised the majority (approximately 99%) of dentist-prescribed AMU, and cephalosporins were the most frequently prescribed antimicrobials (>60% of all antimicrobials). The DID values of outpatient oral AMU were 1.21 for dentists and 12.11 for physicians. The DID value for on-site dispensing was 0.89 in 2017, in which cephalosporins were the predominantly used antimicrobials (DID: 0.60).

Conclusions

Interventions that target dentists in Japan should focus on on-site dispensing of oral antimicrobials (especially cephalosporins) for outpatients. Further studies are needed to ascertain the underlying factors of oral cephalosporin prescriptions to guide the development of effective antimicrobial stewardship programs.

Introduction

The World Health Organization has advocated that each country develops a national action plan to counter the rising global health threat of antimicrobial resistance (AMR). Such plans include targeted reductions in antimicrobial use (AMU) within predetermined time frames and the promotion of antimicrobial stewardship programs (ASPs). Several countries have reported that dentists account for 7–11% of all AMU [1–6]. In the US, dentists constitute the second-leading prescribers of antimicrobials (10%) after physicians (80%) [7], with outpatient prescriptions forming the majority (59.1%) of antimicrobial-related expenditures [8]. Although AMU in dental practice is much lower than that of medical practice in the US, Germany, and England [1–3, 5, 6], a rise in dentist-prescribed AMU has been reported in Canada [4]. That study also suggested a need for ASPs that target dentists due to a propensity to unnecessarily prescribe antimicrobials for periapical abscesses and irreversible pulpitis, as well as their sluggish adoption of updated guidelines that stipulate the reduction of perioperative AMU for patients with valvular heart disease and prosthetic joints [4].

Japan’s National Action Plan on AMR from 2016 to 2020 showed that its national AMU was comparable to that of other industrialized countries in the EU [9]. However, Japan uses a much larger proportion of broad-spectrum antimicrobials (e.g., cephalosporins, macrolides, and fluoroquinolones) and a smaller proportion of narrow-spectrum agents (e.g., penicillin) than these other countries [9]. These trends can potentially contribute to the spread of AMR in Japan, and there is therefore a need to assess and control the use of broad-spectrum antimicrobials. Two studies with small sample sizes in limited settings have reported on the inappropriate use of antimicrobials by Japanese dentists [10, 11]. One of these studies found that over 80% of dentists prescribed prophylactic cephalosporins for dental procedures [10], and the other showed that dentists often prescribed antimicrobials post-procedurally despite limited supporting evidence for their effectiveness [11]. The design of ASPs should be informed by an understanding of current AMU trends, but no studies have explored the nationwide epidemiology of AMU among dentists in Japan.

Thus, we conducted a retrospective population-based study using data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) between 2015 and 2017 to investigate the epidemiology of AMU among Japanese dentists to support the development and implementation of effective ASPs.

Methods

Ethics statement

This study was approved by the ethics committee of the National Center for Global Health and Medicine (Approval Number: NCGM-G-002505-00), and was conducted in accordance with the Declaration of Helsinki. Patient data were anonymized prior to analysis. The ethics committee waived the need for patient consent because the study did not deal with any personally identifiable information.

Study design and data source

This retrospective population-based study was conducted using NDB data from January 2015 to December 2017. In Japan, the national health insurance system provides universal coverage for all citizens and long-term residents. Insurance claims for almost all national health insurance–covered healthcare goods and services are collected and stored in the NDB after anonymization. From the NDB, we extracted all claims for antimicrobials that were prescribed by dentists during the study period. We only obtained aggregate data that did not include personally identifiable information, such as birth dates. In addition, the NDB only includes electronic claims data (without any paper-based claims). With the progression of data digitization, the proportion of electronic claims from dentists had steadily increased from 40% in 2011 to 96% in 2015 [12]. Therefore, we focused on data from 2015 to 2017 even though NDB data were available from 2011 onward. We also acquired data on antimicrobial prescriptions by physicians in 2016. The numbers of dentists and physicians were obtained from the National Surveys of Physicians, Dentists and Pharmacists published by the Ministry of Health, Labour and Welfare of Japan [13, 14]. The open data on physician- and dentist-prescribed AMU were acquired from the AMR Clinical Reference Center website [15].

Prescriptions were categorized into outpatient and inpatient prescriptions, and outpatient prescriptions were further sub-categorized into on-site and off-site dispensing. On-site dispensing was defined as antimicrobial prescriptions that are filled at the prescribing facility. In contrast, off-site dispensing referred to antimicrobial prescriptions that are filled at a third-party retail pharmacy, which allows the prescribing physician/dentist to prescribe any antimicrobial regardless of whether their facility has it in stock.

