Abstract
Objectives
To evaluate an outpatient, antimicrobial stewardship intervention targeting broad-spectrum antimicrobials including third-generation cephalosporins, fluoroquinolones, and macrolides, during an antimicrobial shortage at a Japanese, tertiary hospital.
Methods
This before-and-after interventional study was conducted at a tertiary hospital. The intervention included department-focused and hospital-wide education, local guidelines, weekly post-prescription review and feedback, monthly reports on days of therapy (DOT), a formulary review, and an orientation for newly transferred physicians. Counterfactual monthly outcomes (primary endpoint: DOT per 100 visits (DOT/100V) and number of prescriptions per 1000 visits (Rx/1000V) for the target antimicrobials) were predicted on the basis of pre-intervention data using ordinary least squares regression incorporating oral antimicrobial shortages.
Results
The post-intervention use of third-generation cephalosporins decreased (DOT/100 V mean difference [MD]: −0.87; 95% confidence interval [CI]: −0.97 to −0.76; Rx/1000 V MD: −3.85; 95% CI: −4.06 to −3.65) together with that of fluoroquinolones (DOT/100V: −1.92; 95% CI: −2.33 to −1.51; Rx/1000V MD: −2.14; 95% CI: −2.60 to −1.68). The volume and frequency of macrolide use did not differ significantly, but inappropriate prescriptions of fluoroquinolones (−26.22%) and macrolides (−7.92%) decreased.
Conclusions
This outpatient stewardship programme evaluated within a counterfactual framework accounted for supply shortages, reduced third-generation cephalosporins and fluoroquinolone use, and improved the appropriateness of prescriptions. Sustaining these gains requires on-going evidence-based data-sharing and prescriber-tailored interventions.
Introduction
Antimicrobial resistance (AMR) has become a global public health threat because it narrows treatment options for infectious diseases, thereby leading to prolonged hospitalization, a higher mortality rate and increased medical costs.1–3 Each country has developed its own action plan to combat AMR, with the promotion of antimicrobial stewardship programme (ASP) being the key pillar for reducing the overuse and misuse of antimicrobials, the major drivers of antimicrobial resistance.4 Although most national action plans recognize ASP as a core strategy, previous studies have highlighted substantial variation across countries in the scope, regulatory strength and methods of implementing stewardship.4 High-income countries in Europe often adopt a legally enforced, system-wide ASP framework, whereas the USA prioritizes broad implementation across healthcare settings. In contrast, the Japanese National Action Plan on AMR (2023–2027) emphasizes outpatient antimicrobial use and education, which reflect unique, national priorities and healthcare structures and strongly promotes the implementation of ASP in healthcare facilities.5
Oral antimicrobials account for approximately 90% of all antimicrobial prescriptions, most of which are issued in the outpatient setting.6 The Japanese AMR plan emphasizes reducing the use of oral antimicrobials, particularly those classified as Watch antimicrobials in the World Health Organization’s (WHO) AWaRe classification.7 The Access group comprises antimicrobials that are recommended as first-line options for common infections and is associated with a lower risk of antimicrobial resistance. The Watch category includes agents with a higher resistance potential, such as third-generation cephalosporins, fluoroquinolones and macrolides, which should be prioritized for restriction. In Japan, the proportion of prescriptions for oral Watch antimicrobials is higher than elsewhere.8 Consequently, one of the central goals of Japan’s national action plan is to decrease the use of these Watch antimicrobials while promoting the use of Access antimicrobials whenever appropriate.7 However, previous studies of respiratory tract and urinary tract infections in outpatient care have omitted targeting specific antimicrobial categories.9–11
Therefore, methods of reducing unnecessary prescriptions while also improving the appropriateness of prescriptions are much needed. However, implementing an ASP in a hospital’s outpatient setting (as opposed to clinics) presents several challenges, including difficulty in obtaining reliable prescribing data and insufficient human resources to support monitoring and feedback. Additional prescriber-related challenges include limited consultation time and persistent expectations of receiving an antimicrobial,10 underscoring the need for evidence-based interventions tailored to outpatient care. Although educational interventions and post-prescription feedback have demonstrated their efficacy in promoting appropriate antimicrobial use in primary care,12 there is, as of yet, scant evidence of effective ASP methodologies for regulating the use of oral antimicrobials in the outpatient setting of hospitals compared to the use of intravenous antimicrobials in the inpatient setting. Moreover, physician-related factors, such as the difficulty of changing prescribing behaviours of experienced physicians and the practice of regularly re-assigning physicians from one hospital to another, have led to a loss of trained physicians within a given hospital while diminishing knowledge of antimicrobial stewardship among the staff, thereby eroding the impact of educational interventions.4,13–17
In 2024, the Japanese government introduced financial incentives for hospitals and clinics to increase the proportion of Access antimicrobial use in the outpatient setting with the aim of promoting the selection of appropriate antimicrobials to align with global AMR action plans. However, recent concerns about oral antimicrobial shortages in Japan have created conditions under which first-line Access antimicrobials have become scarce, thus further hindering the promotion of appropriate prescribing practices. Oral antimicrobial shortages are largely attributable to violations of good manufacturing practices by domestic manufacturers of generic, pharmacological products which disrupt the stable supply of several key Access agents.18
The present study aimed to evaluate the efficacy of packaged interventions designed to promote the appropriate use of oral antimicrobials, especially third-generation cephalosporins, fluoroquinolones and macrolides, in outpatient care at a tertiary care centre by treating barriers, such as physician turnover and antimicrobial shortages, as variables in statistical analysis.
