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Introduction: Antimicrobial resistance is a global issue, and implementation of antimicrobial stewardship programs in outpatient settings is crucial. Japan has also focused on outpatient oral antimicrobial stewardship programs and difficulties in standardizing prescriptions have led to overprescription in primary emergency medical centers. There is a lack of research investigating the antibiotic prescription status of pediatric primary emergency medical centers and the benchmark prescription rates in pediatric outpatient settings., Methods: We conducted a multi-center, cross-sectional study of seven pediatric primary emergency medical centers located in five prefectures of Japan. We retrospectively extracted data from health claims or directly obtained them from charts at each institution and evaluated trends in the antibiotic prescription rate based on the AWaRe classification between April 2016 and December 2019., Results: Our study included 383,525 encounters, with the most common infectious disease diagnosis being acute upper respiratory tract infection in 93,449 cases (24.4 %). The antibiotic prescription rate during the study period was 7.4 %, representing a decrease of 46 %, from 10.2 % in 2016 to 5.5 % in 2019. The percentage of prescriptions in the Access group increased at all institutions; however, it exceeded 60 % in only three facilities in 2019. The percentage of third-generation cephalosporins varied among facilities, ranging from 1.7 % to 59.4 %, as of 2019., Conclusions: For pediatric primary emergency medical centers where antimicrobial stewardship programs are implemented, we suggest 5 % as a reasonable benchmark level for the antibiotic prescription rate. Prescribing the antibiotics in the Access groups less frequently remains a domestic challenge in Japan., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest to disclose. Informed Consent and Ethical Approval. We obtained opt-out consent from the patients' parents. This study was approved by the institutional ethics committees of Kobe Children's Hospital (Approval Number 2021–61)., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Most antimicrobials are prescribed to outpatients, making outpatient antibiotic prescription an important target for antibiotic stewardship. A national antimicrobial resistance (AMR) action plan was developed in 2016 by the Japanese government with various antimicrobials steawardship activities for pediatric outpatients. We aimed to evaluate changes in antibiotic use pre- and post-implementation of the AMR action plan., Methods: All antimicrobials prescribed to pediatric outpatients in Japan from 2011 to 2018 were retrospectively analyzed using data from a national database. Antimicrobials dispensed for patients aged ≤19 years were reviewed. Antimicrobial use was surveyed by age, year of use, type of antimicrobial prescribed, and prescribing facility. Five cities were selected as pilot areas to investigate the variations, based on the clinical specialties of the prescribing physicians., Results: Antimicrobial usage varied with age. Specifically, usage decreased post-AMR in patients aged ≤8 years and increased in those aged >15 years. Further, antimicrobial prescriptions tended to decrease after 2016 in primary care clinics and hospitals. In the pilot areas of the study, 35% of all oral antimicrobials were prescribed in otolaryngology departments, and 8% were prescribed in dermatology clinics. Notably, antimicrobial prescriptions from both departments showed an upward trend from 2011 to 2018., Conclusion: The use of antimicrobial agents decreased in children younger than 8 years in pediatric clinics, hospitals, and internal medicine clinics. However, use increased in children older than 15 years and in other specialty clinics. Settings with an increasing use of antimicrobials are potential targets for the next antibiotic stewardship program and should be investigated in detail., (© 2022 Japan Pediatric Society.)

Background: In 2016, the Japanese government set the National Action Plan on antimicrobial resistance to reduce antibiotic prescriptions. However, the trends and variations of antibiotic prescription patterns in a routine healthcare setting during the fiscal year 2013-2018 across different clinics at a national level are unclear., Methods: This retrospective cohort study included all clinics with >100 pediatric outpatients with infectious diseases per month during the fiscal year 2013-2018 using a national database in Japan. We investigated the trends in antibiotic prescription rates and their patterns and variations across different clinics over the six years following the 2019 World Health Organization Access, Watch, Reserve antibiotic groups, and Amoxicillin Index., Results: A total of 2278 clinics with 94,414,170 infectious disease-related visits were eligible for the study. Most clinics showed higher Watch percentages (median 85.4%; IQR, 68.5-95.1) than Access percentages (median, 13.8%; IQR, 4.2-30.7) and Amoxicillin Index (median, 13.3%; IQR, 3.9-30.4). The introduction of the Action Plan changed annual absolute reductions in the antibiotic prescription rates from -16.0 DOTs/1000 visitors (95%CI, -16.4-15.6) to -239.3 per 1000 visitors (95%CI, -240.0-238.6). However, these impacts were heterogeneous across clinics. From 2013 to 2018, 41.4% reduced the antibiotic prescription rates by >33.3% (median, -1035.5 DOTs/1000 visitors; IQR, -1519.4-680.2), 18.7% did not change the rates (median, -40.3 DOTs/1000 visitors; IQR, -168.4-68.6), and 7.3% increased the rates by >10% (499.5 DOTs per 1000 visitors; IQR, 232.6-837.5)., Conclusions: We observed the National Action Plan's impacts and extensive prescription variations across different pediatric clinics. However, one-fourth of clinics did not improve antibiotic prescription patterns even after introducing the Action Plan., (Copyright © 2021. Published by Elsevier Ltd.)