Antimicrobial categories and use

Antimicrobials were categorized based on the World Health Organization’s Anatomical Therapeutic Chemicals (ATC) Classification System and administration route (oral vs. parenteral). AMU was standardized as the defined daily dose, and the volume of use was quantified as the defined daily doses per 1,000 inhabitants per day (DID) [16–18]. The number of inhabitants was obtained from annual population estimates published by the Ministry of Internal Affairs and Communications of Japan [19]. We examined AMU according to the following ATC Level 4 categories: penicillins (ATC code: J01C), cephalosporins (J01DB/J01DC/J01DD/J01DE), macrolides (J01FA), fluoroquinolones (J01MA), and others (J01 excluding the aforementioned codes). Although the ATC code J01DI also includes cephalosporins (ceftobiprole medocaril, ceftaroline fosamil, and ceftolozane/β-lactamase inhibitor combination), these were not used in Japan during the study period. Accordingly, J01DI was sorted into the “others” category.

Outcomes of interest and statistical analysis

We first analyzed the annual trends in dentist-prescribed total AMU stratified by antimicrobial category and administration route between 2015 and 2017. Thereafter, we compared (i) oral AMU in the outpatient setting between dentists and physicians in 2016 (when AMU data from physicians were available) [15] and (ii) oral AMU in the outpatient setting between on-site and off-site dispensing among dentists in 2017. The patterns in oral AMU between dentists and physicians were compared using chi-square tests. Statistical significance was set at P < 0.05 (two-sided). All statistical analyses were performed using SPSS Statistics Version 25 (IBM Corp., Armonk, NY, US).

Results

Annual trends in total AMU among dentists stratified by antimicrobial category and administration route in 2015 to 2017

Table 1 shows the DID values of total AMU among dentists stratified by antimicrobial category. The DID values were 1.23 in 2015, 1.22 in 2016, and 1.21 in 2017. Cephalosporins accounted for the majority of antimicrobials with DID values (proportion of total antimicrobials) of 0.81 (65.6%) in 2015, 0.80 (65.2%) in 2016, and 0.77 (63.7%) in 2017. Over the study period, the DID values of penicillins gradually increased while those of cephalosporins slowly decreased. In contrast, the AMU trends for macrolides and fluoroquinolones were stable over time. The penicillins in Table 1 included antimicrobials with ATC codes J01CA, J01CE, and J01CR. The DID values of J01CA antimicrobials (which include amoxicillin) were 0.10 in 2015, 0.10 in 2016, and 0.12 in 2017. The DID values of J01FF antimicrobials (which include clindamycin) were 0.0017 in 2015, 0.0019 in 2016, and 0.0022 in 2017. Table 2 presents the DID values of total AMU among dentists stratified by administration route. In all three years, outpatient oral antimicrobials comprised the majority of dentist-prescribed AMU (approximately 99%).

Table 1. Annual total antimicrobial use among dentists from 2015 to 2017 stratified by antimicrobial category.

2015 2016 2017
Penicillins 0.10 (8.0) 0.11 (8.8) 0.13 (10.3)
Cephalosporins 0.81 (65.6) 0.80 (65.2) 0.77 (63.7)
Macrolides 0.23 (19.0) 0.30 (18.7) 0.23 (18.8)
Fluoroquinolones 0.067 (5.4) 0.067 (5.4) 0.066 (5.4)
Others 0.023 (1.9) 0.023 (1.9) 0.022 (1.8)
Total 1.23 1.22 1.21
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Values are presented as defined daily doses per 1,000 inhabitants per day (% of total).

Table 2. Annual total antimicrobial use among dentists from 2015 to 2017 stratified by administration route.

2015 2016 2017
Outpatient oral administration 1.213 (99.0) 1.21 (98.9) 1.20 (98.9)
Outpatient parenteral administration <0.010 (0.1) <0.010 (0.1) <0.010 (0.1)
Inpatient oral administration <0.010 (0.5) <0.010 (0.5) <0.010 (0.5)
Inpatient parenteral administration <0.010 (0.4) <0.010 (0.4) <0.010 (0.4)
Total 1.23 1.22 1.21
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Values are presented as defined daily doses per 1,000 inhabitants per day (% of total).

Comparison of outpatient oral AMU between dentists and physicians in 2016

Table 3 shows the outpatient oral AMU for dentists (n = 104,533) and physicians (n = 319,480) in 2016. The DID values were 1.21 for dentists and 12.11 for physicians. In addition, dentists accounted for approximately 9.1% of the national outpatient oral AMU (i.e., outpatient oral AMU for both dentists and physicians). There were significant differences in the proportions of outpatient oral AMU between dentists and physicians (P < 0.001).

Table 3. Comparison of outpatient oral antimicrobial use between dentists and physicians in 2016.

Dentists n = 104,533 Physicians n = 319,480
Penicillins 0.11 (8.7) 0.98 (8.1)
Cephalosporins 0.79 (65.2) 2.80 (23.1)
Macrolides 0.23 (18.9) 4.47 (36.9)
Fluoroquinolones 0.067 (5.5) 2.69 (22.2)
Others 0.022 (1.8) 1.18 (9.7)
Total 1.21 12.11
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Values are presented as defined daily doses per 1,000 inhabitants per day (% of total).

There were significant differences in the proportions of oral antimicrobial use between dentists and physicians (P < 0.001).

