Factors Associated with Geographical Variability of Antimicrobial Use in Japan.

INTRODUCTION: Evidence regarding the factors affecting the geographical variation of antimicrobial use (AMU) is relatively scarce. This study aimed to evaluate factors potentially associated with geographical variability of AMU per day per 1000 habitants in the 47 prefectures of Japan. METHODS: This is an observational ecological study using the Japanese national database in 2019. The outcome was the defined daily doses per 1000 inhabitants per day by prefecture. Multivariable negative binomial regression analysis was conducted using patient- and physician-level variables. RESULTS: The study included 605,391,054 defined daily doses of AMU in 2019 from the 47 prefectures. In the multivariable negative binomial regression analyses for the outcome of total AMU, the proportion of female individuals (adjusted rate ratio [aRR] 1.04 [1.01-1.08] per 1% increase, p = 0.021), the proportion of upper secondary graduates going to further education (aRR 1.01 [1.00-1.01] per 1% increase, p = 0.005), and the annual number of diagnoses related to upper respiratory infections (URIs) per 1000 inhabitants per day (aRR 1.21 [1.10-1.34], p < 0.001) were significantly correlated with total AMU. CONCLUSIONS: In this ecological study, the variability of total AMU by Japanese prefecture was associated with the proportion of female individuals, education level, and the number of URI diagnoses per population. The results suggest the potential need for additional stewardship efforts to reduce unnecessary antimicrobial prescriptions for URI.

Necessity for a System Implementing Therapeutic Drug Monitoring in Outpatient Settings Based on the Actual Use of Voriconazole Using the National Database of Health Insurance Claims and Specific Health Checkups of Japan: A Descriptive Epidemiological Study.

Voriconazole (VRCZ) is an antifungal drug that necessitates therapeutic monitoring (TDM). Typically, TDM is recommended for patients undergoing long-term outpatient treatment. However, in Japan, insurance reimbursement for TDM is only permitted for inpatients. There is a concern that VRCZ use is growing among outpatients, although information regarding this issue remains unavailable. Therefore, we aimed to clarify the use of VRCZ by utilizing data from the National Database of Health Insurance Claims and Specific Health Checkups in Japan. The use of branded and generic oral VRCZ from 2013 to 2019 was calculated using the defined daily doses/1000 inhabitants/d (DID) for each receipt type. Oral VRCZ was used more frequently in the outpatient setting than that in the inpatient setting, with use increasing over time. The use of generic drugs began in 2016 and accounted for 52.5% of the use in 2019 among outpatients. Considering outpatient prescriptions, 76.4-81.0% were dispensed at insurance pharmacies, indicating the need for community pharmacist involvement. Accordingly, the appropriate use of VRCZ in ambulatory care should be promoted in collaboration with community pharmacists, and a reimbursement system should be established to implement TDM in ambulatory care.

Comparing the effects of antimicrobial stewardship at primary emergency centers.

BACKGROUND: Antimicrobial prescription rates tend to be high in outpatient settings and Primary Emergency Medical Centers (PECs) in Japan encounter difficulties in implementing antimicrobial stewardship programs (ASPs). While a nudge-based ASP publishing monthly newsletters reduces inappropriate prescription of oral third-generation cephalosporins (3GCs), which requires considerable effort. Therefore, developing more preferable ASP models in PECs is essential. METHODS: We conducted a three-center, retrospective observational study. Himeji City Emergency Medical Center (Site A) introduced a facility-specific guideline for antimicrobial stewardship with reference to national guidelines. The Kobe Children's Primary Emergency Medical Center (Site B) provided the results of monitoring antibiotics prescription in a monthly newsletter. The Hanshin-Kita Children's First-Aid Center (Site C) did not perform a specific ASP. Prescription rates for 3GCs were categorized into pre- and post-intervention and compared using Poisson regression analysis. The difference-in-difference method was used to assess the effect of these interventions. RESULTS: The numbers of patients pre- and post- intervention were 177,126 and 91,251, respectively. The 3GCs prescription rate at Site A, Site B, and Site C decreased from 6.7%, 4.2%, and 6.1% in 2016 to 2.3%, 1.0%, and 2.0% in 2019, respectively. Site B had a greater reduction than Site A and Site C (relative risk [RR] 0.71 [95% confidence interval (CI): 0.62-0.82]; p < 0.001, RR 0.71, [95% CI: 0.62-0.81]; p < 0.001). There was no significant difference between Site A and Site C (RR 1.00 [95% CI 0.88-1.13]; p = 0.963). CONCLUSION: A facility-specific guideline was less effective than a nudge-based ASP for decreasing oral 3GC prescriptions in PECs.