Methicillin-resistant Staphylococcus aureus infections are a significant cause of morbidity and mortality in pediatric liver transplant (LT) recipients. Physiological changes following LT may affect vancomycin pharmacokinetics; however, appropriate dosing to achieve sufficient drug exposure (i.e., 24-h area under the concentration-time curve [AUC 24 ]/MIC ≥ 400) in pediatric LT recipients has not been reported. This retrospective pharmacokinetics study of LT recipients aged <18 years utilized data on patient characteristics with vancomycin concentrations and dosing information obtained from electronic medical records. Population pharmacokinetics analysis was conducted by nonlinear mixed-effects modeling with the Phoenix NLME software. Potential covariates were screened with univariate and multivariate analysis. Monte Carlo simulations were performed using the final model to explore appropriate dosing. The study included 270 pharmacokinetics profiles encompassing 1,158 concentrations measured in 161 patients. The median age was 13.3 (interquartile range, 7.6 to 53.5) months, serum creatinine (sCr) was 0.16 (0.12 to 0.23) mg/dl, and days from LT (DFLT) was 17 (6 to 31). Multivariate analysis demonstrated that lower sCr and shorter DFLT were associated with higher clearance. By post hoc estimation, the average clearance and volume of distribution were 0.18 liters/h/kg and 1.01 liters/kg, respectively. The Monte Carlo simulations revealed that only 16% of patients achieved an AUC 24 /MIC of ≥400 with the assumed vancomycin MIC of 1 μg/ml. DFLT and sCr were significant covariates for vancomycin clearance in pediatric LT recipients. Standard vancomycin dosing may be insufficient, and higher or more frequent dosing may be required to achieve an AUC 24 /MIC of ≥400 in pediatric LT recipients with normal renal function. IMPORTANCE We evaluated vancomycin pharmacokinetics in pediatric LT recipients and developed a population pharmacokinetics model by considering various factors that might account for alterations in vancomycin pharmacokinetics. Our analyses revealed that lower serum creatinine levels and a shorter duration from the day of LT were associated with higher vancomycin clearance and led to subtherapeutic drug exposure. We also performed Monte Carlo simulations to determine the appropriate dosing strategy in pediatric LT recipients, which revealed that a standard vancomycin dosing might be insufficient and that higher or more frequent dosing might be necessary to achieve an AUC 24 /MIC of ≥400 in pediatric LT recipients with normal renal function. To the best of our knowledge, this is the first study to assess vancomycin pharmacokinetics in pediatric LT recipients by population pharmacokinetics analysis.

This study investigates the optimal meropenem (MEM) dosing regimen for critically ill pediatric patients, for which there is a lack of pharmacokinetic (PK) studies. We conducted a retrospective single-center PK and pharmacodynamic (PD) analysis of 34 pediatric intensive care unit patients who received MEM. Individual PK parameters were determined by a two-compartment analysis. The median (range) age and body weight were 1.4 (0.03 to 14.6) years and 8.9 (2.7 to 40.9) kg, respectively, and eight (23.5%) patients received continuous renal replacement therapy (CRRT), three of whom received extracorporeal membrane oxygenation. Renal function, the systemic inflammatory response syndrome (SIRS) score for the clearance (CL), and the use of CRRT for the central volume of distribution ( V c ) were identified as significant covariates. The mean CL, V c , and peripheral volume of distribution ( V p ) were 0.45 liters/kg/h, 0.49 liters/kg, and 0.34 liters/kg, respectively. The mean population CL of MEM increased by 35% in patients with SIRS and V c increased by 66% in patients on CRRT in the final model. Dosing simulations suggested that the standard dosing regimen provided insufficient PD exposures of a 100% free time above the MIC, and higher doses (40 to 80 mg/kg of body weight/dose every 8 h) with a prolonged 3-h infusion were required to ensure the appropriate PD exposures for patients with SIRS. Our PK model indicated that critically ill pediatric patients are at risk of subtherapeutic exposure under the standard dosing regimen of MEM. A larger, prospective investigation confirming the safety and efficacy of higher concentrations and prolonged infusion of MEM is necessary., (Copyright © 2021 American Society for Microbiology.)