Comparison of outpatient oral AMU between on-site and off-site dispensing among dentists in 2017

Table 4 shows the outpatient oral AMU for on-site and off-site dispensing among dentists in 2017. The DID values were 0.89 for on-site dispensing and 0.31 for off-site dispensing. In addition, on-site dispensing accounted for 74.2% of all outpatient oral AMU among dentists. Cephalosporins were the predominant antimicrobials in both on-site (DID: 0.60; 66.9% of outpatient oral AMU) and off-site (DID: 0.17; 54.1% of outpatient oral AMU) dispensing.

Table 4. Comparison of outpatient oral antimicrobial use between on-site and off-site dispensing among dentists in 2017.

On-site Off-site
Penicillins 0.080 (9.0) 0.042 (13.8)
Cephalosporins 0.60 (66.9) 0.17 (54.1)
Macrolides 0.15 (17.2) 0.073 (23.9)
Fluoroquinolones 0.047 (5.2) 0.019 (6.1)
Others 0.014 (1.6) 0.006 (2.1)
Total 0.89 0.31
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Values are presented as defined daily doses per 1,000 inhabitants per day (% of total).

Discussion

This nationwide study of AMU among Japanese dentists found that the vast majority of their antimicrobial prescriptions were for oral antimicrobials in the outpatient setting (approximately 99%), and that cephalosporins were predominantly used (>60%). These results corroborate those of a previous cross-sectional questionnaire-based study on dentists at community clinics in Japan [20]. The frequent use of cephalosporins in Japan may be due in part to the active promotion of these antimicrobials by pharmaceutical companies. A study conducted in Nepal showed that the top-selling antimicrobials were those that were subjected to intensive promotional activities [21]. Although such promotional activities have since diminished in Japan, the situation was similar to that of Nepal as recently as 10 years ago. These activities may therefore have contributed to the high adoption rate of cephalosporins in Japan’s medical facilities. In our previous analysis of AMU in 31 Japanese hospitals, we found that all the study hospitals had adopted the use of oral third-generation cephalosporins [22]. Furthermore, most of these cephalosporins were Japanese-origin drugs that are not commonly used outside of Japan [17]. The prevalent use of cephalosporins by Japanese dentists is in contrast to the utilization patterns in other countries [4, 5, 23–26]. For example, a national survey of German dentists showed amoxicillin to be the most commonly prescribed antimicrobial (45.8% of total AMU in 2015) [5]. A Canadian study using a population-based prescribing database reported on the dominant use of amoxicillin (1.26 DID out of 1.59 DID; 79.2% of total AMU in 2013) [4]. Similar findings have also been reported in Kuwait [23] and Scotland [24]. In comparisons of antimicrobial prescription rates, amoxicillin was also found to be the dominant antimicrobial in the US (57% in 2015) [25] and Australia (64.3% in 2016) [26]. Our study also showed that the annual DID value of dentist-prescribed oral AMU was 1.21, which accounted for approximately 9.1% of the national outpatient oral AMU. This proportion was similar to that reported in other countries [4–6].

Although our study found that the AMU of Japanese dentists was lower than that of physicians, the former predominantly used cephalosporins, whereas the latter frequently used macrolides and fluoroquinolones in addition to cephalosporins. In general, the causal bacteria of odontogenic infections can be treated with penicillins or penicillin/β-lactamase inhibitor combinations, with a single dose recommended before a procedure. Therefore, it may be beneficial for dentist-centered ASPs to focus on the appropriate use of oral cephalosporins in outpatients. The 2011 version of Japan’s Guidelines for the Clinical Management of Infectious Diseases did not address odontogenic infections [27]. However, these were included in the 2014 version [28, 29] following the emergence of AMR as a major health threat. These guidelines recommend the use of penicillins, not cephalosporins, as first-line therapy for odontogenic infections [29]. Our analysis detected a slight increase in penicillin use accompanied by a minor decrease in cephalosporin use from 2015 to 2017, which may be indicative of a trend toward more appropriate AMU. A previous report suggested that dentists in Japan tend to follow the prescribing habits of more senior dentists without judicious consideration of current best practices [10]. However, we posit that the AMU among dentists will improve as the updated guidelines are increasingly adopted.

Our analysis showed that on-site dispensing accounted for 74.2% (DID: 0.89) of outpatient oral AMU among dentists, and that cephalosporins were the most frequently prescribed antimicrobials (66.9%). In Japan, approximately 80% of all dental facilities are privately owned and operated [30]. Our previous questionnaire-based study showed that the majority of private dental facilities are only able to provide on-site dispensing for two antimicrobials, one of which is frequently a cephalosporin [31]. We posit that the availability of two antimicrobials may be sufficient for most prophylactic or therapeutic applications in these facilities, even in cases where a patient is allergic to one of the antimicrobials. In consideration of these results, a potentially effective ASP for dentists may involve interventions to shift the use of cephalosporins to penicillins at private dental facilities. For example, antimicrobial prescribing has undergone a steady decline in England due to active interventions by the National Health Service, such as the release of antimicrobial stewardship messages that highlight the potential role of clindamycin in causing Clostridioides difficile infections [1]. Furthermore, the decline in antimicrobial prescribing is also expected to continue with the use of the Dental Antimicrobial Stewardship Toolkit [32]. This indicates that interventions aimed at dental facilities can improve antimicrobial prescription practices among dentists, and that standardized and intensive approaches may also be warranted in Japan.