Methods
Ethics
The present study was conducted in accordance with the Declaration of Helsinki and national and institutional standards. The institutional review board at Yokohama Medical Center approved this study on November 14, 2024 (approval number 2024-17).
Study design and setting
The present study was a before-and-after study conducted at Yokohama Medical Center, a tertiary care centre located in Kanagawa Prefecture, Japan, with 490 beds, 25 departments and approximately 15 000 visits per month. This study included a two-year, pre-intervention period (October 2021—September 2023) with a two-month intervention transition period (October 2023—November 2023), followed by a one-year ASP implementation period (December 2023—November 2024). Before September 2023, the study centre had already established an inpatient ASP that monitored intravenous antimicrobial consumption and provided prospective audit and feedback but had no comparable outpatient programme. This study included all patients who visited the outpatient department, except the emergency department and paediatrics, during the study period; and all those to whom an antimicrobial agent was prescribed, regardless of the number of times they might have visited the outpatient department for the same infection.
ASP facilitators
The packaged intervention consisted of (i) a one-time, face-to-face, educational lecture and discussions about common infectious diseases in the departments of urology, otolaryngology and dental oral surgery, where a preliminary survey had identified a high proportion of inappropriate prescriptions of the target antimicrobials, together with a lecture on common, infectious diseases in the general outpatient setting and the concept of ASP; (ii) evidence-based diagnosis and treatment guidelines, including indications for antimicrobial use, drug choices, dosages, intervals and laboratory tests, including cultures, based on various guidelines, textbooks and antibiogram of urine culture at the study centre (Table S1, available as Supplementary data at JAC-AMR Online); (iii) antimicrobial order sets for common infectious diseases in the electronic medical records (EMRs); and (iv) weekly post-prescription review and feedback from a designated infectious disease (ID) physician, who tracked data on prescriptions every week using the EMRs and reviewed each prescription for appropriateness (Table S2). If a prescription was deemed inappropriate, the designated ID physician contacted the prescriber within a week to discuss improvements. Appropriateness was assessed by the ID physician or a pharmacist, with the physician making the final decision when assessment was difficult. It is well known that late-career physicians (years of clinical practice ≥ 21) are less likely to modify their behaviour in response to an intervention. Hence, given the limitations on each member’s full-time equivalent (FTE), the provision of periodic feedback on the antimicrobial stewardship team’s (AST) activities prioritized younger physicians over late-career physicians; (v) monthly reports of changes in DOT per 100 visits (DOT/100V) using third-generation cephalosporins, fluoroquinolones and macrolides were distributed to all the physicians by hospital via an e-mail which included positive feedback if any improvement in prescribing behaviour was noted; (vi) a review of the antimicrobial agents approved for use in the outpatient setting (unification of hospital-adopted third-generation cephalosporins); and (vii) introduction of the outpatient ASP to new physicians who had been assigned to the hospital in April 2024.
