Trend in antibiotic prescription at pediatric primary emergency medical centers in Japan: A multi-center, cross-sectional study.

INTRODUCTION: Antimicrobial resistance is a global issue, and implementation of antimicrobial stewardship programs in outpatient settings is crucial. Japan has also focused on outpatient oral antimicrobial stewardship programs and difficulties in standardizing prescriptions have led to overprescription in primary emergency medical centers. There is a lack of research investigating the antibiotic prescription status of pediatric primary emergency medical centers and the benchmark prescription rates in pediatric outpatient settings. METHODS: We conducted a multi-center, cross-sectional study of seven pediatric primary emergency medical centers located in five prefectures of Japan. We retrospectively extracted data from health claims or directly obtained them from charts at each institution and evaluated trends in the antibiotic prescription rate based on the AWaRe classification between April 2016 and December 2019. RESULTS: Our study included 383,525 encounters, with the most common infectious disease diagnosis being acute upper respiratory tract infection in 93,449 cases (24.4 %). The antibiotic prescription rate during the study period was 7.4 %, representing a decrease of 46 %, from 10.2 % in 2016 to 5.5 % in 2019. The percentage of prescriptions in the Access group increased at all institutions; however, it exceeded 60 % in only three facilities in 2019. The percentage of third-generation cephalosporins varied among facilities, ranging from 1.7 % to 59.4 %, as of 2019. CONCLUSIONS: For pediatric primary emergency medical centers where antimicrobial stewardship programs are implemented, we suggest 5 % as a reasonable benchmark level for the antibiotic prescription rate. Prescribing the antibiotics in the Access groups less frequently remains a domestic challenge in Japan.

Isolated Chronic Mucocutaneous Candidiasis due to a Novel Duplication Variant of IL17RC.

PURPOSE: Inborn errors of the IL-17A/F-responsive pathway lead to chronic mucocutaneous candidiasis (CMC) as a predominant clinical phenotype, without other significant clinical manifestations apart from mucocutaneous staphylococcal diseases. Among inborn errors affecting IL-17-dependent immunity, autosomal recessive (AR) IL-17RC deficiency is a rare disease with only three kindreds described to date. The lack of an in vitro functional evaluation system of IL17RC variants renders its diagnosis difficult. We sought to characterize a 7-year-old Japanese girl with CMC carrying a novel homozygous duplication variant of IL17RC and establish a simple in vitro system to evaluate the impact of this variant. METHODS: Flow cytometry, qPCR, RNA-sequencing, and immunoblotting were conducted, and an IL17RC-knockout cell line was established for functional evaluation. RESULTS: The patient presented with oral and mucocutaneous candidiasis without staphylococcal diseases since the age of 3 months. Genetic analysis showed that the novel duplication variant (Chr3: 9,971,476-9,971,606 dup (+131bp)) involving exon 13 of IL17RC results in a premature stop codon (p.D457Afs*16 or p.D457Afs*17). Our functional evaluation system revealed this duplication to be loss-of-function and enabled discrimination between loss-of-function and neutral IL17RC variants. The lack of response to IL-17A by the patient's SV40-immortalized fibroblasts was restored by introducing WT-IL17RC, suggesting that the genotype identified is responsible for her clinical phenotype. CONCLUSIONS: The clinical and cellular phenotype of the current case of AR IL-17RC deficiency supports a previous report on this rare disorder. Our newly established evaluation system will be useful for the diagnosis of AR IL-17RC deficiency, providing accurate validation of unknown IL17RC variants.

Isolated chronic mucocutaneous candidiasis due to a novel duplication variant of IL17RC.