This study has several limitations. First, the retrospective use of claims data means that we were unable to collect clinically relevant information regarding the prescriptions, such as patient and dentist characteristics, purpose of each prescription (therapeutic or prophylactic), and targeted diseases and procedures. Japan’s Guidelines for the Clinical Management of Infectious Diseases [29] and the Japanese Circulation Society’s 2017 Guidelines on the Prevention and Treatment of Infective Endocarditis [33] recommend the use of antimicrobials for infective endocarditis prophylaxis, which may represent one of the main reasons for antimicrobial prescriptions by dentists. Nevertheless, we were unable to ascertain the specific reason for which each antimicrobial was prescribed. We are currently conducting a questionnaire-based epidemiological study to further investigate the purpose of antimicrobial prescriptions by dentists. Second, the data were collected only from the NDB, which did not include uninsured patients such as tourists. However, these individuals would only account for a very small portion of the total population. Despite these limitations, our study’s strength lies in the use of a national database that encompasses as much as 96% of the total population in Japan [12]. To the best of our knowledge, this is the first nationwide study of the epidemiology of AMU among Japanese dentists. In addition to dentists and physicians, AMU should also be examined in veterinarians as they act as both physicians and pharmacists in Japan and other countries. As the World Health Organization’s One Health approach recommends a holistic and multisectoral approach to AMR measures, there is an urgent need to implement effective ASPs for both human and veterinary medicine [34].

In conclusion, this study showed that dentist-prescribed AMU mostly involved oral antimicrobials for outpatients, and that cephalosporins were predominantly used. Dentists accounted for 9.1% of all outpatient oral AMU in Japan. There is a need for the development and implementation of dentist-centered ASPs that focus on oral cephalosporins for outpatients. Further studies are also needed to identify the factors associated with dentists’ prescription of oral cephalosporins in order to inform the development of more effective ASPs.

Acknowledgments

We thank all the staff of the AMR Clinical Reference Center for their support in establishing Japan’s National Action Plan on AMR from 2016 to 2020.

Data Availability

Data cannot be shared publicly because of including personal information. Data are available from the Ministry of Health, Labour, and Welfare of Japan for researchers who meet the criteria for access to confidential data. Contact information is below: Phone +81-50-5546-9167 email teikyo_rezept@kits.nttdata.co.jp.

Funding Statement

This study was supported by a research grant from the Ministry of Health, Labour and Welfare of Japan (Grant Number: 20HA2003).

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Decision Letter 0

Simon Clegg

10 Nov 2020

PONE-D-20-31740

The First National Survey of Antimicrobial Use Among Dentists in Japan from 2015 to 2017 Based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan

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Reviewer #1: This is an interesting study of the antibiotic prescribing practices of Japanese dentists. The study has made use of national data and the limitations of this are described. The findings are very interesting and while demonstrating a similar proportion of all antibiotic prescring by dentists in Japan to that in other countries, also shows some very big differences - particularly in the very high preference for prescribing cephalosporins.

This is such a striking difference, it perhaps warrants further highlighting. In most other countries where similar studies have been performed the most frequently prescribed antibiotics by dentists are penicillins (particularly amoxicillin). In the Americas this is often followed by clindamycin - particularly in those with penicillin allergy or in Europe, most often metronidazole - again particularly for those with penicillin allergy. In most countries where such studies of dental antibiotic use has been studied, cephalosporins come low in the list of those antibiotics prescribed. If possible, the reasons for the Japanese preference for cephalosporins should be discussed and there should be more discussion and comparison with other countries regarding the most widely used beta lactic alternatives. In that regard the authors should consider mention of a couple of relatively recent studies of dental antibiotic prescribing practice from Australia (Teoh L, Stewart K, Marino R J, McCullough M J. Part 1. Current prescribing trends of antibiotics by dentists in Australia from 2013 to 2016. Aust Dent J 2018) and the USA (Durkin M J, Hsueh K, Sallah Y H et al. An evaluation of dental antibiotic prescribing practices in the United States. J Am Dent Assoc 2017; 148: 878–886.)

It is also important to point out that antibiotic prescribing by dentists falls into two important categories (a) treatment of odontogenic infections) and (b) prophylaxis to prevent infection. And prophylaxis falls into two categories (i) prophylaxis to prevent local infection following dental procedures e.g. post-operative infection following a surgical extraction or implant placement and (ii) prophylaxis to prevent a distant site infection e.g. antibiotic prophylaxis (AP) to prevent infective endocarditis (IE) or prosthetic joint infection. One of the limitations of this type of study is that it cannot distinguish the reason/purpose for which the antibiotic was prescribed - and this should be mentioned in the limitations section. However, AP to prevent IE/prosthetic joint infections accounts for a significant % of all antibiotic prescribing by dentists in most countries and so this warrants mention. Particularly as the Japanese Cardiac Society issue recommendations to dentists that they provide AP to all patients at moderate or high-risk of IE undergoing invasive dental procedures (Nakatani S. et al, Circulation Journal, 2017). Most other countries only recommend AP for those at high-IE-risk, which is only around 10% of the number of individuals who are at moderate or high-risk. Therefore one would expect many more dental patients in Japan to be given AP to prevent IE than in other countries that recommend AP. Furthermore, the Japanese AP guidelines recommend the use of Amoxicillin 2g as a single oral dose 1 hour before the procedure or for those allergic to penicillin Clindamycin 600mg, Azithromycin 500mg or Clarithromycin 400mg. There is no recommendation for cephalosporins to be used orally for AP purposes. This raises questions about the compliance of Japanese dentists with the Japanese guidance on the use of AP to prevent IE and the need for interventions to address this.