Guidelines for the Management of Respiratory Infectious Diseases in Children in Japan 2022.

The members of the Japanese Society for Pediatric Infectious Diseases and the Japanese Society of Pediatric Pulmonology have developed Guidelines for the Management of Respiratory Infectious Diseases in Children with the objective of facilitating appropriate diagnosis, treatment and prevention of respiratory infections in children. The first edition was published in 2004 and the fifth edition was published in 2022. The Guideline 2022 consists of 2 parts, clinical questions and commentary, and includes general respiratory infections and specific infections in children with underlying diseases and severe infections. This executive summary outlines the clinical questions in the Guidelines 2022, with reference to the Japanese Medical Information Distribution Service Manual. All recommendations are supported by a systematic search for relevant evidence and are followed by the strength of the recommendation and the quality of the evidence statements.

Two Pediatric Cases of Food Protein-Induced Enterocolitis Syndrome to Soy Eaten as an Infant Food.

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy that can be caused not only by infant formula but also by infant food. Herein, we report two pediatric cases of FPIES to solid soy foods, such as tofu. The patients presented with repetitive vomiting after eating the trigger food as infant food. Although both cases promptly recovered following the cessation of the trigger food, one case required rapid intravenous hydration for compensated shock. Both cases were diagnosed with FPIES to soy based on the typical presentation and parental interviews regarding food exposure. One case had a positive response to an oral food challenge for tofu, and both cases were negative for soy-specific IgE. One of our cases did not develop FPIES from fermented soy products despite having soy-triggered FPIES. The fermentation process may reduce the allergenicity of soy, but further evidence is required to confirm this hypothesis. There are various trigger foods for solid food FPIES (SFF), and these differ among countries. Solid food FPIES to soy is more common in Japan than in other countries due to the frequent use of tofu in infant food. Increased international awareness of the possibility of tofu-triggered FPIES may be warranted due to the rising global use of tofu in infant food.

Intussusception Initially Diagnosed as a Brief Resolved Unexplained Event (BRUE).

Brief resolved unexplained event (BRUE) are transient and worrying episodes observed in infants and are characterized by changes in skin color, breathing, muscle tone, and/or responsiveness. We describe the case of a female infant who was initially diagnosed with BRUE but was later determined to have intussusception. She presented to our emergency department with a transient pallor and a single episode of vomiting that resolved before her visit. Physicians did not detect any abnormalities on physical or laboratory examinations, so she was diagnosed with BRUE and discharged to be re-evaluated the next day. After returning home, she vomited several times. The patient revisited our hospital the following day and was definitively diagnosed with intussusception using ultrasonography, which was successfully treated using fluoroscopy-guided hydrostatic reduction. This case was initially diagnosed as a BRUE; however, re-evaluation helped in identifying the proper diagnosis of intussusception. Physicians should exercise caution when diagnosing patients with BRUE. When the diagnostic criteria are not completely met, follow-up should be conducted, assuming that the patient has a potentially serious condition.

Investigation of oral macrolide prescriptions in Japan using a retrospective claims database, 2013-2018.

Macrolide usage in Japan exceeds that in Europe and the United States. Investigating the actual conditions in which macrolides are used is important for identifying further interventions for appropriate antimicrobial use; however, this situation has not been evaluated in Japan. Therefore, we aimed to clarify the number of macrolide prescriptions and their changes before and after implementation of the Antimicrobial Resistance (AMR) Action Plan. In addition, we also investigated the names of diseases for which macrolides have been prescribed and the number of days of prescription. A retrospective observational study was conducted using JMDC claims data from January 2013 to December 2018. The proportion of all oral antimicrobials and macrolides used during this period and the diseases for which macrolides were used in the 3 years before and after the AMR Action Plan were determined separately for acute (< 14 prescription days) and chronic (> 14 prescription days) diseases. The number of prescriptions for macrolides constituted approximately 30% of those for all oral antimicrobials; of these, clarithromycin accounted for approximately 60%. Most prescriptions for acute diseases were for common cold, whereas allergic and dermatological diseases were included among chronic diseases. The names of these illnesses did not change before and after the AMR Action Plan. Overall, these results indicate that appropriate macrolide use involves a review of their use for common cold along with appropriate evaluation of their long-term use for skin and allergic diseases. They also indicate the need for further fact-finding studies and ongoing AMR measures.

