Validation and development of population pharmacokinetic model of vancomycin using a real-world database from a nationwide free web application.

INTRODUCTION: Vancomycin requires a population pharmacokinetic (popPK) model to estimate the area under the concentration-time curve (AUC), and an AUC-guided dosing strategy is necessary. This study aimed to develop a popPK model for vancomycin using a real-world database pooled from a nationwide web application (PAT). METHODS: In this retrospective study, the PAT database between December 14, 2022 and April 6, 2023 was used to develop a popPK model. The model was validated and compared with six existing models based on the predictive performance of datasets from another PAT database and the Kumamoto University Hospital. The developed model determined the dosing strategy for achieving the target AUC. RESULTS: The modeling populations consisted of 7146 (13,372 concentrations from the PAT database), 3805 (7540 concentrations from the PAT database), and 783 (1775 concentrations from Kumamoto University Hospital) individuals. A two-compartment popPK model was developed that incorporated creatinine clearance as a covariate for clearance and body weight for central and peripheral volumes of distribution. The validation demonstrated that the popPK model exhibited the smallest mean absolute prediction error of 5.07, outperforming others (ranging from 5.10 to 5.83). The dosing strategies suggested a first dose of 30 mg/kg and maintenance doses adjusted for kidney function and age. CONCLUSIONS: This study demonstrated the updating of PAT through the validation and development of a popPK model using a vast amount of data collected from anonymous PAT users.

Characteristics of urinary tract infections in children with positive urine culture for Aerococcusurinae.

Urinary tract infections caused by Aerococcus urinae have rarely been reported in children, and the clinical characteristics remain unclear. We reviewed medical records of children whose urine cultures grew A. urinae (≥104 CFU/mL) at a tertiary children's hospital in Tokyo, Japan. We found 17 pediatric patients in a review of 22,769 urine cultures between June 2006 and May 2022. The median age of 17 patients was 10.7 years (IQR 8-13 years), and males represented 76.5 % of the patients. Sixteen patients (94.1 %) had underlying urological conditions (neurogenic bladder, vesicoureteral reflux, urethral stenosis, bladder exstrophy, or urinary catheterization). The chief symptoms were fever (35.3 %), malodorous urine (23.5 %), nausea (11.8 %), and back pain (5.9 %). Ten patients were asymptomatic. Pyelonephritis was diagnosed in five male patients. All of them had underlying abnormal conditions of the bladder, and two had malodorous urine. All patients had favorable outcomes after 10-14 days of ampicillin/amoxicillin-based antimicrobial therapy.

Pharmacogenetic implementation for CYP2C19 and pharmacokinetics of voriconazole in children with malignancy or inborn errors of immunity.

BACKGROUND: Voriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19; however, such information is limited for the pediatric population. The primary aim of this study is to establish a voriconazole PK model incorporating CYP2C19 phenotypes in Japanese children with malignancy or inborn errors of immunity. METHODS: CYP2C19 genotypes were assessed by whole-genome genotyping and defined as follows: *17/*17: ultrarapid metabolizer (URM), *1/*17: rapid metabolizer (RM), *1/*1:normal metabolizer (NM), *1/*2, *1/*3, *2/*17:intermediate metabolizer (IM), and *2/*2, *2/*3, *3/*3: poor metabolizer (PM). Population PK analysis was performed. The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination. RESULTS: Voriconazole concentration data were available from 60 patients with a median age of 5.3 years. The phenotypes predicted from CYP2C19 genotypes were RM in 1 (2 %), NM in 21 (35 %) patients, IM in 27 (45 %) patients, and PM in 11 (18 %) patients. Underlying diseases included 38 (63%) patients with hematological malignancy and 18 (30 %) patients with inborn errors of immunity. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of Vmax inhibition [Vmax, inh] = 100 %; Vmax = 0). The estimated parameters of Vmax,inh were +0.8 higher in patients with gamma-glutamyl transpeptidase (γ-GTP) Grade 2 or higher and +2.7 higher when C-reactive protein (CRP) levels were 2.0 mg/dL or higher. CONCLUSION: CYP2C19 genetic polymorphisms, γ-GTP, and CRP affect Vmax,inh of voriconazole in children with malignancy or inborn errors of immunity.

Two Cases of Children With Black Hairy Tongue and Tooth Discoloration Caused by Antibacterial Agents.

Black hairy tongue (BHT) is a lesion in which the filiform papillae of the tongue are significantly extended by hyperkeratosis, thereby giving the tongue a hairy appearance. Here, we report two rare cases of children with BHT and tooth discoloration caused by antimicrobial agents. Case 1: A four-year-old female patient received intravenous linezolid after spinal surgery, and BHT developed on day eight of treatment. Subsequently, the patient developed teeth discoloration. Linezolid was continually administered for 50 days, and BHT and teeth discoloration improved 10 days after the end of linezolid treatment. Case 2: A two-year-old male patient with a brain abscess received intravenous meropenem and vancomycin. On the fourth day of treatment, BHT developed, and teeth discoloration was subsequently observed. Antibiotic therapy was continued for 82 days, and BHT and tooth discoloration improved 20 days after the treatment was discontinued.

