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Background : The nationwide epidemiology and clinical practice patterns for younger children hospitalized with urinary tract infections (UTIs) were unclear. Methods: We conducted a retrospective observational study consisting of 32,653 children aged < 36 months who were hospitalized with UTIs from 856 medical facilities during fiscal years 2011–2018 using a nationally representative inpatient database in Japan. We investigated the epidemiology of UTIs and changes in clinical practice patterns (e.g., antibiotic use) over 8 years. A machine learning algorithm of multivariate time-series clustering with dynamic time warping was used to classify the hospitals based on antibiotic use for UTIs. Results: We observed marked male predominance among children aged < 6 months, slight female predominance among children aged > 12 months, and summer seasonality among children hospitalized with UTIs. Most physicians selected intravenous second- or third-generation cephalosporins as the empiric therapy for treating UTIs, which was switched to oral antibiotics during hospitalizations for 80% of inpatients. Whereas total antibiotic use was constant over the 8 years, broad-spectrum antibiotic use decreased gradually from 5.4 in 2011 to 2.5 days of therapy per 100 patient-days in 2018. The time-series clustering distinctively classified 5 clusters of hospitals based on antibiotic use patterns and identified hospital clusters that preferred to use broad-spectrum antibiotics (e.g., antipseudomonal penicillin and carbapenem). Conclusions: Our study provided novel insight into the epidemiology and practice patterns for pediatric UTIs. Time-series clustering can be useful to identify the hospitals with aberrant practice patterns to further promote antimicrobial stewardship. [ABSTRACT FROM AUTHOR]

Background Several reports have suggested that routine use of anaerobic blood culture bottles together with aerobic bottles may improve blood culture positivity. However, the information is still limited regarding the utility of anaerobic blood culture bottles in the pediatric intensive care unit (PICU), where bacteremia due to anaerobic bacteria is relatively rare. Methods A retrospective observational study was conducted at a PICU in a tertiary children's hospital in Japan from May 2016 to January 2020. Patients aged ≤15 years old with bacteremia, for which both aerobic and anaerobic blood cultures were submitted, were included in the study. We investigated whether the positive blood culture cases were from aerobic or anaerobic bottles. We also compared the amount of blood inoculated into culture bottles to determine the effect of blood volume on the rate of detection. Results During the study period, a total of 276 positive blood cultures from 67 patients were included in this study. Among the paired blood culture bottles, 22.1% were positive only for the anaerobic bottles. Escherichia coli and Enterobacter cloacae were the most common pathogens that were detected in anaerobic bottles only. Obligate anaerobic bacteria were detected in 2 (0.7%) bottles. There was no significant difference in the amount of blood inoculated into aerobic and anaerobic culture bottles. Conclusions The use of anaerobic blood culture bottles in the PICU may increase the detection rate of facultative anaerobic bacteria. [ABSTRACT FROM AUTHOR]

Background: For 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.Methods: We 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.Results: A 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)].Conclusions: Our 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. [ABSTRACT FROM AUTHOR]

Background Several studies have investigated whether pregnancy is a risk factor for developing severe coronavirus disease 2019 (COVID-19); however, the results remain controversial. In addition, the information regarding risk factors for developing severe COVID-19 in pregnant women is limited. Methods A retrospective cohort study analyzing the data from the nationwide COVID-19 registry in Japan was conducted. Propensity score–matched analysis was performed to compare COVID-19 severity between pregnant and nonpregnant women. Multivariate analysis was also conducted to evaluate risk factors for developing moderate-to-severe COVID-19 in pregnant women. Results During the study period, 254 pregnant and 3752 nonpregnant women of reproductive age were identified. After propensity score matching, 187 pregnant women and 935 nonpregnant women were selected. A composite outcome of moderate-to-severe COVID-19 was more frequently observed in pregnant women than that of nonpregnant women (n = 18 [9.6%] vs n = 46 [4.9%]; P  = .0155). In multivariate analysis, the presence of underlying diseases and being in the second-to-third trimester of pregnancy were recognized as risk factors for moderate-to-severe COVID-19 in pregnant women (odds ratio [95% confidence interval]: 5.295 [1.21–23.069] and 3.871 [1.201–12.477], respectively). Conclusions Pregnancy could be a risk factor for moderate-to-severe COVID-19 for women in Japan. In addition to the presence of comorbidities, advanced pregnancy stages may contribute to greater risks for developing moderate-to-severe COVID-19 in pregnant women. [ABSTRACT FROM AUTHOR]

We aimed to define the burden and clinical features of invasive group B streptococcus (GBS) disease in infants younger than 1 year in Japan, to explore transmission route of late-onset disease (LOD), and to identify risk factors associated with recurrent GBS disease. We conducted a retrospective, questionnaire-based nationwide surveillance study between 2016 and 2020. A total of 875 GBS cases were identified, including 186 early-onset disease, 628 LOD, and 61 ultra-late-onset disease. Case fatality rate in each age category was 6.5%, 3.0%, and 3.3%, respectively. Patients with meningitis had neurodevelopmental sequelae in 21.5% (64/297). Annual incidence in infants younger than 1 year and in LOD significantly increased from 0.28 to 0.45/1000 livebirths (p = 0.021) and from 0.19 to 0.29/1000 livebirths (p = 0.046), respectively. Maternal colonization status at the LOD diagnosis was available for 148 mothers, of whom 21/58 (36.2%) had positive rectovaginal swabs and 42/117 (36.2%) had GBS in breastmilk culture. These two sites are potentially infectious routes in LOD. The four leading disease-causing serotypes III, Ia, Ib, and V represented 95% of the available serotypes. Thirty-one recurrent cases were identified, accounting for 3.7% of total patients. A multivariate regression analysis showed that prematurity (p = 0.029) and antepartum maternal GBS colonization (p = 0.032) were significantly associated with risk for the recurrence. Our findings indicated that GBS disease burden still remains with considerable mortality and morbidity in Japan, and provided important information for developing better strategies for the prevention of GBS disease, including maternal vaccination. [ABSTRACT FROM AUTHOR]

Background: The relationship between allergic individuals and their responsiveness to routine vaccines has rarely been investigated. This study examined whether the seroprevalence of measles antibody differed between children with and without allergic diseases in the general pediatric population. Methods: The cross-sectional study was performed within a prospective general birth cohort (a pilot study of the Japan Environment & Children's Pilot Study [JECS]) of children aged 8 years. The clinical history of allergic diseases, measles, and the concentration of measles immunoglobulin G titers in serum enzyme immunoassay were examined. Fisher's exact tests were used to assess the relationships between the allergic characteristics of the children and their measles antibody positivity rates. Results: This study included 162 children. Any allergic disease was reported in 75 (46.3%). The measles antibody positivity rate was 94.7% among children with any allergic diseases and 92.0% among children without allergic diseases. Our results revealed no differences in measles antibody seropositivity between children with allergies and controls. Conclusions: Children with allergies mount and maintain a comparable immune response to the measles vaccine. [ABSTRACT FROM AUTHOR]