Purpose: Inborn errors of the IL-17A/F-responsive pathway lead to chronic mucocutaneous candidiasis (CMC) as a predominant clinical phenotype, without other significant clinical manifestations apart from mucocutaneous staphylococcal diseases. Amongst inborn errors affecting IL-17-dependent immunity, autosomal recessive (AR) IL-17RC deficiency is a rare disease with only three kindreds described to date. The lack of an in vitro functional evaluation system of IL17RC variants renders its diagnosis difficult. We sought to characterize a seven-year-old Japanese girl with CMC carrying a novel homozygous duplication variant of IL17RC and establish a simple in vitro system to evaluate the impact of this variant. Methods: Flow cytometry, qPCR, RNA-sequencing, and immunoblotting were conducted, and an IL17RC-knockout cell line was established for functional evaluation. Results: The patient presented with oral and mucocutaneous candidiasis without staphylococcal diseases since the age of three months. Genetic analysis showed that the novel duplication variant (Chr3: 9,971,476-9,971,606 dup (+ 131bp)) involving exon 13 of IL17RC results in a premature stop codon (p.D457Afs*16 or p.D457Afs*17). Our functional evaluation system revealed this duplication to be loss-of-function and enabled discrimination between loss-of-function and neutral IL17RC variants. The lack of response to IL-17A by the patient's SV40-immortalized fibroblasts was restored by introducing WT-IL17RC, suggesting that the genotype identified is responsible for her clinical phenotype. Conclusions: The clinical and cellular phenotype of the current case of AR IL-17RC deficiency supports a previous report on this rare disorder. Our newly established evaluation system will be useful for diagnosis of AR IL-17RC deficiency, providing accurate validation of unknown IL17RC variants.

Two cases of bacterial meningitis due to meropenem-resistant Streptococcus pneumoniae: A threat of serotype 35B, ST 558 lineage.

Although the pneumococcal conjugate vaccine (PCV) has decreased the incidence of invasive pneumococcal disease (IPD) in children, cases of IPD caused by non-PCV serotypes have been increasing. Here, we report two cases of bacterial meningitis caused by meropenem-resistant Streptococcus pneumoniae; in both the cases, 13-valent PCV (PCV13) had been administered. The isolated S. pneumoniae strains were non-PCV13 serotype 35B and resistant to penicillin G, cefotaxime, and meropenem. In addition, multilocus sequence typing (MLST) revealed the sequence type (ST) to be 558. In case 1, a 6-month-old girl recovered without sequelae after antibiotic therapy comprising cefotaxime and vancomycin, whereas in case 2, a 9-month-old boy was treated with an empirical treatment comprising ceftriaxone and vancomycin administration. However, maintaining the blood concentration of vancomycin within the effective range was difficult, due to which the antibiotics were changed to panipenem/betamipron. During the treatment, he presented with seizures, which were effectively controlled with antiepileptic drugs. The rate of incidence of penicillin-susceptible IPD has been substantially increasing after the introduction of PCV. However, an upsurge in IPD cases due to multidrug-resistant (MDR) serotype 35B has been reported in countries where PCV13 was introduced before introducing in Japan. Moreover, an increase in the proportion of MDR serotype 35B and decrease in the susceptibility to broad-spectrum antimicrobials, including meropenem, have been reported. Hence, the number of meningitis cases caused by MDR serotype 35B/ST558 may increase in the future.

Trends in varicella and mumps vaccination rates in children under 3 years of age in a tertiary children's hospital in Japan.

BACKGROUND: In Japan, the voluntary vaccination rate is not known accurately. Although two doses of the measles and rubella vaccines have been part of the universal vaccine program since 2006, the varicella vaccine was added in October 2014 while the mumps vaccine still remains voluntary. The aim of this study was to evaluate trends in the live measles, rubella, varicella and mumps vaccination rates in Japan. METHODS: This retrospective cohort study was conducted at Tokyo Metropolitan Children's Medical Center between October 2012 and December 2016. Patients aged 1-2 years who were admitted to the Department of General Pediatrics were enrolled. The trend in the vaccination rate against measles, rubella, varicella, and mumps was examined. RESULTS: The measles and rubella vaccination rate was 80-90%. The varicella vaccination rate in the second quarter of 2012, the third quarter of 2014, and the fourth quarter of 2016 was 34.6%, 67.1%, and 80.7%, respectively. The mumps vaccination rate in the second quarter of 2012, the third quarter of 2014, and the fourth quarter of 2016 was 27.6%, 59.5%, and 61.8%, respectively. CONCLUSIONS: The varicella and mumps vaccination rate improved until 2014 despite the fact that they were voluntary vaccinations. After varicella vaccination was added to the universal vaccination program, the varicella vaccination rate continued to improve. The mumps vaccination, which was not included, failed to improve, suggesting that the universal vaccination program contributed to increasing the uptake of the vaccines it includes.

Multidrug-resistant Gram-negative Bacterial Bloodstream Infections in Children's Hospitals in Japan, 2010-2017.