Launch of Board Certification in Pediatric Infectious Diseases in Japan.

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.

Safety and antibody response of the BNT162b2 SARS-CoV-2 vaccine in children aged 5-11 years with underlying diseases: A prospective observational study.

BACKGROUND: Data on the safety and antibody response of the BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine in children aged 5-11 years with underlying diseases are limited. Thus, our study aimed to address this gap. METHODS: This prospective observational study investigated the antibody titers for SARS-CoV-2 spike protein receptor-binding domain (S-IgG) and nucleocapsid protein (N-IgG) in patients aged 5-11 years with chronic underlying diseases following two doses of BNT162b2. Additionally, a questionnaire was used to assess adverse events (AEs) arising within 7 days after each dose. Data on severe AEs arising within 28 days after each dose were extracted from the patients' electronic medical records. RESULTS: Among 122 patients, 24.6% (30/122) were immunocompromised. Furthermore, 79 patients experienced at least one AE following vaccination, but all recovered without sequelae, including one severe case after the first dose. The seropositivity rate after the second dose was 99.1% (116/117). Excluding 19 N-IgG-positive patients, the geometric mean antibody titer (GMT) was significantly higher in immunocompetent patients than in immunocompromised patients (1496 U/mL [95% confidence interval 1199-1862] vs. 472 U/mL [200-1119], p = 0.035). Additionally, the GMT of S-IgG was higher in N-IgG-positive patients than in N-IgG-negative patients (8203 [5847-11482] U/mL vs. 1127 [855-1486] U/mL, p < 0.001). CONCLUSIONS: BNT162b2 is acceptably safe and immunogenic for children aged 5-11 years with underlying diseases. Although seroconversion was satisfactory in immunocompromised patients, the titers were lower than in immunocompetent patients.

Melting temperature mapping method in children: Rapid identification of pathogenic microbes.

INTRODUCTION: The melting temperature (Tm) mapping method (TM) identifies bacterial species by intrinsic patterns of Tm 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. REGISTERING CLINICAL TRIALS: UMIN000041359https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000047220.

Association between use of antipyretics and antibody titers after two doses of the BNT162b2 SARS-CoV-2 vaccine in adolescents and young adults with underlying diseases.

There are few reports on the association between antipyretic use and antibody titers in adolescents and young adults following SARS-CoV-2 vaccination. Multivariable linear regression analyses were performed to examine the association between antipyretic use and antibody titers. The use of antipyretics was not associated with antibody titers (ß coefficient [95% CI] = -0.107 [-0.438 to 0.224]).

[ANTIMICROBIAL ALLERGY ASSESSMENT DURING PREGNANCY FOR APPROPRIATE ANTIMICROBIAL USE AT DELIVERY].

BACKGROUND: Avoidance of suspect drugs based solely on a history of drug allergy is detrimental to disease outcomes. Many antimicrobial allergy labels are not usually true allergy. Some studies have demonstrated that antimicrobial allergy assessments can be safely performed on pregnant women. The purpose of this study was to examine the usefulness of antibiotic allergy assessment during pregnancy in Japan. METHODS: We reviewed pregnant women who reported antimicrobial allergies and were referred to the allergy center. Allergists conducted an interview and skin test and selected antibiotics that could be used at delivery. RESULTS: Twenty-four pregnant women were referred to as having antimicrobial allergies. Most of the suspected antimicrobials were cephalosporin (13 cases, 52%) and penicillin (9 cases, 36%). Five women were ruled out only by our interviews. Of the remaining 20 cases, 10 were immediate type, 6 were non-immediate type, and 4 were unknown. All 21 pregnant women who needed antimicrobials were able to use the first-line drugs (ß-lactam antimicrobials) at the time of delivery. No surgical site infections or allergic reactions were observed. CONCLUSION: Pregnant women with antimicrobial allergy labels could be evaluated by antimicrobial allergy assessment during pregnancy, and first-line antimicrobials were safely and properly used at delivery.

Clinical and Laboratory Diagnosis of Exanthems Among Japanese Children Younger Than 6 Years Old in the Post-Measles-Rubella Vaccine Era.

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.

No Additional Risk of Ampicillin Rash Among Pediatric Liver Transplant Recipients With Concurrent Epstein-Barr Virus Infection.