Live attenuated vaccines are contraindicated for patients on immunosuppressive agents or biological agent, except for live attenuated varicella vaccine, although previous reports showed their effectiveness and safety. This study is the nationwide cross-sectional research about the current utilization of live attenuated vaccines for patients on immunosuppressive agents or biological agents in Japan. We sent questionnaires to pediatric centers and examined whether each institution offered live attenuated vaccines to patients with immunosuppressive agents or biological agents (institutional research). We also examined adverse events associated with live attenuated vaccines between 2013 and 2017 (patient research). In the institutional research, 46 out of 334 institutions (13.8%) administered live attenuated vaccines to patients receiving immunosuppressive agents. In contrast, only six out of 270 institutions (2.2%) administered live attenuated vaccines to patients receiving biological agents. However, 66.3% of physicians answered that patients receiving immunosuppressive agents should be immunized with live attenuated vaccines, and only 7.0% disagreed with them. In the patient research, data for 781 patients were collected. Vaccine-associated infections were observed in only two patients (0.3%), both of whom had varicella, although they recovered promptly. No life-threatening adverse events were noted. Conclusion: In pediatric centers, the demand for live attenuated vaccines in patients receiving immunosuppressive agents was high and most physicians think they should be immunized. Immunization with live attenuated vaccines appeared safe in patients receiving immunosuppressive agents, although further studies are needed for patients receiving biological agents What is known: • Live attenuated vaccines (LAV) are generally contraindicated for patients on immunosuppressive agents (IS) or biological agents (BA), except for live attenuated varicella vaccine, as immunocompromised patients are at greater risk for serious viral infection from the vaccine strains. • Viral infections, such as measles and varicella, cause serious complications in children receiving IS. • Several previous reports showed that LAV is relatively effective and safe for patients receiving IS. What is new: • In Japan, the demand for LAV in patients receiving IS was high, and most physicians hoped they should be immunized. • Vaccine-associated infection is rarely observed in patients with IS after LAV administration. • Immunization with LAV appeared safe in patients receiving IS. Trial registration: University Hospital Medical Information Network (UMIN). Trial registration number: UMIN000029176. Date of registration: 2017/09/19. [ABSTRACT FROM AUTHOR]

Background: The strategy to eradicate polio is based on preventing infection by immunizing all children until the world is polio‐free. However, data regarding efficacy of polio‐containing vaccination in immunocompromised patients such as LT recipients are limited. Methods: We conducted an observational study at the largest pediatric transplant center in Japan from January 2011 to January 2015. LT recipients were enrolled after transplantation, and those who had completed the Japanese polio vaccination program were eligible for the study. Patients' demographics were collected from their medical records. Antibody titers against poliovirus serotypes 1‐3 were measured using the neutralization test at the routine follow‐up visits after enrollment. Factors associated with seropositivity against each type of poliovirus were evaluated. Results: Sixty‐four patients who had received the complete polio vaccination series were enrolled in the study. Of these, 37 patients had received all series of polio‐containing vaccination before LT. Median age of the patients was 75 months. Their underlying diseases included the following: 40 (63%) with cholestatic liver diseases and 11 (17%) with metabolic disorders. After a median interval of 43 months after LT, seropositivity rates against poliovirus 1, 2, and 3 were 93.8% (60/64), 92.2% (59/64), and 54.7% (35/64), respectively. Among 32 patients who had received only oral polio vaccine (OPV), seropositivity against poliovirus 3 was particularly low (25.0%). No factors associated with seropositivity against each type of poliovirus were identified. Conclusions: In the LT recipients, seropositivity for poliovirus 3 was low, suggesting a need for additional inactivated polio‐containing vaccination after LT, especially for patients who had received only OPV. [ABSTRACT FROM AUTHOR]

Background: Herpes zoster (HZ) may cause complications; however, information regarding complications of HZ in children is relatively sparse. We reviewed cases of HZ in children retrospectively and investigated the risk factors contributing to the development of complications. Methods: A retrospective observational study was conducted at a tertiary care children's hospital in Japan. Children receiving a diagnosis of HZ between January 2010 and October 2016 were identified from electronic medical records. In this study, the following diseases were recognized as complications of HZ: bacterial skin infection, facial paralysis, meningitis, uveitis and keratitis, postherpetic neuralgia, acute retinal necrosis, pneumonia, and otitis interna. Details regarding clinical information of HZ patients with complications were described. Results: We found 138 cases with HZ. Among these, 58 (42%) occurred in immunocompetent children and 80 cases (58%) occurred in immunocompromised children. Complications were observed in 10 cases of immunocompromised children and in eight cases of immunocompetent children. Although secondary bacterial skin infection was the most common complication (n = 6, 33.3%), severe complications such as facial paralysis (n = 3, 16.7%), meningitis (n = 2, 11.1%), uveitis and keratitis (n= 2, 11.1%), acute retinal necrosis (n = 1, 5.6%), pneumonia (n = 1, 5.6%), and otitis interna (n = 1, 5.6%) were observed. Patients with complications tended to have a rash on the head or neck, compared with those without complications (n = 9, 50% vs n = 18, 15%; P = 0.001). Conclusions: Severe HZ complications may occur in immunocompetent children. Development of a rash on the head or neck might be a risk factor for complications. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to describe the epidemiology of childhood group B streptococcus (GBS) disease including late late-onset disease (LLOD) and to clinically characterize recurrent cases and twin-sibling cases in Japan. Methods: We collected information on infants (<1 year of age) with invasive GBS disease and institutional information about births and transfers through a nationwide questionnaire between 2011 and 2015. Results: We identified 133 infants with early-onset disease (EOD), 274 late-onset disease (LOD), and 38 LLOD from 149 institutes. The case fatality rate (CFR) of EOD, LOD, and LLOD was 4.5, 4.4, and 0%, respectively. CFR in EOD was significantly ( P < 0.001) associated with preterm birth, but not that in LOD and LLOD. Twenty-nine percent of infants with meningitis (49/169) had neurologic sequelae. We showed clinical details of 12 recurrent cases that accounted for 2.8% of the total patients, and 4 sets of both twins affected; 4 of 12 recurrent cases and 3 of 4 twin-sibling sets were also associated with preterm birth. Based on the livebirth number of 581,488, the instituted-based incidence of EOD, LOD, and LLOD was estimated as 0.09 (95% CI 0.06-0.11), 0.12 (95% CI 0.11-0.14), and 0.01 (95% CI 0.01-0.02) per 1000 livebirths, respectively. Conclusions: CFR of EOD and LOD in Japan is comparable with that in high-income European countries or the United States, and their incidence is much lower. Our findings also describe the clinical details of LLOD, recurrent infections, and infections in twin siblings. This study is the largest among Asian childhood GBS studies ever reported. [ABSTRACT FROM AUTHOR]

The article offers information on Impact of the 3-day rule for stool culture in a children's hospital. Topics include Clinical and laboratory information was extracted for each patient from the electronic medical records. Clostridioides difficile infection was excluded because of the known high incidence of asymptomatic carrier status in children, especially in neonates and infants.