I don't know if there is any recommendation for Japanese dentists to provide AP for patients with prosthetic joints but dentists in the US and some other countries are recommended to provide such AP.

The current categorisation of antibiotics into such broad categories seems rather a blunt instrument. Are the investigators not able to provide a breakdown of the types of penicillins - at least Amoxicillin v other penicillins to allow better comparison with the findings in other countries and a better understanding of compliance with Japanese AB and AP prescribing guidelines? Similarly, for comparison with other international studies data on the prescribing of clindamycin would be very helpful - if available

Reviewer #2: I had the fortune to review “The First National Survey of Antimicrobial Use Among Dentists in Japan from 2015 to 2017 Based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan”.

My expertise is medical microbiology, dentistry and senior author of a comparable study in a different country.

With this background I have carefully read you very well performed, very well written, and very important study which should be published with priority.

A few recommendations to further improve this survey.

“Several countries have reported that dentists account for 7–11% of all AMU [1–6]. In the US, dentists constitute the second-leading prescribers of antimicrobials (10%) 60 after physicians (80%) [7],”

The message here is that physicians (by 80%) and dentists (by 10%) are THE prescribers of antibiotics and the address for need for stewardship. You might add a sentence about veterinarian and the fact that they are doctor and pharmacologist in personal union, at least in some countries. The stewardship should reach them also and quickly.

The second comment is related to this impressively high prescription rate of cephalosporins in Japan (above 60%). In other countries it is listed “among others” with only a few prescriptions at dental practices. To avoid such false prescriptions in the future, it is relevant to track the origin of problem. For instance, in our country clindamycin was (and is) a blockbuster in dentistry. The simple reason is the intense promotion by the corresponding manufacturer. That means, antibiotics of most attention (not of most efficacy) are prescribed. What could be the reason for such an over-prescription in Japan? It is known that there is cross-allergy between penicillins and cephalosporins (about 20%). My hypothesis is that the origin is related to allergy rates, namely that cephalosporins are generally regarded as safer? You might proof this hypothesis.

No other comments.

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PLoS One. 2020 Dec 28;15(12):e0244521. doi: 10.1371/journal.pone.0244521.r002

Author response to Decision Letter 0

7 Dec 2020

Reviewer #1’s Comments:

1. If possible, the reasons for the Japanese preference for cephalosporins should be discussed and there should be more discussion and comparison with other countries regarding the most widely used beta lactic alternatives.

Thank you for your thoughtful and constructive feedback regarding our manuscript.

We are grateful for this important suggestion. A possible reason for the preference for cephalosporins in Japan’s medical facilities may be the active promotion of these antimicrobials by pharmaceutical companies. A recent study reported that the top-selling antimicrobials in Nepal were those with a higher number of promotional activities [21]. Although such activities have since diminished in Japan, the situation was similar to that of Nepal until only 10 years ago. These promotions may have contributed to the high adoption rate of cephalosporins in medical facilities in Japan when compared to those in other countries. In fact, we have previously shown in an analysis of 31 Japanese hospitals that all the study hospitals had adopted the use of oral third-generation cephalosporins [22]. Furthermore, most of these cephalosporins were Japanese-origin drugs that are not commonly used outside of Japan. Based on the results of our previous questionnaire-based study on AMU among dentists in Japan [31], we are currently conducting a nationwide questionnaire-based epidemiological study to determine the factors that influence prescriptions of third-generation cephalosporins among 1700 dentists throughout the country. We have added this information to the Discussion section.

(Before: Discussion, Page 14, Line 201)

These results corroborate those of a previous cross-sectional questionnaire-based study on dentists at community clinics in Japan [20].

(After: Discussion)

These results corroborate those of a previous cross-sectional questionnaire-based study on dentists at community clinics in Japan [20]. The frequent use of cephalosporins in Japan may be due in part to the active promotion of these antimicrobials by pharmaceutical companies. A study conducted in Nepal showed that the top-selling antimicrobials were those that were subjected to intensive promotional activities [21]. Although such promotional activities have since diminished in Japan, the situation was similar to that of Nepal as recently as 10 years ago. These activities may therefore have contributed to the high adoption rate of cephalosporins in Japan’s medical facilities. In our previous analysis of AMU in 31 Japanese hospitals, we found that all the study hospitals had adopted the use of oral third-generation cephalosporins [22]. Furthermore, most of these cephalosporins were Japanese-origin drugs that are not commonly used outside of Japan [17].

References (References 21 and 22 have been added.)