BACKGROUND: Epstein-Barr virus (EBV) infection frequently develops in children undergoing liver transplantation (LT) because of mandated immunosuppressive therapy. There is a risk of ampicillin rash when penicillin derivatives are used in patients with EBV-associated infectious mononucleosis. Hence, the administration of penicillin derivatives may raise concerns about ampicillin rash in patients with high EBV loads. However, no studies confirmed the risk of administering penicillin derivatives to EBV-infected children after LT. METHODS: This retrospective study was conducted at the largest pediatric transplantation center in Japan. We investigated all pediatric liver transplant recipients who received penicillin derivatives within 2 years of LT between 2014 and 2020. We separated the cohort into EBV-positive and EBV-negative groups to assess the frequency of ampicillin and antibiotic-associated rash. RESULTS: Two hundred eighty-six liver transplant recipients were enrolled. There were 111 recipients in the EBV-positive group and 175 recipients in the EBV-negative group. In the EBV-positive group, 49 patients had high EBV DNA loads (≥1000 copies/µg DNA). None of the patients in either group developed ampicillin rash, and the frequency of antibiotic-associated rash did not differ [8/111 (7.2%) vs. 10/175 (5.7%), P = 0.797]. Additional subgroup analysis revealed no difference in the frequency of antibiotic-associated rashes regardless of the presence or absence of high EBV loads. CONCLUSIONS: In this study, ampicillin rash was not observed, and antibiotic-associated rash was not associated with concurrent EBV infection. Penicillin derivatives can be used safely, even in liver transplant recipients with persistent asymptomatic EBV infection.

Drug Formulation for Pediatric Oral Antimicrobial Agents in Japan: Current Status, Prospects, and Challenges.

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.

Clinical efficacy of remdesivir for COVID-19 in children: A propensity-score-matched analysis.

Clinical efficacy of remdesivir in children with COVID-19 is unclear. This propensity-score-matched retrospective cohort study of children with COVID-19 showed that the rate of patients achieving defervescence on Day 4 was higher in the remdesivir group than in the non-remdesivir group, but was not statistically different (86.7% vs 73.3%, P = 0.333).

The Utility of Performing Anaerobic Blood Cultures in Pediatric Intensive Care Units.

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.

Necrotizing fasciitis following rapidly deteriorating neonatal omphalitis with good initial presentation.

Neonatal omphalitis is a postpartum infection of periumbilical superficial soft tissues that usually has a good prognosis in developed countries. In rare cases, it could progress to periumbilical necrotizing fasciitis (NF), which is an infection of the deep soft tissues, including muscle fascia, and has a high mortality rate. However, the signs and timing of developing NF secondary to omphalitis are unclear. We encountered a neonatal case of NF following omphalitis. In the initial days of the clinical course, general symptoms and condition of the patient were good, and abdominal physical findings were mild; however, the patient rapidly developed NF. The patient was successfully treated by emergent surgical debridement, broad-spectrum antibiotics, and intensive care. To determine the area of blood perfusion, we intravenously injected indocyanine green by intraoperative angiography, and then extensively removed necrotic and hypoperfused tissues. In neonatal omphalitis, the deterioration can suddenly occur despite good initial conditions; intensive monitoring should be required during the first few days of the clinical course.

Prognostic factors among patients with Shiga toxin-producing Escherichia coli hemolytic uremic syndrome: A retrospective cohort study using a nationwide inpatient database in Japan.

INTRODUCTION: 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. MATERIAL AND METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Etiology of Severe Acute Hepatitis in a Pediatric Transplant Center in Japan.

The proportion of pediatric cases with severe acute hepatitis of unknown etiology in the coronavirus disease 2019 era was higher than that in the pre-coronavirus disease 2019 era in Japan's largest pediatric transplant center. Further research and monitoring are essential.

Acute and Postacute Clinical Characteristics of Coronavirus Disease 2019 in Children in Japan.

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.

Prescribed daily-dose-based metrics of oral antibiotic use for hospitalized children in Japan.

Objective: Defined daily-dose (DDD)-based metrics are frequently used to measure antibiotic consumption. However, they are unsuitable for the pediatric population because they are defined using the maintenance dose for 70-kg adults. Moreover, children have large body weight variations. We assessed the prescribed daily dose (PDD) and PDD-based metrics of oral antibiotics for children to develop an alternative to DDD-based metrics in Japan. Design: We performed observational study using data from the Japanese administrative claims database between April 2018 and March 2019. Methods: Of 453,001 patients (aged 1 month-15 years), 564,326 admissions to 1,159 hospitals were included. We showed the median PDD (mg/day and mg/kg/day) and PDD-based metrics for 8 antibiotics for each age category (1 month to <1 year old and 1-6, 7-12, and 13-15 years old). We also assessed the relationship between PDD-based metrics and days of therapy (DOT)-based metrics using a scatter plot and correlation. Results: In total, 86,389 patients (19.1%) were prescribed oral antibiotics; amoxicillin, macrolides, and third-generation cephalosporins were the most common. The PDD (mg/day) for each antibiotic increased with age to 7-12 years old, when an adult dose was reached. The PDD (mg/kg/day) decreased with age to 13-15 years old, due to increasing body weight. The relationship between PDD per 1,000 patient days and DOT per 1,000 patient days differed depending on the antibiotic. Conclusions: PDD-based metrics stratified by age could characterize antibiotic consumption, even with body-weight variations. Therefore, PDD-based metrics, in addition to DOT-based metrics, are helpful benchmarks for antibiotic use in children.