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

The melting temperature (T m) mapping method (TM) identifies bacterial species by intrinsic patterns of T m values in the 16S ribosomal RNA gene (16S rDNA) extracted directly from whole blood. We examined potential clinical application of TM in children with bloodstream infection (BSI). This was a prospective observational study at a children's hospital in Japan from 2018 to 2021. In patients with diagnosed or suspected BSI, we investigated the match rates of pathogenic bacteria identified by TM and blood culture (BC), the inspection time to identification of TM, and the amount of bacterial DNA in blood samples. The median age of 81 patients (93 samples) was 3.6 years. Of 23 samples identified by TM, 11 samples matched the bacterial species with BC (positive-match rate, 48 %). Of 64 TM-negative samples, 62 samples were negative for BC (negative-match rate, 97 %). Six samples, including one containing two pathogenic bacterial species, were not suitable for TM identification. In total, the matched samples were 73 of 93 samples (match rate, 78 %). There were seven samples identified by TM in BC-negative samples from blood collected after antibiotic therapy. Interestingly, the bacteria were matched with BC before antibiotic administration. These TM samples contained as many 16S rDNA copies as the BC-positive samples. The median inspection time to identification using TM was 4.7 h. In children with BSI, TM had high negative-match rates with BC, the potential to identify the pathogenic bacteria even in patients on antibiotic therapy, and more rapid identification compared to BC. UMIN000041359 https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000047220. [ABSTRACT FROM AUTHOR]

The objective of this study was to describe the recent epidemiology of Pneumocystis pneumonia (PCP) in Japan using a nationwide database. We extracted data of inpatients with PCP from the Diagnostic Procedure Combination database, a national inpatient database in Japan, from January 2010 to December 2016. During the study period, 4293 PCP patients were identified, including 4073 adults and 220 children. In adults, the most common comorbidity was hematologic malignancy (31%), followed by diabetes mellitus (30%), rheumatic/collagen diseases (26%), and solid organ tumors (18%). In children, there were few patients with rheumatic diseases (5%) or diabetes mellitus (2%), but immunodeficiency (without human immunodeficiency virus) was more common (28%). Few biological products were used for adult and pediatric patients; CD20 inhibitors, TNF-α inhibitors, interleukin receptor inhibitors, and CTLA-4 inhibitor were used for 8.6% and 2.4%, 1.3% and 0%, 1.2% and 4.7%, and 0.2% and 0% of adult and pediatric patients, respectively. Based on data stratified by bed count, the annual numbers of PCP patients in Japan were estimated as 2221 adults and 123 pediatric patients. The mortality was higher in adults (27%) than in pediatric patients (21%) (P = 0.041). The underlying disease and mortality were apparently different between adult and pediatric PCP patients. [ABSTRACT FROM AUTHOR]

• We evaluated trends of pediatric varicella and herpes zoster incidence for 18 years. • Varicella was largely reduced after the vaccine introduction and COVID-19 pandemic. • The vaccine and COVID-19 pandemic had a small impact on herpes zoster incidence. • Risk of herpes zoster was low in children born after the routine vaccine. To determine the epidemiological trends in pediatric varicella and herpes zoster incidence and changes in healthcare resource use from 2005 to 2022 using a nationally representative database in Japan. We conducted a retrospective observational study consisting of 3.5 million children with 177 million person-months during 2005–2022 using Japan Medical Data Center (JMDC) claims database in Japan. We investigated trends in incidence rates of varicella and herpes zoster and changes in healthcare resource use (e.g., antiviral use, office visits, and healthcare costs) over 18 years. Interrupted time-series analyses were used to investigate the impact of the routine varicella vaccination program in 2014 and infection prevention measures against COVID-19 on incidence rates of varicella and herpes zoster and related healthcare utilization. After the introduction of the routine immunization program in 2014, we observed level changes in incidence rates (45.6 % reduction [95 %CI, 32.9–56.0] of varicella cases, antiviral use (40.9 % reduction [95 %CI, 25.1–53.3]), and relevant healthcare costs (48.7 % reduction [95 %CI, 38.2–57.3]). Furthermore, infection prevention measures against COVID-19 were associated with additional level changes in varicella rates (57.2 % reduction [95 %CI, 44.5–67.1]), antiviral use (65.7 % reduction [59.7–70.8]), and healthcare costs (49.1 % [95 %CI, 32.7–61.6]). In contrast, the changes in incidence and healthcare costs for herpes zoster were relatively small, which showed 9.4 % elevated level change with a decreasing trend and 8.7 % reduced level change with a decreasing trend after the vaccine program and the COVID-19 pandemic. The cumulative incidence of herpes zoster in children born after 2014 was lower than that before 2014. Varicella incidence and healthcare resource use were largely affected by the routine immunization program and infection prevention measures against COVID-19, while these impacts on herpes zoster were relatively small. Our study indicates that immunization and infection prevention measures largely changed pediatric infectious disease practices. [ABSTRACT FROM AUTHOR]

Shiga toxin-producing Escherichia coli (STEC) causes hemorrhagic colitis and hemolytic uremic syndrome (STEC-HUS). Understanding its prognostic factors is essential for immediate interventions. We examined early-phase unfavorable prognostic factors among patients with STEC-HUS using a nationwide database. This is a retrospective cohort study to analyze practice patterns and identify prognostic factors among patients with STEC-HUS. We used the Diagnosis Procedure Combination Database, which includes approximately half of the acute-care hospitalized patients in Japan. We enrolled patients who were hospitalized for STEC-HUS from July 2010 to March 2020. The composite unfavorable outcome included in-hospital death, mechanical ventilation, dialysis, and rehabilitation at discharge. Unfavorable prognostic factors were assessed using a multivariable logistic regression model. We included 615 patients with STEC-HUS (median age, 7 years). Of them, 30 (4.9%) patients had acute encephalopathy and 24 (3.9%) died within 3 months of admission. Unfavorable composite outcome was observed in 124 (20.2%) patients. Significant unfavorable prognostic factors were age of 18 years or older, methylprednisolone pulse therapy, antiepileptic drug administration, and respiratory support within 2 days of admission. Patients requiring early steroid pulse therapy, antiepileptic drugs, and respiratory support were considered to be in poor general condition; such patients should receive aggressive intervention to avoid worse outcomes. [ABSTRACT FROM AUTHOR]