ASP barriers
Since 2021, Japan has encountered significant challenges in implementing effective ASP in the outpatient setting primarily because of shortages of key oral beta-lactam antibiotics.18 Shortages of amoxicillin, amoxicillin/clavulanate, cefalexin, and cefuroxime disrupted standard treatment and necessitated alternative agents such as third-generation cephalosporins and fluoroquinolones, which militated against the established ASP guidelines. Additionally, some physicians’ resistance to revising the established antimicrobial formularies further obstructed the optimization of ASP strategies. Compounding these issues, the annual rotation or reassignment of physicians to different hospitals disrupted the continuity of antimicrobial therapy by requiring a repetition of training and orientation, thus hindering the consistent application of the ASP protocol. The physicians and pharmacists in the AST each had approximately 0.1 FTE, which further limited the intensity of the ASP intervention.
Data collection
The following data were extracted from the EMRs: (i) monthly number of patient visits per department; (ii) patient demographics (age and sex); and (iii) detailed information about antimicrobial prescriptions, including the antimicrobial agent prescribed, dosage, duration and indications. On the basis of these data, the DOT/100V and the number of prescriptions per 1000 visits (Rx/1000V) were calculated as the primary evaluation metrics. Table S3 shows the families of the target antimicrobials. The appropriateness of the prescriptions was assessed by the clinical indications documented in the EMR.
Questionnaires
Online surveys were also administered to assess the knowledge, attitudes and AMR practices of physicians working in outpatient care at the study centre before and after the introduction of outpatient ASP. A pre-intervention questionnaire was administered in December 2023 immediately after the intervention was implemented and a post-intervention questionnaire was administered in December 2024, one year after the initiation of the intervention. The pre-intervention responses were collected from all the physicians, and the post-intervention responses were collected from physicians who responded to the pre-intervention questionnaire.
Outcomes
The primary outcome was the change in the number of prescriptions per antimicrobial family in terms of the monthly DOT/100V and the monthly Rx/1000V after the intervention. The secondary outcomes were changes in (i) the proportion of inappropriate prescriptions for third-generation cephalosporins, fluoroquinolones and macrolides and (ii) knowledge, attitudes and practices pertaining to AMR in the pre- and post-intervention periods.
Statistical analysis
To address the effect of ASP barriers, variables indicative of antimicrobial shortages and staff turnover were incorporated into prediction models of antimicrobial use. Based on actual values from the pre-intervention period (October 2021—September 2023), the DOT/100V and the monthly Rx/1000V were forecast using ordinary least squares (OLS) regression, which accommodates unpredictable external factors, such as antimicrobial shortages. Explanatory variables included the calendar month, staff turnover at the beginning of the fiscal year, number of patients per month,19 number of antimicrobial prescriptions per month,20 shortages of amoxicillin, amoxicillin/clavulanate, cefalexin and cefuroxime, and lag time ≤ 3 months (Table S4). For each antimicrobial, covariate selection was guided by the Bayesian information criterion (BIC) and clinical plausibility. Predicted values were interpreted as counterfactual estimates of antimicrobial use in the absence of the intervention. To evaluate the effectiveness of the intervention, the predicted and observed monthly DOT/100V and Rx/1000V during the post-intervention period (December 2023—November 2024) were compared using a two-tailed t-test (P < 0.05). The mean difference (MD), defined as the observed minus predicted value, and its 95% confidence interval (CI) were calculated. The same OLS regression was applied to assess for any change in the proportion of inappropriate prescriptions before and after the intervention. All statistical analyses were performed using Stata/MP 18.0 (Stata Corp LLC, College Station, TX, USA). The institutional review board at Yokohama Medical Center approved this study on November 14, 2024 (approval number 2024-17).
Results
Patient characteristics
In total, 344 330 and 173 327 patients visited the hospital during the pre-intervention and intervention period, respectively, during which 15 506 (4.5%) and 7420 (4.3%) prescriptions were issued. The mean age of the patients was 67.7 and 62.2 years, and the proportion of male patients was 44.3% and 43.6% during the respective period.
Changes in DOT/100V and the Rx/1000V in the post-intervention period
The DOT/100Vsignificantly decreased during the post-intervention period for both third-generation cephalosporins and fluoroquinolones (MD: −0.87; 95% CI: −0.97 to −0.76 and MD: −1.92; 95% CI: −2.33 to −1.51, respectively). The Rx/1000 V also significantly decreased during the post-intervention period for both third-generation cephalosporins and fluoroquinolones (MD: −3.85; 95% CI: −4.06 to −3.65 and MD: −2.14; 95% CI: −2.60 to −1.68, respectively). In contrast, no significant change was observed in either the DOT/100V or the Rx/1000V for macrolides (MD: 0.80; 95% CI: −0.24 to 1.84 and MD: 0.89; 95% CI: −0.21 to 1.99, respectively). In the prediction models, covariate selection guided jointly by BIC and clinical plausibility revealed that calendar month, staff turnover, reported number of antimicrobial prescriptions per month, and amoxicillin shortage with lag time ≤ 2 months were often important predictors across antimicrobial families (Table S5). The analysis for cefuroxime was unable to be done due to the insufficiency of data resulting from the shortage (Figures 1, 2, Figures S1, S2). Among the targeted departments, the post-intervention DOT/100V decreased significantly in the urology department for third-generation cephalosporins and fluoroquinolones, and in the dental surgery department for fluoroquinolones and macrolides, whereas no significant change was observed in the otolaryngology department for any of the three classes (Figure S3).