BACKGROUND: The risk factors of multidrug-resistant (MDR) Gram-negative bacilli (GNB) bloodstream infection (BSI) are not yet known in children. Our aim was to evaluate risk factors and outcomes associated with MDR GNB BSI in children. METHODS: Patients with GNB BSI were enrolled between April 2010 and March 2017 at 8 children's hospitals in Japan. Clinical and microbiologic data were collected retrospectively. The risk factors and outcomes of MDR and non-MDR GNB BSI were compared. RESULTS: In total, 629 GNB BSI episodes met the case definition. The median age and proportion of males were 2 years (interquartile range, 0.3-8.7) and 50.7%, respectively. An underlying disease was found in 94% of patients. The proportion of BSI cases that developed >48 hours after admission was 76.2%. MDR comprised 24.5% of BSI cases. The MDR rate did not change over time (P = 0.540). The effective coverage rate of the initial empiric therapy for the MDR and non-MDR BSI cases was 60.4% and 83.4%, respectively (P < 0.001). The all-cause mortality rate at 28 days for all BSI, MDR-BSI and non-MDR BSI cases was 10.7%, 13.6% and 9.7%, respectively (P = 0.167). MDR BSI was independently associated with cancer chemotherapy within 30 days (odds ratio [OR] 43.90), older age (OR 1.05) and admission to the neonatal ward (OR 0.019). CONCLUSIONS: One-fourth of GNB BSI cases were MDR. Cancer chemotherapy and older age were risk factors for MDR GNB BSI in children's hospitals. MDR did not increase the all-cause mortality rate.

The North Wind and the Sun: Pediatric Antimicrobial Stewardship Program Combining Restrictive and Persuasive Approaches in Hematology-Oncology Ward and Hematopoietic Stem Cell Transplant Unit.

BACKGROUND: The Japanese government's goal for the reduction of antimicrobial consumption is two-thirds of the 2013 rate by 2020. While the antimicrobial stewardship programs (ASPs) are essential in health care facilities, ASP data on pediatric hematology-oncology and hematopoietic stem cell transplant (HSCT) patients are limited. Our aim was to evaluate the impact of restrictive and persuasive ASP on immunocompromised children. METHODS: The ASP for hematology-oncology and HSCT patients at Tokyo Metropolitan Children's Medical Center was assessed. Phase 1 was a postprescriptive review of carbapenem conducted between April 2010 and September 2011. Phase 2 consisted of the preauthorization of carbapenem, prospective audit with feedback, a weekly luncheon meeting among physicians, consensus on febrile neutropenia management, and implementation of viral molecular diagnostics between October 2011 and September 2015. Both phases were compared for day-of-therapy per 1,000 patient-days, cost of intravenous antimicrobial agents, average hospitalization duration, all-cause mortality, infection-related mortality at 30 days, and appropriateness of empirical treatment of bacteremia. RESULTS: The ASP did not differ from phase 1 to phase 2 in terms of average hospitalization length, mortality rate, or appropriateness of empirical treatment for bacteremia. Day-of-therapies of cefepime, piperacillin/tazobactam, meropenem, vancomycin, liposomal amphotericin B, and fosfluconazole decreased by 20%, 45%, 57%, 38%, 85% and 44%, respectively (P < 0.05). The total cost of antibiotic and antifungal agents decreased by 27%, for a savings of $59,905 USD annually. CONCLUSION: Restrictive and persuasive ASP in the hematology-oncology ward and the HSCT unit safely decreased the use of antibacterial and antifungal agents.

Sustained pediatric antimicrobial stewardship program with consultation to infectious diseases reduced carbapenem resistance and infection-related mortality.

OBJECTIVE: The impact of pediatric antimicrobial stewardship programs (ASP) on antimicrobial resistance (AMR) remains largely unknown. This study aimed to evaluate the AMR for carbapenem of Gram-negative bacilli (GNB) and carbapenem use with infectious diseases consultation after the implementation of an ASP. METHODS: This quasi-experimental study was conducted at Tokyo Metropolitan Children's Medical Center in Japan. The pre- and post-intervention periods were April 2010 to September 2011 and October 2011 to March 2017, respectively. The pre-intervention phase consisted of consultations with the infectious diseases service alone. The ASP was implemented during the post-intervention phase. The carbapenem resistance rates of GNB were calculated. The correlation between carbapenem resistance rates and carbapenem day of therapy (DOT) was examined. The outcome metrics were compared by average length of hospitalization, all-cause mortality, and infection-related mortality. RESULTS: A positive correlation was observed between the carbapenem resistance rate in Pseudomonas aeruginosa and DOT (0.76, p=0.04). The carbapenem resistance rate in P. aeruginosa (p<0.01) and DOT (p<0.01) decreased significantly in the post-intervention period. The length of hospitalization (p<0.01) and infection-related mortality (p=0.05) decreased in the post-intervention period. CONCLUSIONS: A sustained ASP with additional consultation with the infectious disease service reduced carbapenem use and resistance in P. aeruginosa, leading to favorable outcomes in terms of length of hospitalization and infection-related mortality.