Information regarding effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant strains on clinical manifestations and outcomes of coronavirus disease 2019 (COVID-19) in pregnant women is limited. A retrospective observational study was conducted using the data from the nationwide COVID-19 registry in Japan. We identified pregnant patients with symptomatic COVID-19 hospitalized during the study period. The Delta and Omicron variants of concern (VOC) predominant periods were defined as August 1 to December 31, 2021 and January 1 to May 31, 2022, respectively. Clinical characteristics were compared between the patients in the Delta and Omicron VOC periods. In addition, logistic regression analysis was performed to identify risk factors for developing moderate-to-severe COVID-19. During the study period, 310 symptomatic COVID-19 cases of pregnant women were identified; 111 and 199 patients were hospitalized during the Delta and Omicron VOC periods, respectively. Runny nose and sore throat were more common, and fatigue, dysgeusia, and olfactory dysfunction were less common manifestations observed in the Omicron VOC period. In the multivariable logistic regression analysis, onset during the later stage of pregnancy (OR: 2.08 [1.24–3.71]) and onset during the Delta VOC period (OR: 2.25 [1.08–4.90]) were independently associated with moderate-to-severe COVID-19, whereas two doses of SARS-CoV-2 vaccine were protective against developing moderate-to-severe COVID-19 (OR: 0.34 [0.13–0.84]). Clinical manifestations of COVID-19 in pregnant women differed between the Delta and Omicron VOC periods. SARS-CoV-2 vaccination was still effective in preventing severe COVID-19 throughout the Delta and Omicron VOC periods. [ABSTRACT FROM AUTHOR]

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. 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. 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). 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. [ABSTRACT FROM AUTHOR]

The characteristics of pneumococcal isolates and their associations with outcomes in pediatric meningitis are unclear. This study aimed to clarify serotypes and resistance genotypes of Streptococcus pneumoniae from children with meningitis and evaluate the patient prognoses and backgrounds. Large-scale surveillance was conducted from 2002 to 2016 through periods I–V. Serotypes and penicillin (PEN) resistance genotypes were analyzed for pneumococcal isolates (n = 459) and cerebrospinal fluid (CSF) samples (n = 25). Furthermore, underlying diseases (n = 251), prognoses (n = 202), and laboratory data were evaluated. The number of meningitis cases decreased drastically after the introduction of 7-valent pneumococcal conjugate vaccine (PCV7) to −53.6% and after switching to PCV13 to −70.2%. In particular, this reduction was apparent at ≤3 years of age. The proportion of the PCV7 serotype decreased sharply from 70.1% before introduction to 2.6% during period V; however, the non-vaccine type increased from 17.5% to 87.2%. The PEN resistance rate (gPRSP) was decreased from approximately 49% to 12.2% during period V. Among cases revealed prognosis, sequelae and mortality rates were 16.3% and 5.4%, respectively. The rate of the patients with underlying diseases was 26.3% and relatively high in ≥6 years. Laboratory data associated with a poor prognosis were low white blood cell count (<12.7 × 103/μL), low platelet count (<28.1 × 104/μL), low CSF-glucose (<36 mg/dL), and high CSF-protein (≥142 mg/dL). Changes in serotype prevalence warrant continuous monitoring to observe future trends of pneumococcal meningitis, and further developments in multivalent conjugate vaccines are required. [ABSTRACT FROM AUTHOR]

In 2019, the Japanese Society of Chemotherapy and the Japanese Association for Infectious Diseases reported nationwide, cross-sectional questionnaire survey data investigating the clinical status of clinic doctors' attitudes to antimicrobial stewardship. This study aimed to identify factors determining clinic doctors' attitudes concerning antimicrobial prescription for patients with a common cold or bronchitis. In February 2018, 1500 randomly selected community-based medical clinics in Japan were sent a questionnaire. Primary and secondary endpoints were clinic doctors' attitudes concerning antimicrobial prescription, and antimicrobial medication types prescribed for patients with a common cold or bronchitis, respectively. We used multivariable linear regression analysis to identify factors associated with primary and secondary outcomes. We analyzed 269 of 274 responses (response rate, 18.3%). Linear regression analysis was used to identify determinants of proactive attitudes to antimicrobial prescription, including whether clinic doctors encountering patients with upper respiratory symptoms and no underlying illnesses, and diagnosed with a common cold would prescribe antimicrobial medication (β = 0.283, t = 4.279, p = 0.000); whether clinic doctors frequently experienced requests from patients (or their families) with a common cold to prescribe antimicrobial medication (β = 0.389, t = 6.133, p = 0.000), and; clinic doctors' awareness of antimicrobial stewardship in the past year (β = −0.157, t = −2.456, p = 0.015). Determinants of proactive attitudes to prescribing broader-spectrum antimicrobials for patients with a common cold included clinic doctors' attitudes concerning antimicrobial prescription (β = 0.165, t = 2.622, p = 0.009), whether the respondent was a pediatrician (β = −0.288, t = −4.583, p = 0.000), and clinic doctors' attitudes to antimicrobial prescription (β = 0.262, t = 4.075, p = 0.000) for patients with bronchitis. This study identified factors among clinic doctors that determined their attitudes to antimicrobial prescription concerning patients with a common cold or bronchitis. Identification and targeting of clinic doctors who unnecessarily prescribe antimicrobial medication is urgently required to promote antimicrobial stewardship in an outpatient setting. [ABSTRACT FROM AUTHOR]

Streptococcus pneumoniae with a mucoid-type capsule is associated with invasive pneumococcal diseases (IPDs). Despite the introduction of pneumococcal vaccines, IPDs caused by mucoid-type isolates are still prevalent. The present study aimed to characterize mucoid-type S. pneumoniae isolated from IPD patients throughout Japan in 2017 (post-vaccination era). A total of 225 mucoid-type isolates were collected. The serotype, antimicrobial susceptibility, and multilocus sequence type of these isolates were determined. The prevalence of IPDs caused by mucoid-type isolates was high in adults, especially in the elderly (≥65 years of age), and prognosis in these patients was significantly poor. Of the mucoid-type isolates, the predominant serotype was serotype 3 (84.4%), and the remaining were serotypes 37 (15.1%) and 8 (0.4%). Antimicrobial susceptibility showed that most mucoid isolates exhibited the penicillin-intermediate resistant S. pneumoniae genotype (gPISP). However, the serotype 3 isolate exhibited the penicillin-resistant S. pneumoniae genotype (gPRSP). This gPRSP isolate was classified into ST166, which is related to serotypes 9 V and 11 strains. Sequence analysis of the capsule-coding regions and its flanking regions indicated that recombination occurred upstream and downstream of the capsule-coding region, suggesting that gPRSP (serotype 9 V/ST166) obtaining the type-3 capsule gene cluster resulted in the emergence of gPRSP (serotype 3/ST166). Our findings indicated that IPDs caused by mucoid-type S. pneumoniae are still a serious concern and mucoid-type S. pneumoniae with novel phenotype could emerge via capsular switching in response to environmental changes such as introduction of vaccines and improper use of antimicrobial agents. [ABSTRACT FROM AUTHOR]