Figure 1.
Monthly changes in the number of prescriptions per antimicrobial category expressed as DOT per 100 visits. The solid line represents a fractional polynomial approximation of the predicted values from pre-intervention data to facilitate visualization of non-linear temporal trends. The shaded area indicates the 95% prediction interval based on pre-intervention data. The blue area indicates the post-intervention period, during which the mean difference between the observed and the predicted values, along with its 95% confidence interval, was used to assess whether any significant change occurred post-intervention. Abbreviations: CI, confidence interval; 3GC, third-generation cephalosporins; 1GCs, first-generation cephalosporins.
Figure 2.
Monthly changes in the number of prescriptions per antimicrobial category expressed as the number of prescriptions per 1000 visits. The solid line represents a fractional polynomial approximation of the predicted values from pre-intervention data to facilitate visualization of non-linear temporal trends. The shaded area indicates the 95% prediction interval based on pre-intervention data. The blue area indicates the post-intervention period, during which the mean difference between the observed and predicted values, along with its 95% confidence interval, was used to assess whether any significant change occurred post-intervention. Abbreviations: 3GC, third-generation cephalosporins; CI, confidence interval; 1GCs, first-generation cephalosporins.
Change in the proportion of inappropriate prescriptions of the target antimicrobials
During the post-intervention period, the proportion of inappropriate prescriptions of fluoroquinolones (MD: −26.22; 95% CI: −36.56 to −15.89) and macrolides (MD: −7.92; 95% CI: −13.09 to −2.74) decreased significantly (Figure 3). In contrast, no significant decrease in inappropriate prescriptions of third-generation cephalosporins was observed. Across hospital departments, the distribution of inappropriate prescriptions across departments shifted in the post-intervention period (Figure 4); the urology department accounted for a smaller share of the hospital-wide inappropriate prescriptions of third-generation cephalosporins and fluoroquinolones, and the otolaryngology department accounted for a larger share of the hospital-wide inappropriate prescriptions for these drugs while it remained second highest in inappropriate prescriptions of macrolides during both periods. The dental surgery department ranked first in the number of inappropriate macrolide prescriptions in both periods and first in the number of inappropriate fluoroquinolone prescriptions in the post-intervention period. In contrast, when the within-department proportion of inappropriate prescriptions was examined, no apparent decrease was observed after the intervention in any of the targeted departments, except for macrolides in the otolaryngology department (Figure S4).
Figure 3.
Monthly changes in the proportion of inappropriate prescriptions of third-generation cephalosporins, fluoroquinolones, and macrolides. The solid line represents a fractional polynomial approximation of the predicted values from pre-intervention data to facilitate visualization of non-linear temporal trends. The shaded area indicates the 95% prediction interval based on pre-intervention data. The blue area indicates the post-intervention period, during which the mean difference between the observed and predicted values, along with its 95% confidence interval, was used to assess whether any significant change occurred post-intervention. Abbreviations: CI, confidence interval; 3GC, third-generation cephalosporins.
Figure 4.
Departments accounting for the largest share of inappropriate prescriptions before (Pre) and after (Post) the intervention. Each 100% stacked bar shows the proportion of inappropriate prescriptions attributable to each clinical department for third-generation cephalosporins, fluoroquinolones, and macrolides. Departments ranked fourth or below are combined as ‘Other departments.’ The value in each segment is that department's percentage share of all inappropriate prescriptions for the given antibiotic class and period. Abbreviations: OBG, Obstetrics & Gynaecology; Pul., Pulmonary; Rheum., Rheumatology.