Impact of computerized pre-authorization of broad spectrum antibiotics in Pseudomonas aeruginosa at a children's hospital in Japan.

BACKGROUND: The spread of antimicrobial-resistant organisms is a global concern. To stem this tide, an antimicrobial stewardship program at hospitals is essential to optimize the prescription of broad spectrum antibiotics. In this study we examined the impact of computerized pre-authorization for broad spectrum antibiotics for Pseudomonas aeruginosa at a children's hospital. METHODS: An antimicrobial stewardship program at Tokyo Metropolitan Children's Medical Center was assessed between March 2010 and March 2015. A paper-based post-prescription audit was switched to computerized pre-authorization for broad antipseudomonal agents in October 2011. The prescriber was required to obtain approval from physicians in the pediatric infectious diseases division before prescribing restricted antimicrobial agents. Approved prescriptions were processed and logged electronically. We evaluated days of therapy per 1000 patient-days, the cost of antibiotics, and the susceptibility of P. aeruginosa to piperacillin, ceftazidime, cefepime, piperacillin/tazobactam, carbapenems, and ciprofloxacin. Also, the average length of admission and infection-related mortality at 30 days were compared pre- and post-intervention. RESULTS: Administration of carbapenems, piperacillin/tazobactam, and ceftazidime decreased significantly after the introduction of computerized pre-authorization. Antibiotic costs were reduced by JPY2.86 million (USD 26,000) annually. None of the antipseudomonal agents showed decreased sensitivity. The average length of admission was shorter in post-intervention. Infection-related mortality at 30 days showed no difference between the pre- and post-intervention periods. CONCLUSION: An antimicrobial stewardship program using computerized pre-authorization decreased the use and cost of broad spectrum antibiotics without significant difference in infection-related mortality at 30 days, although our study did not improve susceptibilities of P. aeruginosa.

Molecular epidemiologic study of community-associated methicillin-resistant Staphylococcus aureus with Panton-Valentine leukocidin gene among family members in Japan.

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is one of the worldwide concerns of antimicrobial chemotherapy. An accumulation of ten patients in five families (A-E) suffering from skin and soft tissue infection (SSTI) of CA-MRSA was experienced in 2012, in Fuchu-shi, Tokyo, Japan. Molecular epidemiological investigation was performed for the 10 MRSA strains obtained from 8 children and 2 of their parents to assess endemic patterns of CA-MRSA in the community. Results of molecular typing, presence of toxin genes and antimicrobial susceptibilities were analyzed combined with the patients' clinical information. Each family had its own unique MRSA strain: A, ST30-SCCmec IVd; B, ST8-SCCmec IVd; C, ST8-SCCmec IVa; D, ST8-SCCmec IVl; E, ST8-SCCmec IVl and ST858-SCCmec IVl. Seven strains from the families A-C carried Panton-Valentine leukocidin gene. Three strains from the families D and E carried toxic shock syndrome toxin gene. Strains belonged to the same family demonstrated genetically related banding patterns of pulsed-filed gel electrophoresis. The family C experienced intrafamilial transmission of USA300-0114. Our data showed the MRSA clones disseminating in this community were highly diverse. They contained USA300-0114 clone, the rapidly distributing clone in the world, as well as MRSA clones identified in Japan. Our results suggested intrafamilial transmission of MRSA could be initial phenomenon of wide transmission in a community, therefore CA-MRSA SSTI in children and their family members should be monitored closely in order to notice the spread of highly pathogenic and transmittable strains.

Cefazolin therapy for methicillin-susceptible Staphylococcus aureus bacteremia in Japan.