Because of the overabundance of vaccination information on the internet, in the media, and on social media, providing clear and correct information on immunization is critical for parental decision-making. In 2018, the Japan Pediatric Society created and distributed a Vaccine Information Statement (VIS) to provide appropriate immunization information to caregivers. The objectives of the present study were to evaluate the effect of the VIS on immunization rates, adherence to schedule, and parental understanding of immunization in Japan. This cross-sectional study was conducted at 18 centers in 2 prefectures in Japan. Caregivers were assigned to an intervention group, which received the VIS and a questionnaire when their child reached the age of 1 month, and a control group, which received only the questionnaire. Using the self-reported questionnaires, we evaluated vaccination rates and schedule adherence at age 2 months, and parental knowledge, attitudes, and beliefs regarding immunization. Three months later, the questionnaires were returned, and the findings were compared between the 2 groups. We contacted 422 and 428 persons in the intervention and control groups, respectively, and 111/422 (26.3%) and 119/428 (27.8%) returned the surveys. Vaccination rates and adherence rates for the first dose of 4 recommended vaccines did not differ significantly (P > 0.25); however, there were some positive effects on items related to vaccine knowledge (P = 0.03), perceived benefits (P = 0.02), perceived barriers (P < 0.001), and perceived behavioral control (P = 0.01). The VIS improved parent comprehension of infant immunization. Future studies should examine if the effects of such an intervention persist and affect vaccine uptake throughout childhood. [ABSTRACT FROM AUTHOR]

Japan was ranked as the worst country of 36 high-income countries in terms of oral antibiotic consumptions for children. Knowing the patterns and variations of antibiotic use for pediatric inpatients with uncomplicated respiratory infections is an important step to promote judicious antibiotic use. Discharge records were extracted for children aged between 3 months and 15 years with acute lower respiratory tract infections for the fiscal years 2010–2014 using a national inpatient database in Japan. We investigated the trends in antibiotic use using mixed effect regression models and ascertained variations and clustering of the practice patterns across different hospitals using unsupervised machine learning methodology. A total of 280,298 children were included in the study. Total and broad-spectrum antibiotic use, except for fluoroquinolone, showed decreasing trends from 2010 to 2014. Additionally, the proportions of patients who received no antibiotics or only penicillin increased from 17.1% to 9.9% in 2010 to 24.5% and 13.7% in 2014, respectively. Cluster analysis showed that only one-quarter of hospitals used no antibiotics for 28.8% of children and only penicillin for 53.7% of children. In the remaining clusters of hospitals, the piperacillin, 3rd generation cephalosporins, and penicillin beta-lactamase inhibitors were used for 68.5%, 68.5%, and 69.6% of the patients who received antibiotics. Slightly increasing trends in narrow-spectrum antibiotics were observed. However, the treatment strategy in only one-quarter of hospitals was consistent with the current recommendations. Hospital level interventions to promote and monitor antibiotic use could be helpful to improve antibiotic use for pediatric inpatients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Clinics are high prescribers of antimicrobials in Japan, but the present situation and the attitude of clinic doctors toward prescribing them remain unclear. To investigate the present situation at clinics and clinic doctors' attitude toward antimicrobial stewardship. A questionnaire survey of clinic doctors. A questionnaire targeting doctors was sent to 1500 clinics that were randomly selected from across the country. Among 274 respondents (response rate, 18.3%), 269 provided consent and their responses were analyzed. Awareness of the National Action Plan on Antimicrobial Resistance and the Manual of Antimicrobial Stewardship was low, but awareness of antimicrobial stewardship was high. A certain proportion of doctors prescribed antimicrobials for the common cold and acute bronchitis, and macrolides were the most commonly prescribed group of antimicrobials. Such prescription was not based solely on the doctors' knowledge but was also influenced by complex factors such as the doctor–patient relationship. Various measures such as improving doctor–patient communication and improving clinic doctors' knowledge are necessary to promote antimicrobial stewardship in the outpatient setting. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