17. Tsutsui A, Yahara K, Shibayama K. Trends and patterns of national antimicrobial consumption in Japan from 2004 to 2016. J Infect Chemother. 2018;24: 414-21. doi:10.1016/j.jiac.2018.01.003

20. Amari Y, Uehara Y, Watanabe Y, Inui A, Sugihara E, Yokokawa H, et al. Status of antimicrobial use among dentists in Japan. J Gen Hosp Med. 2014;6: 8-15.

21. Koju P, Rousseau SP, Van der Putten M, Shrestha A, Shrestha R. Advertisement of antibiotics for upper respiratory infections and equity in access to treatment: a cross-sectional study in Nepal. J Pharm Policy Pract. 2020;13(4). doi:10.1186/s40545-020-0202-1

22. Kusama Y, Muraki Y, Mochizuki T, Kurai H, Gu Y, Ohmagari N. Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals. J Infect Chemother. 2020;26(2):211-215. doi:10.1016/j.jiac.2019.08.013

31. Koizumi R, Kusama Y, Ishikane M, Tanaka C, Ono A, Gu Y, et al. Cross-sectional study to clarify the status of antimicrobial prescribing at outpatient care among dentists. Kansenshogaku Zasshi. (in press)

2. In that regard the authors should consider mention of a couple of relatively recent studies of dental antibiotic prescribing practice from Australia (Teoh L, Stewart K, Marino R J, McCullough M J. Part 1. Current prescribing trends of antibiotics by dentists in Australia from 2013 to 2016. Aust Dent J 2018) and the USA (Durkin M J, Hsueh K, Sallah Y H et al. An evaluation of dental antibiotic prescribing practices in the United States. J Am Dent Assoc 2017; 148: 878–886.)

Thank you for your suggestion. We have added the suggested studies of dental antibiotic prescribing practice to the Discussion section.

(Before: Discussion, Page 14, Line 201)

The prevalent use of cephalosporins by Japanese dentists is in contrast to the utilization patterns in Germany and the US [5, 21]. A national survey of German dentists showed amoxicillin to be the most commonly prescribed antimicrobial (45.8% of total AMU in 2015) [5], and a study of dental-related emergency department visits in the US revealed that penicillins accounted for over 60% of total AMU [21].

(After: Discussion)

The prevalent use of cephalosporins by Japanese dentists is in contrast to the utilization patterns in other countries [4, 5, 23-26]. For example, a national survey of German dentists showed amoxicillin to be the most commonly prescribed antimicrobial (45.8% of total AMU in 2015) [5]. A Canadian study using a population-based prescribing database reported on the dominant use of amoxicillin (1.26 DID out of 1.59 DID; 79.2% of total AMU in 2013) [4]. Similar findings have also been reported in Kuwait [23] and Scotland [24]. In comparisons of antimicrobial prescription rates, amoxicillin was also found to be the dominant antimicrobial in the US (57% in 2015) [25] and Australia (64.3% in 2016) [26].

References (References 23–26 have been added.)

4. Marra F, George D, Chong M, Sutherland S, Patrick DM. Antibiotic prescribing by dentists has increased Why? J Am Dent Assoc. 2016;147: 320-7. doi:10.1016/j.adaj.2015.12.014

5. Halling F, Neff A, Heymann P, Ziebart T. Trends in antibiotic prescribing by dental practitioners in Germany. J Cranio-Maxillofacial Surg. 2017;45: 1854-9. doi:10.1016/j.jcms.2017.08.010

23. Salako NO, Rotimi VO, Adib SM, Al-Mutawa S. Pattern of antibiotic prescription in the management of oral diseases among dentists in Kuwait. J Dent. 2004;32(7):503-509. doi:10.1016/j.jdent.2004.04.001

24. Roy KM, Bagg J. Antibiotic prescribing by general dental practitioners in the Greater Glasgow Health Board, Scotland. Br Dent J. 2000;188(12):674-676. doi:10.1038/sj.bdj.4800574

25. Durkin MJ, Hsueh K, Sallah YH, et al. An evaluation of dental antibiotic prescribing practices in the United States HHS Public Access. J Am Dent Assoc. 2017;148(12):878-886. doi:10.1016/j.adaj.2017.07.019

26. Teoh L, Stewart K, Marino RJ, McCullough MJ. Current prescribing trends of antibiotics by dentists in Australia from 2013 to 2016. Part 1. Aust Dent J. 2018;63(3):329-337. doi:10.1111/adj.12622

3. One of the limitations of this type of study is that it cannot distinguish the reason/purpose for which the antibiotic was prescribed - and this should be mentioned in the limitations section.

Thank you for the advice. We think that the major purpose of antimicrobials in our study setting is the prevention of infective endocarditis (IE). If oral medications are available, the Japanese Circulation Society Guidelines (2017) [33] recommend amoxicillin for IE prophylaxis; for patients with penicillin allergy, other antimicrobials such as clindamycin, azithromycin, or clarithromycin should be used. However, due to the nature of our database, we were unable to ascertain the detailed reason/purpose for which each antimicrobial was prescribed. To further investigate the reasons for prescribing antimicrobials by dentists, we are currently conducting a large-scale questionnaire-based epidemiological study. As advised, we have addressed this limitation in the revised manuscript.