Background: The overutilization of healthcare and overuse/misuse of antibiotics in Japan are responsible for the increase in healthcare expenditure and the development of antimicrobial resistance. The Japanese government started paying incentives to medical facilities for primary care physician registrations, but the impact of this new policy is still unclear., Methods: We conducted a retrospective cohort study for all pediatric outpatients from April 2015 to December 2016 in Japan, targeting 1.4 million children under 2 years of age. We investigated the effects of primary care physician registration on physician visits, total antibiotic use and admission rates using difference-in-differences (DID) and causal mediation analyses., Results: DID analyses showed that primary care registration policy contributed to increases in total physician visits, total and broad-spectrum antibiotic use and radiologic study utilization, but reduced out-of-hour visits and did not affect hospitalization rates. Similar results were obtained when we adjusted for and matched on potential confounders. Causal mediation analyses found that the greatest pathway was controlled by direct effects of 53.2 DOTs per 1000 person-months (95% CI: 29.1-77.2), indicating that the effect of new health policy that did not mediate increased outpatient visits mostly contributed to the excess use of antibiotics., Conclusions: The health policy further increased antibiotic use. On April 2018, a new health policy of paying incentives for not prescribing antibiotics to children with respiratory infection or gastroenteritis was initiated. Further studies are needed whether this new health policy can mitigate the overutilization of healthcare and antibiotic use.

Antimicrobial stewardship programs (ASP) for oral antibiotics is still uncommon, despite the fact that oral antibiotics prescription accounts for 90% of total antibiotic consumption in developed countries. We introduced preauthorization and prospective audit and feedback (PAF) system on broad-spectrum oral antimicrobials as a part of ASP intervention from October 2015 in a tertiary children's hospital in Japan. Antimicrobial consumption and cost of targeted oral antimicrobials decreased from 11.1 days of therapy (DOT) per 1000 outpatient visits and 860,040 yen ($ 7167: 1 $ = 120 yen) to 1.9 DOT per 1000 outpatient visits and 142,200 yen ($ 1185) annually, respectively (p < 0.001). Interrupted time-series analysis showed that prescriptions for targeted antimicrobials decreased rapidly after initiation of preauthorization (p < 0.001). Prescriptions for non-targeted oral antimicrobial increased temporarily (p < 0.001), but a decreasing trend was found after the initiation (p < 0.001). In pre-intervention period, the main indications for using targeted antimicrobials were upper and lower respiratory infection, urinary tract infections, prophylaxis for medical procedures and otitis media, but only 21.4% of them were appropriate prescription. The appropriate prescription rate of post -intervention period increased to 58.5%. During the study period, the susceptibility pattern of major bacteria to these antimicrobials did not change. In conclusion, introduction of the preauthorization and PAF for selected oral antimicrobials decreased the antimicrobial use of both targeted and non-targeted antimicrobials. This intervention may be an effective method of ASP for other children's hospitals., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Few studies have characterized the clinical manifestations of delayed antibiotic hypersensitivity (AH) diagnosed using objective methods. The lymphocyte transformation test (LTT) is a reproducible method to diagnose type IV hypersensitivity. The purpose of the study was to evaluate the characteristics of delayed AH diagnosed on LTT in children., Methods: We performed a retrospective analysis of patients who were evaluated for AH using LTT at National Center for Child Health and Development, Tokyo, from 2002 to 2014. We extracted patient demographics, type and duration of antibiotics, and clinical characteristics from the medical records. Clinical manifestations were compared between LTT-positive and LTT-negative cases., Results: Seventy-five cases for which 101 drugs were tested were included in this study. LTT was positive against 34 drugs in 26 cases. Median age was 5 years (IQR, 1-9 years), and 49% of patients had underlying disease. LTT was performed at a median of 18 days (IQR, 4-59 days) after the suspected episode. The median number of days from the initiation of therapy to the onset of symptoms was 4. Rash was the most common manifestation (89%). Fever (>38°C) was observed in 20 cases (27%). Onset of fever preceded the rash in nine cases (45%), appeared simultaneously in five (25%), appeared afterwards in four (20%), and was unknown in two (10%). Fever was an independent factor associated with AH when comparing LTT-positive and LTT-negative cases (OR, 3.61; 95%CI: 1.03-12.64)., Conclusions: Fever was a common presenting symptom of delayed AH in children aged ≤18 years., (© 2019 Japan Pediatric Society.)