Questionnaires
Among the physicians who responded to the pre-intervention survey, approximately 60% also responded to the post-intervention survey (Table S6), i.e. the remaining 40% either did not respond to the post-intervention survey or had been assigned to work at another hospital. More than 85% of the physicians responded that they intended to change their antimicrobial prescription practices after attending the in-hospital lecture on appropriate outpatient antimicrobial use held in October 2023 (Figure 5). One year after the lecture, 72% of the same respondents reported having changed their prescribing practices, and 79% indicated their intention to continue improving their behaviour. Post-intervention, the proportion of physicians who reported being aware of AMR and prescribing fewer antimicrobials, including third-generation cephalosporins and fluoroquinolones, increased. The proportion of physicians responding that they would prescribe third-generation cephalosporins or fluoroquinolones, the targets of the present intervention, for cystitis and cellulitis decreased. However, in actual practice, the proportion of physicians reporting the use of these agents for cystitis, about which local guidelines make no specific recommendation, remained steady at 36%–38% (Figure 4). This pattern was more pronounced among late-career physicians (Table S7).
Figure 5.
Before-after comparison of physicians’ knowledge, attitudes, and practices related to AMR in outpatient care after the implementation of the outpatient ASP. *: |standardized residual| ≥ 1.96. Differences between groups were analysed using the chi-square test with post-hoc residual analysis (|standardized residual| ≥ 1.96 indicating significance). Abbreviations: TMP-SMX, trimethoprim–sulfamethoxazole.
Discussion
The present study combined hospital-wide outpatient ASP with a department-specific approach, in contrast to previous studies in clinics.9–11 Its distinctive features included a drug-specific intervention based on the national AMR Action Plan rather than a disease-specific one, and the use of OLS regression incorporating external factors, instead of the interrupted time series analysis common in conventional before-after studies,5,9,19–22 implemented during a shortage of key antimicrobials.
As a result of the intervention, the DOT/100V and the Rx/1000V for third-generation cephalosporins and fluoroquinolones significantly decreased, with a notable reduction becoming apparent in the rate of inappropriate prescriptions of fluoroquinolones. The approach used in the urology department, which involved presenting antibiograms based solely on urine cultures together with educational lectures, was particularly successful. Furthermore, the provision of educational activities to all the clinical departments contributed to reducing the number of inappropriate prescriptions. Given the inappropriateness of third-generation cephalosporins in the outpatient setting, their removal from the hospital formulary was planned before the start of the intervention. However, opposition among the physicians arose due to concerns about the instability of the antimicrobial supply, which ultimately led to rescinding the decision to remove the drugs, thus underscoring the critical role of managing the formulary in antimicrobial stewardship.
In contrast, despite intensive interventions targeting macrolides, no significant change was observed in either their DOT/100V or the number of their prescriptions. Nonetheless, documentation of the reasons for prescribing the drugs increased, and the rate of inappropriate prescriptions significantly decreased post-intervention. The chief indications for macrolide use at the study centre are nontuberculous mycobacterial infection (NTM), chronic rhinosinusitis and periodontal disease. Although macrolide therapy is the standard treatment worldwide for NTM rather than for sinusitis or periodontal disease, the Japanese guidelines recommend them as first-line options for the latter two conditions; the physicians may have perceived their use as appropriate, thereby contributing to the marginal improvement observed. Additional barriers included the low frequency of culture testing in these departments, which hampered data sharing, as well as the small number of both junior and older physicians, with the latter being mostly responsible for the bulk of the inappropriate prescriptions. These challenges are not unique to our institution; similar difficulties have been reported elsewhere.23,24 Although no previous studies have described specific barriers to ASP interventions in departments of otolaryngology and dental surgery, departments of surgery generally have a lower rate of adherence to local guidelines and a tendency towards overprescription than medical departments,25,26 a finding confirmed by the present study.
The number of antimicrobial prescriptions of all families remained generally unchanged; however, DOT/100V decreased, indicating that the duration of therapy per prescription was shorter. This development may have been facilitated by the specification of treatment durations in the local guidelines. While the use of 1st generation cephalosporins decreased due to the shortage, the use of penicillin’s, which are also recommended as first-line agents, increased despite the shortage, suggesting that variations in the supply of antimicrobial agents can influence prescribing behaviours. Prescriptions of several Access-group agents increased while tetracyclines and penems decreased, a favourable shift.