To cultivate specialists in pediatric infectious diseases (ID) in Japan, the Japanese Society for Pediatric Infectious Diseases initiated board certification for pediatric ID in 2017. Previously, in 2014, we had formed a committee for board certification in pediatric ID and discussed the fundamentals of the board certification system, including the goals, requirements for designated training institutions, provisional certification of pediatric ID specialists and eligibility for and content of the board certification examination. After approval from 31 programs, the pediatric ID programs started in 2017 with 8 fellows in 7 programs. The first 6 graduates received board certification in 2020. To date, 61 pediatricians have been board certified as pediatric ID specialists. In parallel, we introduced board certification for pediatricians who work mainly in primary care settings and have a special interest in pediatric ID. This system has certified 338 pediatricians. During and after the development of the programs, we achieved substantial progress in highlighting the pivotal role of pediatric ID specialists, including the establishment and maintenance of antimicrobial stewardship programs, pediatric ID consultations and introduction of viral diagnosis by polymerase chain reaction at institutions. However, several issues need to be addressed, including the establishment of independent pediatric ID departments in institutions, payment of consultation fees, program site visits, maintenance of certification and cultivation of physician-scientists. These challenges will be the focus of future efforts., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: COVID-19 has become widespread in Japanese children. However, the impact of varying immunization coverage on the seroprevalence of SARS-CoV-2 in children is unknown., Methods: We examined the SARS-CoV-2 antibody in children aged 0 to 18 who were hospitalized at a university hospital from June 2020 through May 2023. The SARS-CoV-2 anti-nucleoprotein (N) antibody and anti-RBD spike (S) protein antibody was measured., Results: A total of 586 cases were enrolled. The median age was 4 years old (interquartile range 1-9), and 362 (61.8 %) were male. The seroprevalence of anti-S antibodies gradually increased from October 2021 and reached 60 percent by early 2023. The anti-N antibody increased starting in January 2022 and reached 50 percent in May 2023. There was a discrepancy in the seroprevalence of anti-S and N antibodies in children 0 years of age or 12 years and older until the fall of 2022. This discrepancy was minimal for children 1-4 years of age and relatively small in the 5-11-year-old group., Discussion: The data suggests that approximately half of the children in our cohort had been infected with SARS-CoV-2 by May 2023. The discrepancy in seropositivity between the anti-S and N antibodies corresponded to the reported vaccine uptake of each target age group, which suggested protective effects of immunization. However, this effect appeared to diminish after early 2023., Conclusion: Age dependent discrepancy between SARS-CoV-2 anti-N and anti-S antibody in children reflected differences in vaccine coverage., Competing Interests: Declaration of competing interest IM has received honoraria for lectures from; Pfizer, AstraZeneca, Shionogi, Meiji Seika Pharma, Daiichi-sankyo, Biken, Takeda pharmaceuticals, and Sanofi. The other authors have no conflict of interest to declare., (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: The COVID-19 pandemic posed substantial challenges to healthcare systems. Understanding the responses of pediatric health services is crucial for future pandemic planning and preparedness, yet such data remains limited., Methods: In this retrospective cohort study, we analyzed data from administrative databases developed by Japan Medical Data Center and DeSC Healthcare Inc. The dataset comprised records of 2,612,511 children, totaling 60,224,888 person-months, from January 2020 to May 2022. Multivariate generalized estimation equations were used to examine the incidence rates of COVID-19 and associated health resource use., Results: Our analysis revealed that the incidence rates of COVID-19 gradually increased from Wave I (2.2 cases per 100,000 person-months) to Wave V (177.8cases per 100,000 person-months), with a notable elevation during Wave VI (2367.7 cases per 100,000 person-months). While nucleic acid amplification tests were primarily used during Waves I-V, the use of rapid antigen tests markedly increased in Wave VI. The hospitalization rates increased gradually from 0.2 in Wave I to 10.2 events per 100,000 person-months in Wave VI, and the case-hospitalization risk decreased from 14.9% in Wave II to 0.7% in Wave VI. Additionally, we observed decreasing trends in the use of antibiotics (Wave I, 31.8%; Wave VI, 9.0%), whereas antipyretic use rose from Wave I (56.1%) to Wave VI (86.6%)., Conclusions: Our study highlighted essential changes in the nationwide pediatric healthcare system's response to the COVID-19 pandemic. These findings provide valuable insights into the future pandemic planning and preparedness., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article to disclose., (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: Exanthems are a common reason for visits to the pediatric emergency department. However, epidemiological data in the post-measles-rubella vaccine era is limited., Objective: We sought to determine the recent causes of exanthems in children younger than 6 years old in the pediatric emergency department., Methods: A prospective single-center study was conducted in Japan from August 2019 to March 2020. Children younger than 6 years old with exanthems were enrolled. Exanthems were classified into 7 morphological patterns. Varicella, herpes zoster, impetigo, urticaria and Kawasaki disease were diagnosed clinically. Nasopharyngeal swab specimens were collected from patients with nonspecific exanthems and evaluated by polymerase chain reaction (PCR) assays capable of detecting 24 pathogens. The final diagnosis was made by discussion of 3 physicians based on clinical course and microbiology., Results: There were 9705 pediatric visits, of which 296 (3%) had exanthems and were younger than 6 years old. Clinical diagnosis was possible for 160 (54%), including urticaria in 110 (37%), Kawasaki disease in 29 (10%), impetigo in 10 (3%), varicella or herpes zoster in 7 (2%) and group A Streptococcus in 4 (1%). Among the remaining 136 (46%) children, 75 (25%) underwent testing by PCR. One or more pathogens were detected in 49 (65%), specifically enterovirus in 14 (19%), cytomegalovirus in 13 (17%), human herpesvirus type-6 in 12 (16%), adenovirus in 11 (15%) and human herpesvirus type-7 in 8 (11%). Final infectious disease diagnoses were roseola infantum in 11 (15%), enterovirus in 9 (12%), adenovirus in 6 (8%), mixed virus infection in 5 (7%), group A Streptococcus in 3 (4%), parechovirus-A in 3 (4%) and influenza in 3 (4%)., Conclusions: The most common causes of pediatric exanthems were noninfectious diseases and viral exanthema. PCR assay was instrumental for etiological diagnosis of nonspecific exanthems., Competing Interests: All authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The trends in clinical practice patterns and health resource use, as well as risk factors for severe conditions among children hospitalized with coronavirus disease-2019 (COVID-19), remain unclear., Materials and Methods: We conducted a retrospective observational study consisting of 9876 children hospitalized with COVID-19 during 2020-2022 using the Medical Data Vision database in Japan. We investigated trends in patient characteristics, health resource use, treatment patterns and laboratory data. Additionally, log-binomial regression models were used to investigate the risk factors associated with severe COVID-19 among pediatric inpatients with COVID-19., Results: We observed decreasing trends in the lengths of hospital stays, healthcare costs, computed tomography use, and antibiotic use, and increasing trends in treatment with intravenous hydration and use of antipyretics, antiepileptics, antiemetics and antivirals from the first wave to the seventh wave of COVID-19 pandemic. During the 3-year period, the risk of severe COVID-19 was almost stable at 3%. Risk factors associated with severe COVID-19 were children less than 1 year old [risk ratio (RR): 1.69; 95% confidence interval (CI): 1.02-2.78], the number of complex chronic diseases (RR for 1 disease: 4.49; 95% CI: 2.76-7.32; RR for 2 or more diseases: 10.2; 95% CI: 5.19-20.3) and asthma (RR: 1.84; 95% CI: 1.06-3.20)., Conclusions: Our study observed the changes in practice patterns and health resource use for children hospitalized with COVID-19 and identified risk factors associated with severe COVID-19. These findings indicate the importance of vigilant monitoring and tailored treatment strategies in children with these risk factors., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The development of antibiotics that are acceptable and easy for children to take and use is highly desirable. As advocated by the World Health Organization, solid oral formulations with excellent shelf-life, taste masking and dose adjustment are attracting attention as appropriate pediatric oral antimicrobial formulations, but liquid