The Incidence of Serious/Invasive Bacterial Diseases in Infants 90 Days Old or Younger at an Emergency Hospital in Japan.

Background The incidence of severe bacterial infections (SBIs) in infants aged ≤90 days is thought to have decreased because of widespread vaccination programs. However, relevant epidemiological data in Japan are scarce. Materials and methods This observational, single-center study investigated the epidemiology of fever in infants aged ≤90 days. SBI was defined as the presence of meningitis, urinary tract infections (UTIs), or bacteremia. Invasive bacterial infection (IBI) was defined as the presence of meningitis, bacteremic UTI, or bacteremia. We determined the incidence of UTIs, bacteremia, meningitis, SBIs, and IBIs in the following three age groups: 0-28, 29-60, and 61-90 days. We subsequently calculated the relative incidence for the groups aged 29-60 and 61-90 days, using the group aged 0-28 days as the reference group.  Results Herein, 58, 124, and 166 infants were included in the 0-28 days, 29-60 days, and 61-90 days age groups, respectively. Of the total number of patients, 15.5%, 8.9%, and 16.9% in the 0-28 days, 29-60 days, and 61-90 days age groups, respectively, were diagnosed with SBI. The relative incidences were 1 for the 0-28 days group (reference group), 0.67 for the 29-60 days group (95% confidence interval [CI], 0.39-1.15), and 1.08 for the 61-90 days group (95% CI, 0.58-2.00). Of the total number of patients, 10.3%, 3.2%, and 0.6% in the 0-28 days, 29-60 days, and 61-90 days age groups, respectively, were diagnosed with IBI. Relative incidences were 1 (reference group), 0.50 (95% CI, 0.29-0.88), and 0.28 (95% CI, 0.19-0.41) for the 0-28 days, 29-60 days, and 61-90 days age groups, respectively. All cases of IBI were caused by Group B streptococcus (GBS), except for two cases of bacteremia, which were caused by Haemophilus influenzae.  Conclusion The incidence of SBI was similar in the 0-28 days and 61-90 days age groups. However, the incidence of IBI decreased with increasing age. The incidence of UTIs was highest in the 61-90 days age group, and that of meningitis and bacteremia decreased with increasing age.

A Case of Eating Disorder Diagnosed As Orthorexia Nervosa.

A 13-year-old girl presented to our hospital with chief complaints of rapid weight loss, fatigue, discomfort, chills in the extremities, and alopecia. We initially suspected anorexia nervosa (AN). However, she did not express fear of gaining weight or have a distorted perception of her weight or body shape; thus, her presentation was not typical of AN. We also suspected avoidant/restrictive food intake disorder (ARFID), but she did not exhibit any food-avoidance behaviors. However, she was obsessed with nutrition control, so we diagnosed her with orthorexia nervosa (ON). She was hospitalized, given education on proper nutrition, and her eating behavior subsequently improved. After discharge, we administered the ORTO-15, which assesses the propensity for ON, and her score met the diagnostic criteria for ON. The incidence of ON has increased during the COVID-19 pandemic. In this case, her obsession was brought about by information she read in magazines and on social media that promoted an unbalanced diet centered almost exclusively on vegetables. Pediatricians should raise awareness of misinformation regarding children's health to ensure healthy growth.

Effects of population age structure on parenteral antimicrobial use estimations.