Background: Antimicrobial resistance is a major public health concern. In 2016, the Japanese government launched a national action plan aimed at achieving a 33% and 50% reduction in the number of total and oral antimicrobial prescriptions (cephalosporins, macrolides, and quinolones) from the 2013 figures by 2020, respectively. The purpose of this study was to investigate the indications for recent antimicrobial prescriptions and to identify the primary targets for intervention to achieve the aims of the government's action plan., Methods: Using the national health claims database, we retrospectively analyzed oral antibiotic prescriptions for Japanese children aged ≦ 15 years from 2013 to 2016. The trends were analyzed based on days of therapy (DOT) per infectious disease-related visit for each antibiotic. For patients whose chief diagnosis was an infectious disease, the number of antimicrobial prescriptions per diagnosis, their proportion, and the details of the type of antimicrobial were investigated., Results: In total, 297,197,328 infectious disease-related visits were identified during 2013-2016. Total antimicrobial prescriptions showed a 3.7% reduction from 1.519 DOT/visitor in 2013 to 1.463 DOT/visitor in 2016 (P trend  < 0.001). Antimicrobials were prescribed for 31.7% and 36.9% of children with upper and lower respiratory tract infection, accounting for 54.6% and 26.2% of all antimicrobial prescriptions, respectively. Third generation cephalosporins and macrolides comprised the majority of these prescriptions., Conclusions: Antimicrobials were commonly prescribed for children with respiratory infections. Therefore, promoting appropriate antimicrobial use in this population is required to achieve the 2020 goals set by the action plan., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

In Japan, 92.6% of antibiotics consumed are oral agents; most of these are for outpatients. A significant proportion is known to be dispensed for children; however, the specific pattern of antibiotic prescription in accordance with clinical specialty is still unclear. The aim of our study was to identify the key targets for the optimization of oral antibiotic use in children. We analyzed data on oral antimicrobial prescription patterns for children ＜ 16 years old of age in 3 urban districts by using a national database in Japan. Oral prescriptions were categorized according to their class, spectrum, clinical specialty, and type of clinical setting. The antibiotic spectrum was categorized as narrow, broad, or ultra-broad. In total, 132,869,332 antibiotic prescriptions were collected for analysis. The proportions of narrow-spectrum, broad-spectrum, and ultra-broad-spectrum antibiotics were 10.9%, 73.7%, and 15.4% in primary care clinics and 23.4%, 71.1%, and 5.4% in hospitals, respectively. Prescriptions from pediatricians and otolaryngologists in primary care clinics were predominant in the 3 studied areas. Third-generation cephalosporins, quinolones, penems, and carbapenems were prescribed mostly by pediatricians and otolaryngologists. Ultra-broad spectrum antibiotics used in primary care clinics and antibiotics particular to each specialty were identified as key targets for the optimization of oral antibiotic use for pediatric outpatients.

The significance of anaerobic bacteria as a pathogen in urinary tract infection (UTI) in children is unclear. A two-month-old infant presenting with poor feeding received a diagnosis of polymicrobial anaerobic UTI by next-generation sequencing and was found to have obstructive uropathy. Anaerobic bacteria may be a cause of UTI in children with urinary tract obstruction., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: This study investigated recent trends in antibiotic use and factors associated with antibiotic use among children with acute infectious diarrhea. We obtained records of outpatients aged under 18 years diagnosed with acute infectious diarrhea from the Japan Medical Data Center database during 2012-2015., Objective: We investigated prescription patterns of antibiotics at their initial visit and evaluated factors associated with antibiotic usage using multivariable log-binomial regression models., Results: Overall, we identified 4493 patients diagnosed with acute infectious diarrhea; 29.6% received antibiotics. The most commonly prescribed antibiotic is fosfomycin (20.3%). In multivariable log-binomial regression analysis, out-of-hour visits, clinical diagnoses of suspected bacterial enterocolitis, private outpatient clinics, and pediatric departments are significantly associated with higher prevalence of antibiotic use., Conclusions: Antibiotics are over-prescribed for children with acute infectious diarrhea. Our investigation provides important information to promote education of physicians and of health policy considerations for appropriate antibiotic prescription practices.