formulations remain the most common worldwide. Apparently unique to Japan, the most common formulations of oral antimicrobials for pediatric use are dispensed as a powder with most being flavored powders. Powdered formulations are packaged in single doses, which eliminates the need for parents to weigh them before administration and may reduce the possibility of dosage errors. On the other hand, there are some formulations that require large doses of powder due to inappropriate concentrations, granular formulations that have a rough texture that affects palatability, and some formulations that require flavoring agents to mask the bitter taste of the main drug. Such inappropriate formulations have a significant impact on adherence to antimicrobial therapy. It remains unclear whether solid oral dosage forms might be as acceptable worldwide as in Japan. To ensure that appropriate antimicrobials are delivered to children worldwide, a direction for the development of appropriate dosage forms in children needs to be established., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: To determine the epidemiological trends in pediatric influenza and changes in healthcare resource use from 2005 to 2021 using nationally representative outpatient database in Japan., Methods: We conducted a retrospective cohort study consisting of 3.5 million children with 177 million person-months during 2005-2021 using Japan Medical Data Center claims database in Japan. We investigated trends in incidence rates of influenza and changes in healthcare resource use (eg, use of antivirals) over 17 years. Generalized estimation equations were used to investigate the impact of the 2009 influenza pandemic and the coronaviral disease 2019 (COVID-19) pandemic on incidence rates of influenza and related healthcare utilization., Results: Annual incidence rates of influenza were estimated at 55 cases per 1000 person-years with a 93% relative increase [95% confidence interval (CI): 80%-107%] during the 2009 influenza pandemic and a 99.4% relative reduction (95% CI: 99.3%-99.4%) during the COVID-19 pandemic. Similar patterns were observed for health resource use, total healthcare costs, admission rates and antiviral agent use. Approximately 80% of children with influenza received prescriptions for antivirals. The most prescribed antivirals were oseltamivir, but we observed a temporal increase in zanamivir use during 2007-2009, an increasing trend in laminamivir use during 2010-2017, a temporal increase in baloxavir use in 2018. Symptomatic medications with serious side effects (codeine, salicylate, sedative antihistamine) showed decreasing trends over the study period., Conclusions: Influenza incidence and healthcare resource use were largely affected by the 2009 influenza pandemic and the COVID-19 pandemic. Our study indicates improvement of quality in healthcare delivered to children., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The clinical features of coronavirus disease 2019 (COVID-19) in children have been changing because of the emergence and rapid spread of variants of concern (VOC). The increase in cases infected with VOC has brought concern with persistent symptoms after COVID-19 in children. This survey aimed to analyze the clinical manifestations and persistent symptoms of pediatric COVID-19 cases in Japan., Methods: We analyzed the clinical manifestations of pediatric COVID-19 cases reported between February 2020 and April 2022 in Japan, using a dedicated database updated voluntarily by the members of the Japan Pediatric Society. Using the same database, we also analyzed persistent symptoms after COVID-19 in children who were diagnosed between February 2020 and November 2021., Results: A total of 5411 and 1697 pediatric COVID-19 cases were included for analyzing clinical manifestations and persistent symptoms, respectively. During the Omicron variant predominant period, the percentage of patients with seizures increased to 13.4% and 7.4% in patient groups 1-4 and 5-11 years of age, respectively, compared with the pre-Delta (1.3%, 0.4%) or Delta period (3.1%, 0.0%). Persistent and present symptoms after 28 days of COVID-19 onset were reported in 55 (3.2%)., Conclusions: Our survey showed that the rate of symptomatic pediatric COVID-19 cases increased gradually, especially during the Omicron variant predominant period, and a certain percentage of pediatric cases had persistent symptoms. Certain percentages of pediatric COVID-19 patients had severe complications or prolonged symptoms. Further studies are needed to follow such patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Infectious diseases after transplantation account for significant morbidity and mortality in children undergoing transplantation; the importance of pediatric transplant infectious disease (TID) specialists has therefore been recognized. Although tremendous advancement continues in transplantation medicine, pediatric-specific data and evidence are limited. In Japan, the majority of TIDs had not been managed by infectious disease specialists because pediatric infectious diseases have not been recognized as a solo subspecialty until recently in Japan. However, in the last decade, there was a new movement for pediatric TID in Japan; some pediatric infectious disease specialists trained outside Japan have been playing an important role in managing pediatric TID in a few academic and pediatric institutions. In this review article, we introduce the current status of infectious complications related to pediatric hematopoietic cell and solid organ transplantation, highlighting currently available local evidence, common practice and issues in the field of pediatric TID in Japan., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Pharmacologic knowledge is important for pediatricians conducting feasible pharmacokinetic or pharmacodynamic (PK/PD) studies or applying effective antimicrobial therapies in children. Because of the difficulties in conducting PK/PD studies in children, antimicrobial PK/PD data in children are still limited. To fill in the lack of knowledge, promotion of population PK/PD analysis, which allows us to handle sparse sampling data from individual patients, is important because it is considered a suitable methodology to conduct PK/PD studies in children with limited blood drug concentration data for PK/PD analysis. Population PK/PD analysis is also useful in the clinical setting to provide individualized optimal dosage for each patient with various conditions. Here we summarized the current aspects of pediatric PK/PD studies of antimicrobials in Japan from clinical and research perspectives, specifically focusing on the importance of population PK/PD analysis., Competing Interests: K.S. received payment for lectures from Mitsubishi Tanabe Pharma, Astellas, AbbVie GK, and G.H.N. received grants from the Japan Agency for Medical Research and Development, consulting fees from Taisho Pharmaceutical Co., Ltd., Sato Pharmaceutical Co., Ltd., Nippon Zoki Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Japan Inc., Eli Lilly Japan K.K. and Astra Zeneca K.K., and payment for lectures from Shionogi & Co., Ltd. and Chugai Pharmaceutical Co., Ltd. K.M. received grant support from Meiji Seika Pharma Co., Ltd. and Sumitomo Pharma Co., Ltd. and payment for lectures from Meiji Seika Pharma Co., Ltd. Y.T. received grant support from Shionogi & Co., Ltd. and payment for lectures from Astellas Pharma Inc. and MSD Japan. I.M. received payment for lectures and consultations from Sanofi, Takeda Pharmaceuticals, Astellas Pharma Inc., Janssen Pharmaceuticals, Fujifilm Toyama Chemical Co., Biomelieux Japan, Abbott Japan Co. and AbbVie GK. The other authors have have no conflicts of interest to disclose. This work was supported by the Japan Society for the Promotion of Science KAKENHI (grant no. 21K16332)., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Antimicrobial resistance (AMR) is a threat to patient health. However, data to optimize antimicrobial use are limited. Furthermore, reducing antibiotic use raises concerns regarding patient safety. The effectiveness of antibiotics in reducing the prevalence of AMR is controversial. Researchers at the Japanese Red Cross Ishinomaki Hospital (JRCIH), the only tertiary care hospital in the medical zone, along with local medical and pharmacy associations and public health centers have been leading the AMR control program since 2018. The program involves lectures aimed at optimizing antimicrobial use, regular publication of surveillance data of drug-resistant strains at the JRCIH, and presentation of first-line treatments for community-acquired infections. The delivery of oral antimicrobial agents across the region in 2020 was 28.7% lower than that in 2013, with delivery of cephalosporins, quinolones, and macrolides decreasing by 34.8%, 46.8%, and 56.0%, respectively. Despite these reductions, there has been no associated increase in the number of patients with severe infectious diseases admitted to the JRCIH. The rates of representative drug-resistant bacterial strains, such as extended-spectrum beta-lactamase-producing Escherichia coli and methicillin-resistant Staphylococcus aureus, decreased by half. Herein, we demonstrated the potential of collaborative efforts to optimize antimicrobial agent use and reduce the AMR prevalence without compromising patient safety.