This is a retrospective cohort study of patients who were treated with cefazolin for methicillin-susceptible Staphylococcus aureus bacteremia, at Tokyo Women's Medical University Hospital between January 2006 and December 2010. During the study period, 84/140 (60%) patients received cefazolin (mean age, 54 years; range, 0-94 years, male patients 64%). Of these, 60/84 (71%) cases were hospital acquired infections, 55/84 (65%) had heart disease, and 19/84 (23%) had moderate to severe heart failure (New York Heart Association class III/IV). The treatment failure rate at 12 weeks was 35% (n = 29). All-cause mortality were 15% (n = 13) after 12 weeks and 21% (n = 18) after a year. Secondary endocarditis and neurological events were observed in 10% (n = 8) and 2% (n = 2). Moderate to severe heart failure and retained intravascular devices were associated with treatment failure at 12 weeks by multivariate analysis (P < 0.01, P = 0.018). Our results suggest that hospital-acquired methicillin-susceptible S. aureus bacteremia can cause severe complications in patients with moderate to severe heart failure who retain their intravascular devices. Both effective antimicrobial therapy and removal of infected foci are essential for S. aureus bacteremia treatments.

Disseminated cryptococcosis in a non-Hodgkin's lymphoma patient with late-onset neutropenia following rituximab-CHOP chemotherapy: a case report and literature review.

Rituximab-related late-onset neutropenia (R-LON) is an adverse event associated with rituximab. A 65-year-old woman presented with diffuse large B-cell lymphoma of the kidney without bone marrow involvement. She was treated with 4 cycles of CHOP chemotherapy consisting of doxorubicin, cyclophosphamide, vincristine, and prednisolone at 4-week intervals. Rituximab was also administrated of the second, third, fourth CHOP cycles. She developed a high fever of 38°C, nausea, and severe neutropenia following the four cycles of R-CHOP chemotherapy. Her leukocyte count was 160/µl without neutrophils. Initially, a blood and pleural fluid and cerebrospinal fluid cultures were positive for Cryptococcus neoformans. Once she became asymptomatic following treatment with fluconazole and neutropenia was recovered with lenograstim, she had neck stiffness and admitted soon. Cerebro-spinal fluid (CSF) culture was positive for Cryptococcus neoformans. Treatment with amphotericin B(AMPH-B) and flucytosine(5-FC) was initiated as diagnosis of cryptococcus meningitis. Lenograstim was administrated for 9 months, and amount of dose was 9,750 µg. Cryptococcosis with malignant lymphoma is rare disease, and previously 17 cases were reported. Of note, mortality of disseminated cryptococcosis with malignant lymphoma is 54%. The more and more rituximab is widely used; the cases of severe infection in R-LON may increase.

[Listeriosis in non-Hodgkin's lymphoma following outpatient R-CHOP therapy].

Non-Hodgkin's lymphoma, a hematolymphoid malignancy, puts subjects at risk for complete infection. A 65-year-old man with non-Hodgkin's lymphoma Stage IV had undergone 5 R-CHOP courses in May 2008. Six days later, he was hospitalized for a high fever for which he was initially administered cefepime. When blood culture was positive for Listeria monocytogenes, he was administered ampicillin. His medical interview indicated that he had gone hunting and dressed wild animal meat at his mountain retreat, where he was exposed to wild animals and their excreta following R-CHOP course 5. CSF was not checked because his general condition was good. On hospital day 2, his fever dropped, and he was discharged following two weeks of ampicillin administration. Listeriosis cases reported in Japan number far fewer than in the United States, France or Germany. From January 1983 to February 2009, 153 cases were reported in Japan, 12 of whom were cancer patients. Despite the high incidence of meningitis with listeriosis, 7 of the 12 were not examined for CSF--an examination necessary in listeriosis, however well the subject appears.

Ceftriaxone plus gentamicin or ceftriaxone alone for streptococcal endocarditis in Japanese patients as alternative first-line therapies.

This study included 31 patients who had definite or possible infectious endocarditis as defined by the modified Duke's criteria Of these patients, 27 were treated with ceftriaxone plus gentamycin combination therapy and four with ceftriaxone monotherapy. Of these 31 cases, 29 had infections with Streptococcus species, and showed good responses to penicillin G and cefotaxime. Excluding one patient who died because of the underlying disease, all patients achieved clinical cure after treatment with either of the two regimens, showing no recurrence during a follow-up period of 6 months after completion of drug treatment. Although valve replacement was performed in 10 patients during the follow-up period, there were no recurrences in any of these patients 6 months postoperatively. Ceftriaxone allows a simple regimen of once-daily administration. Although indications are limited, ceftriaxone therapy is feasible on an outpatient basis, offering favorable medical economics. Consistent with previous reports, the therapeutic effect of ceftriaxone was equivalent to that of penicillin G in this study, showing this agent to be an alternative first-line drug for infectious endocarditis.