Antimicrobial use (AMU) is conventionally reported as unadjusted defined daily doses (DDDs) or population-adjusted DDDs per 1000 inhabitants per day (DID). DID is frequently used to monitor national AMU trends, this metric does not intrinsically take temporal changes in population age structure into account. We examined the effects of population age structure on DID estimates of parenteral AMU in Japan, and predicted future trends in DDDs based on population projections. Parenteral AMU data from 2013 to 2018 were acquired from a national claims database. We assessed temporal trends in parenteral AMU by age group (children aged < 15 years, working-age persons aged 15-64 years, and older persons aged ≥ 65 years) using both DID and DDDs. In addition, we modeled DDD predictions based on age-specific population projections from 2019 to 2030. DID values for older persons were 8.08-10.15 times and 5.43-5.63 times higher than in children and working-age persons, respectively. DID was stable, but DDDs increased in older persons. The prediction models showed that DDDs will continue to increase until 2030 if DID remains steady or decreases. DID estimates were skewed by the older population. More rigorous antimicrobial stewardship efforts targeting geriatric care are needed to counter the aging-associated increase in AMU.

Physician practices in the diagnosis and treatment of infectious diseases in home care settings: A questionnaire study.

To elucidate the current practices of infectious disease management in home care settings in Japan, we sent a questionnaire to 36 physicians working at 13 clinics that specialize in providing care to patients in their homes or residential care facilities. The questionnaire described three hypothetical scenarios (aspiration pneumonia, pyelonephritis, and neoplastic fever) in older patients with terminal cancer, and 25 respondents answered questions on testing and treatment strategies. Most respondents chose to obtain cultures for aspiration pneumonia (sputum) and for pyelonephritis (urine), although fewer respondents chose to obtain blood cultures. For neoplastic fever, most of respondents elected to continue observation without antibiotic treatment. The most frequently selected antibiotics were cephalosporins and quinolones. The results indicated that most respondents would perform bacterial culture tests before prescribing antibiotics and observe patients when bacterial infections are not suspected. Standardized guidelines are needed to optimize infectious disease management in home care.

Influence of pharmacists and infection control teams or antimicrobial stewardship teams on the safety and efficacy of vancomycin: A Japanese administrative claims database study.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) has a high mortality and requires effective treatment with anti-MRSA agents such as vancomycin (VCM). Management of the efficacy and safety of VCM has been implemented with the assignment of pharmacists in hospital wards and the establishment of teams related to infectious diseases. However, there are no reports evaluating the association between these factors and the efficacy and safety of VCM in large populations. METHODS: This study used the Japanese administrative claims database accumulated from 2010 to 2019. The population was divided into two groups, therapeutic drug monitoring (TDM) group and non-TDM group, and adjusted by propensity score matching. We performed multivariate logistic regression analysis to determine the influence of pharmacists and infection control teams or antimicrobial stewardship teams on acute kidney injury (AKI) and 30-day mortality. RESULTS: The total number of patients was 73 478 (TDM group, n = 55 269; non-TDM group, n = 18 209). After propensity score matching, 18 196 patients were matched in each group. Multivariate logistic regression analysis showed that pharmacological management for each patient contributed to the reduction of AKI (odds ratio [OR]: 0.812, 95% confidence interval [CI]: 0.723‒0.912) and 30-day mortality (OR: 0.538, 95% CI: 0.503‒0.575). However, the establishment of infectious disease associated team in facilities and the assignment of pharmacists in the hospital wards had no effect on AKI and 30-day mortality. In addition, TDM did not affect the reduction in AKI (OR: 1.061, 95% CI: 0.948‒1.187), but reduced 30-day mortality (OR: 0.873, 95% CI: 0.821‒0.929). CONCLUSION: Pharmacologic management for individual patients, rather than assignment systems at facilities, is effective to reduce AKI and 30-day mortality with VCM administration.

Search for Indexes to Evaluate Trends in Antibiotic Use in the Sub-Prefectural Regions Using the National Database of Health Insurance Claims and Specific Health Checkups of Japan.

The evaluation indexes of antimicrobial use (AMU) in sub-prefectural regions have not been established because these regional units are susceptible to the effects of population inflows and outflows. We defined the difference in AMU calculated each year as a new evaluation index and compared the AMU of secondary medical areas with those already reported for Japan and each prefecture. Patients/1000 inhabitants/day (PID) for oral antibiotics in 2013 and 2016 were calculated using the National Database of Health Insurance Claims and Specific Health Checkups. ΔPID was defined as the difference between the PIDs in 2013 and 2016. Differences in AMUs for Japan and prefectures that have already been published were also calculated, and the concordance rate with ΔPID in each secondary medical area was evaluated. Antibiotics and age groups with less than 50% concordance between secondary medical area and previously reported AMU changes were observed. This revealed that even at the secondary medical area level, which is more detailed than the prefectural level, the AMU changes were not consistent. Therefore, in order to appropriately promote measures against antimicrobial resistance, we suggest the necessity of not only surveying AMU at the national or prefectural levels but also examining sub-prefectural trends in AMU.