We describe a domestic case of retropharyngeal abscess (RPA) in a child caused by a community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) isolate that was genetically proven to be the USA300 clone (sequence type [ST]8-SCCmec IVa-Panton-Valentine leukocidin [PVL]). USA300 generally has a PVL gene, an epidemiologic association with severe and recurrent skin and soft tissue infection, and is the leading cause of RPA in the United States. A 1-year-old previously healthy girl visited the emergency department with fever, sore throat, and a difficulty in moving her neck. The patient had no recent medical exposure or history of travel abroad. Enhanced computed tomography revealed a bulky low-density area with ring enhancement in the retropharyngeal and right parapharyngeal spaces. MRSA was isolated from pus obtained from surgical drainage, and antibiotics were continued for a total of 21 days. MRSA was analyzed by whole genome sequencing and compared with representative USA300 isolates. The strain was typed as ST8-t9829-SCCmec IVa with PVL and arginine catabolic mobile element, and its sequence was 99.8% identical to USA300 isolates. The present case supports the possibility that USA300 is potentially spreading in the Japanese community and raises the possibility of USA300 invasive infections without a clear route of infection.

Background: The role of antibiotics in the treatment of Shiga toxin-producing Escherichia coli (STEC) infection is controversial., Objectives: To evaluate the association between treatment (antibiotics, antidiarrheal agents, and probiotics) for STEC infection and hemolytic uremic syndrome (HUS) development., Patients and Methods: We performed a population-based matched case-control study using the data from the National Epidemiological Surveillance of Infectious Diseases (NESID) between January 1, 2017 and December 31, 2018. We identified all patients with STEC infection and HUS as cases and matched patients with STEC infection without HUS as controls, with a case-control a ratio of 1:5. Further medical information was obtained by a standardized questionnaire. Multivariable conditional logistic regression model was used., Results: 7760 patients with STEC infection were registered in the NESID. 182 patients with HUS and 910 matched controls without HUS were selected. 90 patients with HUS (68 children and 22 adults) and 371 patients without HUS (266 children and 105 adults) were included in the main analysis. The matched ORs of any antibiotics and fosfomycin for HUS in children were 0.56 (95% CI 0.32-0.98), 0.58 (0.34-1.01). The matched ORs for HUS were 2.07 (1.07-4.03), 0.86 (0.46-1.61) in all ages treated with antidiarrheal agent and probiotics., Conclusions: Antibiotics, especially fosfomycin, may prevent the development of HUS in children, while use of antidiarrheal agents should be avoided., Competing Interests: The authors have declared that no competing interests exist.

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: The COVID-19 pandemic has affected the lives of people of all ages. Most reports on pediatric cases suggest that children experience fewer and milder symptoms than do adults. This is the first nationwide study in Japan focusing on pediatric cases reported by pediatricians, including cases with no or mild symptoms., Methods: We analyzed the epidemiological and clinical characteristics and transmission patterns of 840 pediatric (<16 years old) COVID-19 cases reported between February and December 2020 in Japan, using a dedicated database which was maintained voluntarily by members of the Japan Pediatric Society., Results: Almost half of the patients (47.7%) were asymptomatic, while most of the others presented mild symptoms. At the time of admission or first outpatient clinic visit, 84.0% of the cases were afebrile (<37.5°C). In total, 609 cases (72.5%) were exposed to COVID-19-positive household members. We analyzed the influence of nationwide school closures that were introduced in March 2020 on COVID-19 transmission routes among children in Japan. Transmission within households occurred most frequently, with no significant difference between the periods before and after declaring nationwide school closures (70.9% and 74.5%, respectively)., Conclusions: COVID-19 symptoms in children are less severe than those in adults. School closure appeared to have a limited effect on transmission. Controlling household transmission from adult family members is the most important measure for prevention of COVID-19 among children., (© 2021 Japan Pediatric Society.)

Recent guidelines suggest that LAVs may be given to LT recipients meeting certain criteria. However, information is still limited. We sought to evaluate the safety of LAVs, including measles, mumps, rubella, and varicella to LT recipients following our clinically based immunization protocol for LT recipients. We conducted a case-series analysis on safety of LAVs for measles, rubella, varicella, and mumps given to LT recipients at our institution from July 2010 to July 2019. Patients who underwent LT at age <20 years who visited our immunization clinic were included. LT recipients were vaccinated if 2 years had lapsed from LT, had no signs of rejection within 6 months, and were on minimal immunosuppressants. Patient demographics, underlying diseases, type and number of vaccines administered, date of vaccination, and adverse events occurring within 4 weeks after vaccination were extracted from their medical records. During the study period, LAVs were administered 422 times to 209 patients who met criteria and included 225 doses of MR combination vaccine, 224 doses of varicella vaccine, and 215 doses of mumps vaccine. Underlying diseases included cholestatic liver diseases (n = 125), followed by metabolic diseases (n = 33) and acute liver failure (n = 19). Nine non-critical adverse events (2.1%) possibly associated with LAVs were reported, but there were no serious adverse events, including hospitalizations or deaths. In conclusion, LAVs administered to LT recipients were safe without any serious adverse events following our relatively simple institutional protocol., (© 2020 Wiley Periodicals LLC.)

We report a fatal case of hemolytic uremic syndrome with urinary tract infection in Japan caused by Shiga toxin-producing Escherichia coli. We genotypically identified the isolate as OX18:H2. Whole-genome sequencing revealed 3 potentially pathogenic lineages (OX18:H2, H19, and H34) that have been continuously isolated in Japan.

Competing Interests: The authors declare no funding or conflicts of interest.

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.

Bordetella pertussis (B. pertussis) infection occasionally causes severe respiratory infections in children. Potential association between virulence-associated gene alleles and severe clinical outcomes has been suggested; however, frequencies of these alleles in pediatric patients with severe pertussis have not been clarified. We retrospectively tested stored respiratory samples collected from B. pertussis-positive patients by polymerase chain reaction targeting for major virulence-associated genes; fimbrae (fim) serotype 3 (fim3), pertactin (prn), pertussis toxin A (ptxA), and pertussis toxin promotor (ptxP). Based on the identified sequences, multilocus sequence typing (MLST) was conducted. Association of gene allele frequency and clinical outcomes such as management in pediatric intensive care unit, intubation, and mortality was analyzed. Out of 25 patients with available samples, the most prevalent allele for each virulence-associated gene was fim3A (17/21, 83%), ptxA1 (20/23, 87%), prn2 (13/16, 81%), and ptxP3 (14/17, 82%). In the study, total of 3 MLST types were identified; MLST-1 from 3 patients (19%), MLST-2 from 10 patients (63%), and MLST-4 from 3 patients (19%). Detection rate of the major MLST type; MLST-2 was significantly higher for patients who required intubation compared to those who did not (6/6, 100% vs 4/10, 40%; p = 0.034). In conclusion, MLST-2 was the most common MLST type in B. pertussis isolated from Japanese children with severe pertussis. Further studies investigating its causal association with disease severity is warranted., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Our infection control team initiated active screening for multidrug-resistant organisms (MDROs) among children who had been hospitalized abroad before their admission to our hospital. MDROs were detected in 19 of 34 cases (56%), including 3 isolates of Enterobacteriaceae harboring carbapenemase genes still rare in Japan. Early recognition of MDROs by screening this population may be required to avoid the introduction of new modes of resistance into the hospital environment., (Copyright © 2019 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)