Objectives: Antibiotics are the most frequently prescribed medicines for children, however inappropriate antibiotic prescribing is prevalent. This study investigated recent trends in antibiotic use and factors associated with appropriate antibiotic selection among children with group A streptococcal infections in Japan., Methods: Records of outpatients aged <18years with a diagnosis of group A streptococcal infection were obtained using the Japan Medical Data Center database. Prescription patterns for antibiotics were investigated and factors associated with penicillin use were evaluated using a multivariable log-binomial regression model., Results: Overall, 5030 patients with a diagnosis of group A streptococcal infection were identified. The most commonly prescribed antibiotics were third-generation cephalosporins (53.3%), followed by penicillins (40.1%). In the multivariable log-binomial regression analysis, out-of-hours visits were independently associated with penicillin prescriptions [prevalence ratio (PR)=1.10, 95% confidence interval (CI) 1.03-1.18], whereas clinical departments other than paediatrics and internal medicine were related to non-penicillin prescriptions (PR=0.57, 95% CI 0.46-0.71)., Conclusions: Third-generation cephalosporins were overprescribed for children with group A streptococcal infections. This investigation provides important information for promoting education for physicians and for constructing health policies for appropriate antibiotic prescription., (Copyright © 2018 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.)

Pertussis is characterized by intense, prolonged coughing in children often followed by a distinctive whooping sound on inspiration. However, the clinical manifestations and natural course of pertussis in disabled children are largely unknown. We experienced a case of pertussis in a disabled girl who had previously undergone a tracheostomy and laryngotracheal separation. She presented with increased tracheal secretions and required hospitalization but did not develop a cough. Pertussis was suspected from the sputum Gram stain, which revealed numerous, short gram-negative rods that did not grow on chocolate agar. A nucleic acid amplification test was positive for Bordetella pertussis and the patient improved on azithromycin. Pertussis may present without its cardinal symptoms in disabled children., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The resistance of Staphylococcus aureus (S. aureus) to antibiotics is an increasing problem. Clindamycin has been used as empiric therapy for the rising incidence of community-acquired methicillin-resistant S. aureus (MRSA). As such, the local rate of inducible resistance against clindamycin is an important consideration. This multicenter study was conducted to identify the incidence of inducible clindamycin resistance of S. aureus isolates in Tokyo, the most populous city in Japan. A total of 2408 adult and pediatric samples were collected from a university hospital and two pediatric hospitals between January 2011 and December 2011. Among the 2341 samples analyzed, the incidence of inducible clindamycin resistance in erythromycin-resistant and clindamycin-susceptible/intermediate isolates was found to be 91% (n = 585), a figure much higher compared to most reports from other countries. In conclusion, we found a very high rate of inducible clindamycin resistance in macrolide-resistant S. aureus isolates in our geographic area., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

BackgroundFor addressing antibiotic overuse, Japan designed a health care policy in which eligible medical facilities could claim a financial reward when antibiotics were not prescribed for early-stage respiratory and gastrointestinal infections. The policy was introduced in a pilot manner in paediatric clinics in April 2018.MethodsWe conducted a quasi-experimental, propensity score-matched, difference-in-differences (DID) design to determine whether the nationwide financial incentives for appropriate non-prescribing of antibiotics as antimicrobial stewardship [800 JPY (≈7.3 US D) per case] were associated with changes in prescription patterns, including antibiotics, and health care use in routine paediatric health care settings at a national level. Data consisted of 9 253 261 cases of infectious diseases in 553 138 patients treated at 10 180 eligible or ineligible facilities.ResultsA total of 2959 eligible facilities claimed 316 770 cases for financial incentives and earned 253 million JPY (≈2.29 million USD). Compared with ineligible facilities, the introduction of financial incentives in the eligible facilities was associated with an excess reduction in antibiotic prescriptions [DID estimate, -228.6 days of therapy (DOTs) per 1000 cases (95% CI, -272.4 to -184.9), which corresponded to a relative reduction of 17.8% (95% CI, 14.8 to 20.7)]. The introduction was also associated with excess reductions in drugs for respiratory symptoms [DID estimates, -256.9 DOTs per 1000 cases (95% CI, -379.3 to -134.5)] and antihistamines [DID estimate, -198.5 DOTs per 1000 cases (95% CI, -282.1 to -114.9)]. There was no excess in out-of-hour visits [DID estimate, -4.43 events per 1000 cases (95% CI, -12.8 to 3.97)] or hospitalizations [DID estimate, -0.08 events per 1000 cases (95% CI, -0.48 to 0.31)].ConclusionsOur findings suggest that financial incentives to medical facilities for not prescribing antibiotics were associated with reductions in prescriptions for antibiotics without adverse health care consequences. Japan's new health policy provided us with policy options for immediately reducing inappropriate antibiotic prescriptions by relatively small financial incentives.