Measures Against Antimicrobial Resistance in Children in Japan: Current Status and Future Prospects.

Antimicrobial resistance (AMR) is a major problem in public health. Japan is addressing this problem with various measures based on the National Action Plan on AMR, published in 2016. In Japan, the fight against AMR is hindered by issues with the health care system, including the lack of a general practitioner registration system, an abundance of private clinics and health care for infants and toddlers being essentially free of charge. As measures against AMR in inpatient care, thorough infection prevention and the Japanese government's incentivization of collaboration in infection prevention among hospitals and regions have helped to improve infection prevention. As measures against AMR in outpatient care, the creation of official Japanese government guidelines on antimicrobial stewardship has facilitated the implementation of antimicrobial stewardship in clinics. Another unique measure taken in Japan is incentivizing the nonprescription of antimicrobials for respiratory tract infections and diarrhea. Although Asia is a hot spot for AMR bacteria, the fight against AMR is affected by various factors, including insufficient precautions against nosocomial infections and the absence of surveillance systems. To combat these problems, Japan must take a strong leadership role. AMR is a problem not only at the level of individual countries but on a global scale and should, therefore, be addressed through joint action among nations.

A study of trends and factors associated with therapeutic drug monitoring (TDM) implementation for arbekacin treatment using a large Japanese medical claims database.

INTRODUCTION: Reimbursements for pharmacist interventions and infectious disease teams have recently been introduced in Japan. Arbekacin (ABK) is used to treat pneumonia and sepsis caused by methicillin-resistant Staphylococcus aureus, and therapeutic drug monitoring (TDM) is recommended. This study aimed to clarify the trend in TDM implementation for ABK over time and the factors associated with TDM implementation using a claims database. METHODS: Data of patients aged ≥15 years who received ABK for ≥3 consecutive days between 2010 and 2019 were extracted from a large Japanese medical claims database. The proportion of reimbursements claimed for TDM, pharmacist interventions, and the setup of infectious disease teams for each year were calculated. The factors associated with TDM implementation were identified using multivariate logistic regression analysis. RESULTS: The proportion of TDM implementation for ABK increased by 9.1% from 2010 to 2019, but it remained less than 40% throughout this period. The proportion of TDM implementation was higher in patients who claimed reimbursements for pharmacist interventions than in patients who did not. Logistic regression analysis showed that the stationing of pharmacists in wards and long-term ABK treatment were significantly associated with TDM implementation. CONCLUSIONS: From 2010 to 2019, the proportion of TDM implementation for ABK was significantly low. Moreover, the factors associated with TDM implementation were clarified. An environment wherein pharmacists can help implement TDM for patients receiving ABK would be beneficial.

Antimicrobial Use Fell Substantially in Japan in 2020-The COVID-19 Pandemic May Have Played a Role.

This study investigated the impact of the COVID-19 pandemic on antimicrobial use (AU) trends in Japan in 2020 and explored its potential effects on appropriate AU. Using nationwide antimicrobial sales data, we examined the annual and monthly trends in AU from 2016-2020 according to the AWaRe classification (Access and Watch categories) and administration route (oral and injectable). To analyze the possible impact of the COVID-19 pandemic on AU, seasonal autoregressive integrated moving average (SARIMA) models were used to predict AU in 2020 (based on the trends from 2016-2019) under the assumption that the pandemic did not occur. We observed a substantial reduction in AU in 2020 compared with preceding years. In addition, the reductions in AU for total antimicrobials and Watch category antimicrobials were greater than predicted regardless of administration route. These results suggest that the COVID-19 pandemic contributed to the observed reductions in AU, but it is also possible that the changes reflect recent efforts to improve AU. Continued AU surveillance and research are needed to optimize prescribing practices through appropriate antimicrobial stewardship.