The survey results suggested that the physicians’ knowledge and attitudes towards the relevant issues had improved following the implementation of the ASP. However, in practice, a subset of physicians, particularly older individuals, continued to prescribe agents not recommended by the local guidelines. Factors influencing behavioural changes may extend beyond those measurables by prescribing data or surveys. Taken together, these findings suggested that barriers to the promotion of outpatient ASP included recommendations of the national guidelines, antimicrobial shortages, paucity of evidence-based treatment recommendations due to restriction on data on infectious diseases, and the late-career physicians’ reluctance to change their prescribing behaviours.
Beyond these specific barriers, the present study should be viewed in a broader context. Whereas antimicrobial stewardship in Japan has been concentrated largely in the inpatient setting, outpatient stewardship—despite outpatient oral agents accounting for the largest share of national antimicrobial consumption—has remained comparatively understudied, an imbalance mirrored internationally.27,28 By evaluating a drug-targeted, hospital-based outpatient programme under real-world supply constraints, this study helps fill a recognized evidence gap in hospital-based outpatient stewardship.
This study has several limitations. First, it was conducted at a single, regional hospital in Japan, and institution-specific factors may have influenced the results. Second, the inadequacy of individualized feedback to the older physicians due to the limited working hours of the AST may have caused their suboptimal response to the intervention and may have affected the outcomes. In contrast, the resources of the AST were focused strategically on the younger physicians, who were expected to modify their behaviour to a greater degree, thereby helping to sustain the efficacy of the ASP. Third, this study did not assess long-term outcomes, such as the suppression of antimicrobial-resistant organisms, which is the ultimate goal of any ASP. Fourth, clinical, outpatient outcomes were not assessed. Given that a shortage of antimicrobial agents may result in limiting the use of first-line agents, which in turn increases the use of alternative agents and the rate of associated adverse events and treatment failure,29 these potential outcomes warrant further study. Fifth, the survey respondents may have been disproportionately drawn from physicians more engaged with AMR issues, thereby introducing a possible bias. Moreover, as the determinants of prescribing behaviour were not directly assessed, there may have been additional, unidentified barriers. To maximize the efficacy of an ASP, an implementation science approach to elucidating facilitators and barriers is likely to be valuable.30 Finally, although the OLS regression incorporating external factors had greater predictive value, it is not an established method, and it is also unclear whether the selection of the variables was optimal.
Conclusions
This study assessed the impact of a packaged, outpatient intervention for oral antimicrobial use during antimicrobials shortage by applying a novel OLS regression incorporating external factors in the outpatient setting of a tertiary care centre. This study extends rigorous stewardship into hospital outpatient care, with implications for ambulatory stewardship both within and beyond Japan. The key facilitators included the sharing of objective data, such as antibiogram, while the barriers comprised antimicrobial shortages, prescriber-related factors and the influence of national guidelines. Future efforts should focus on evidence-based data-sharing and prescriber-tailored interventions, which have the potential to help outpatient ASPs become sustainable and internationally relevant.
Supplementary Material
Acknowledgements
We are indebted to James R. Valera for his assistance with editing this manuscript.
Contributor Information
Hiroshi Horiuchi, Department of Infectious Diseases, Institute of Science Tokyo, Graduate School of Medical and Dental Sciences, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Department of Infection Control, National Hospital Organization, Yokohama Medical Center, Kanagawa, Japan.
Yasuaki Tagashira, Department of Infectious Diseases, Institute of Science Tokyo, Graduate School of Medical and Dental Sciences, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Center for Infectious Disease Education and Analysis, Institute of Science Tokyo (TCIDEA), Tokyo, Japan.
Asami Takizawa, Department of Infection Control, National Hospital Organization, Yokohama Medical Center, Kanagawa, Japan.
Kunihiko Takahashi, Department of Biostatistics, M&D Data Science Center, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, Japan.
Yoshiaki Gu, Department of Infectious Diseases, Institute of Science Tokyo, Graduate School of Medical and Dental Sciences, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Center for Infectious Disease Education and Analysis, Institute of Science Tokyo (TCIDEA), Tokyo, Japan.
Funding
None.
Transparency declarations
All the authors: none to declare.
Author contributions
H.H. and Y.T. designed the study protocol. H.H. and A.T. collected clinical data, and H.H. and K.T. analysed the data and composed the figures. H.H. and Y.T. drafted the first version of the manuscript. Y.T. and Y.G. revised the manuscript, and all the authors contributed to the final version of the manuscript for submission.
Supplementary data
Figures S1 to S4 and Tables S1 to S7 are available as Supplementary data at JAC-AMR Online.
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