(Before: Limitation, Page 16, Line 248)

This study has several limitations. First, the retrospective use of claims data means that we were unable to collect clinically relevant information regarding the prescriptions, such as patient and dentist characteristics, purpose of each prescription (therapeutic or prophylactic), and targeted diseases and procedures. Second, the data were collected only from the NDB, which did not include uninsured patients such as tourists.

(After: Limitation)

This study has several limitations. First, the retrospective use of claims data means that we were unable to collect clinically relevant information regarding the prescriptions, such as patient and dentist characteristics, purpose of each prescription (therapeutic or prophylactic), and targeted diseases and procedures. Japan’s Guidelines for the Clinical Management of Infectious Diseases [29] and the Japanese Circulation Society’s 2017 Guidelines on the Prevention and Treatment of Infective Endocarditis [33] recommend the use of antimicrobials for infective endocarditis prophylaxis, which may represent one of the main reasons for antimicrobial prescriptions by dentists. Nevertheless, we were unable to ascertain the specific reason for which each antimicrobial was prescribed. We are currently conducting a questionnaire-based epidemiological study to further investigate the purpose of antimicrobial prescriptions by dentists. Second, the data were collected only from the NDB, which did not include uninsured patients such as tourists.

References (Reference 33 has been added.)

29. Kaneko A, Aoki T, Ikeda F, Kawabe R, Satoh T, Tsumura N. The 2016 JAID/JSC guidelines for clinical management of infectious disease−Odontogenic infections. J Infect Chemother. 2018;24: 320-4. doi:10.1016/j.jiac.2017.09.014

33. Nakatani S. Guideline on Prevention and Treatment of Infective Endocarditis. Circ J. 2019;83:1767-1809. doi:10.1253/circj.CJ-19-0549

4. The current categorisation of antibiotics into such broad categories seems rather a blunt instrument. Are the investigators not able to provide a breakdown of the types of penicillins - at least Amoxicillin v other penicillins to allow better comparison with the findings in other countries and a better understanding of compliance with Japanese AB and AP prescribing guidelines? Similarly, for comparison with other international studies data on the prescribing of clindamycin would be very helpful - if available.

Thank you for your suggestion. We agree that the current categorization is rather broad. If we collected more detailed data on the classification of antimicrobials, it may be possible to compare the use of amoxicillin and clindamycin (in addition to cephalosporins) with that of other countries. This may even help to identify the factors other than the promotional activities of pharmaceutical companies that explain why cephalosporins are the most commonly prescribed antimicrobial among Japanese dentists. However, our study was based on ATC Level 4 codes, which made it difficult to identify ampicillin and clindamycin use. The identification of ampicillin and clindamycin requires ATC Level 5 codes, in which amoxicillin is coded as J01CA04 and clindamycin is coded as J01FF01. The “penicillins” in our study comprised a combination of three sub-categories (J01CA, J01CE, and J01CR) at ATC Level 4; here, amoxicillin belongs to J01CA. The DID values of J01CA—including amoxicillin—were 0.10 in 2015, 0.10 in 2016, and 0.12 in 2017. These values were almost equivalent to those of “penicillins” in our study. Similarly, clindamycin belongs to J01FF at ATC Level 4. The DID values of J01FF—including clindamycin—were 0.0017 in 2015, 0.0019 in 2016, and 0.0022 in 2017. We have added these results to the Results section, and hope this helps provide insight for readers to make any comparisons if needed.

(Before: Result, Page 10, Line 155)

In contrast, the AMU trends for macrolides and fluoroquinolones were stable over time. Table 2 presents the DID values of total AMU among dentists stratified by administration route.

(After: Result)

In contrast, the AMU trends for macrolides and fluoroquinolones were stable over time. The penicillins in Table 1 included antimicrobials with ATC codes J01CA, J01CE, and J01CR. The DID values of J01CA antimicrobials (which include amoxicillin) were 0.10 in 2015, 0.10 in 2016, and 0.12 in 2017. The DID values of J01FF antimicrobials (which include clindamycin) were 0.0017 in 2015, 0.0019 in 2016, and 0.0022 in 2017. Table 2 presents the DID values of total AMU among dentists stratified by administration route.

Reviewer #2’s Comments:

1. You might add a sentence about veterinarian and the fact that they are doctor and pharmacologist in personal union, at least in some countries. The stewardship should reach them also and quickly.

Thank you for your thoughtful and constructive feedback regarding our manuscript.

We agree with your suggestion. While physicians and dentists are the main ASP targets in human medicine, veterinarians are also a vital target for AMR in animal medicine under the WHO’s One Health approach. As advised, we have added the suggested information to the Discussion section with an additional reference.

(Before: Discussion, Page 17, Line 254)

To the best of our knowledge, this is the first nationwide study of the epidemiology of AMU among Japanese dentists.

(After: Discussion)

To the best of our knowledge, this is the first nationwide study of the epidemiology of AMU among Japanese dentists. In addition to dentists and physicians, AMU should also be examined in veterinarians as they act as both physicians and pharmacists in Japan and other countries. As the World Health Organization’s One Health approach recommends a holistic and multisectoral approach to AMR measures, there is an urgent need to implement effective ASPs for both human and veterinary medicine [34].

References (Reference 34 has been added.)

34. World Health Organization. Global Action Plan on Antimicrobial Resistance. Vol 10.; 2015. Accessed November 25, 2020. https://www.who.int/antimicrobial-resistance/global-action-plan/en/

2. The second comment is related to this impressively high prescription rate of cephalosporins in Japan (above 60%). In other countries it is listed “among others” with only a few prescriptions at dental practices. To avoid such false prescriptions in the future, it is relevant to track the origin of problem. For instance, in our country clindamycin was (and is) a blockbuster in dentistry. The simple reason is the intense promotion by the corresponding manufacturer. That means, antibiotics of most attention (not of most efficacy) are prescribed. What could be the reason for such an over-prescription in Japan? It is known that there is cross-allergy between penicillins and cephalosporins (about 20%). My hypothesis is that the origin is related to allergy rates, namely that cephalosporins are generally regarded as safer? You might proof this hypothesis.

Thank you very much for your comments and hypothesis. As you pointed out, cephalosporins may be prescribed if there are concerns for penicillin allergy. However, cephalosporins are not recommended as the primary alternative drug for such cases in Japan’s guidelines. We agree that a possible reason for the preference for cephalosporins in Japan’s medical facilities may be due to the active promotion of these antimicrobials by pharmaceutical companies. A recent study reported that the top-selling antimicrobials in Nepal were those with a higher number of promotional activities [21]. Although such activities have since diminished in Japan, the situation was similar to that of Nepal until only 10 years ago. These promotions may have contributed to the high adoption rate of cephalosporins in medical facilities in Japan when compared to those in other countries. In fact, we have previously shown in an analysis of 31 Japanese hospitals that all the study hospitals had adopted the use of oral third-generation cephalosporins [22]. Additionally, most of these cephalosporins were Japanese-origin drugs that are not commonly used outside of Japan. Nevertheless, we recognize that this is a hypothesis, and needs further empirical investigation. Therefore, based on the results of our previous questionnaire-based study on AMU among dentists in Japan [31], we are currently conducting a nationwide questionnaire-based epidemiological study to determine the factors (including the perceived safety of cephalosporins with respect to allergy rates) that influence prescriptions of third-generation cephalosporins among 1700 dentists throughout the country. We have added this information to the Discussion section.

(Before: Discussion, Page 14, Line 201)

These results corroborate those of a previous cross-sectional questionnaire-based study on dentists at community clinics in Japan [20].

(After: Discussion)

These results corroborate those of a previous cross-sectional questionnaire-based study on dentists at community clinics in Japan [20]. The frequent use of cephalosporins in Japan may be due in part to the active promotion of these antimicrobials by pharmaceutical companies. A study conducted in Nepal showed that the top-selling antimicrobials were those that were subjected to intensive promotional activities [21]. Although such promotional activities have since diminished in Japan, the situation was similar to that of Nepal as recently as 10 years ago. These activities may therefore have contributed to the high adoption rate of cephalosporins in Japan’s medical facilities. In our previous analysis of AMU in 31 Japanese hospitals, we found that all the study hospitals had adopted the use of oral third-generation cephalosporins [22]. Furthermore, most of these cephalosporins were Japanese-origin drugs that are not commonly used outside of Japan [17].

References (References 21 and 22 have been added.)

17. Tsutsui A, Yahara K, Shibayama K. Trends and patterns of national antimicrobial consumption in Japan from 2004 to 2016. J Infect Chemother. 2018;24(6):414-421. doi:10.1016/j.jiac.2018.01.003

20. Amari Y, Uehara Y, Watanabe Y, Inui A, Sugihara E, Yokokawa H, et al. Status of antimicrobial use among dentists in Japan. J Gen Hosp Med. 2014;6: 8-15.

21. Koju P, Rousseau SP, Van der Putten M, Shrestha A, Shrestha R. Advertisement of antibiotics for upper respiratory infections and equity in access to treatment: a cross-sectional study in Nepal. J Pharm Policy Pract. 2020;13(4). doi:10.1186/s40545-020-0202-1

22. Kusama Y, Muraki Y, Mochizuki T, Kurai H, Gu Y, Ohmagari N. Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals. J Infect Chemother. 2020;26(2):211-215. doi:10.1016/j.jiac.2019.08.013

31. Koizumi R, Kusama Y, Ishikane M, Tanaka C, Ono A, Gu Y, et al. Cross-sectional study to clarify the status of antimicrobial prescribing at outpatient care among dentists. Kansenshogaku Zasshi. (in press)

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Decision Letter 1

Simon Clegg

11 Dec 2020

The First National Survey of Antimicrobial Use Among Dentists in Japan from 2015 to 2017 Based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan

PONE-D-20-31740R1

Dear Dr. Kusama,

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Additional Editor Comments:

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Acceptance letter

Simon Clegg

16 Dec 2020

PONE-D-20-31740R1

The First National Survey of Antimicrobial Use Among Dentists in Japan from 2015 to 2017 Based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan

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