Publications by authors named "Yoshiki Kusama"

104 Publications

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

Pediatr Infect Dis J 2022 Sep 21;41(9):e383-e387. Epub 2022 Jun 21.

Division of Infection Control and Prevention, Medical Mycology Research Center, Chiba University, Chiba, Japan.

Antimicrobial resistance (AMR) is a major problem in public health. Japan is addressing this problem with various measures based on the National Action Plan on AMR, published in 2016. In Japan, the fight against AMR is hindered by issues with the health care system, including the lack of a general practitioner registration system, an abundance of private clinics and health care for infants and toddlers being essentially free of charge. As measures against AMR in inpatient care, thorough infection prevention and the Japanese government's incentivization of collaboration in infection prevention among hospitals and regions have helped to improve infection prevention. As measures against AMR in outpatient care, the creation of official Japanese government guidelines on antimicrobial stewardship has facilitated the implementation of antimicrobial stewardship in clinics. Another unique measure taken in Japan is incentivizing the nonprescription of antimicrobials for respiratory tract infections and diarrhea. Although Asia is a hot spot for AMR bacteria, the fight against AMR is affected by various factors, including insufficient precautions against nosocomial infections and the absence of surveillance systems. To combat these problems, Japan must take a strong leadership role. AMR is a problem not only at the level of individual countries but on a global scale and should, therefore, be addressed through joint action among nations.
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http://dx.doi.org/10.1097/INF.0000000000003612DOI Listing
September 2022

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

Antibiotics (Basel) 2022 Jun 2;11(6). Epub 2022 Jun 2.

Department of Clinical Pharmacoepidemiology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.

The evaluation indexes of antimicrobial use (AMU) in sub-prefectural regions have not been established because these regional units are susceptible to the effects of population inflows and outflows. We defined the difference in AMU calculated each year as a new evaluation index and compared the AMU of secondary medical areas with those already reported for Japan and each prefecture. Patients/1000 inhabitants/day (PID) for oral antibiotics in 2013 and 2016 were calculated using the National Database of Health Insurance Claims and Specific Health Checkups. ΔPID was defined as the difference between the PIDs in 2013 and 2016. Differences in AMUs for Japan and prefectures that have already been published were also calculated, and the concordance rate with ΔPID in each secondary medical area was evaluated. Antibiotics and age groups with less than 50% concordance between secondary medical area and previously reported AMU changes were observed. This revealed that even at the secondary medical area level, which is more detailed than the prefectural level, the AMU changes were not consistent. Therefore, in order to appropriately promote measures against antimicrobial resistance, we suggest the necessity of not only surveying AMU at the national or prefectural levels but also examining sub-prefectural trends in AMU.
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http://dx.doi.org/10.3390/antibiotics11060763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9219656PMC
June 2022

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

J Infect Chemother 2022 Sep 20;28(9):1266-1272. Epub 2022 May 20.

Department of Clinical Pharmacoepidemiology, Kyoto Pharmaceutical University; 5 Misasagi-nakauchi-cho, Yamashina-ku, Kyoto, 607-8414, Japan. Electronic address:

Introduction: Reimbursements for pharmacist interventions and infectious disease teams have recently been introduced in Japan. Arbekacin (ABK) is used to treat pneumonia and sepsis caused by methicillin-resistant Staphylococcus aureus, and therapeutic drug monitoring (TDM) is recommended. This study aimed to clarify the trend in TDM implementation for ABK over time and the factors associated with TDM implementation using a claims database.

Methods: Data of patients aged ≥15 years who received ABK for ≥3 consecutive days between 2010 and 2019 were extracted from a large Japanese medical claims database. The proportion of reimbursements claimed for TDM, pharmacist interventions, and the setup of infectious disease teams for each year were calculated. The factors associated with TDM implementation were identified using multivariate logistic regression analysis.

Results: The proportion of TDM implementation for ABK increased by 9.1% from 2010 to 2019, but it remained less than 40% throughout this period. The proportion of TDM implementation was higher in patients who claimed reimbursements for pharmacist interventions than in patients who did not. Logistic regression analysis showed that the stationing of pharmacists in wards and long-term ABK treatment were significantly associated with TDM implementation.

Conclusions: From 2010 to 2019, the proportion of TDM implementation for ABK was significantly low. Moreover, the factors associated with TDM implementation were clarified. An environment wherein pharmacists can help implement TDM for patients receiving ABK would be beneficial.
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http://dx.doi.org/10.1016/j.jiac.2022.05.007DOI Listing
September 2022

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

Int J Infect Dis 2022 Jun 17;119:13-17. Epub 2022 Mar 17.

This study investigated the impact of the COVID-19 pandemic on antimicrobial use (AU) trends in Japan in 2020 and explored its potential effects on appropriate AU. Using nationwide antimicrobial sales data, we examined the annual and monthly trends in AU from 2016-2020 according to the AWaRe classification (Access and Watch categories) and administration route (oral and injectable). To analyze the possible impact of the COVID-19 pandemic on AU, seasonal autoregressive integrated moving average (SARIMA) models were used to predict AU in 2020 (based on the trends from 2016-2019) under the assumption that the pandemic did not occur. We observed a substantial reduction in AU in 2020 compared with preceding years. In addition, the reductions in AU for total antimicrobials and Watch category antimicrobials were greater than predicted regardless of administration route. These results suggest that the COVID-19 pandemic contributed to the observed reductions in AU, but it is also possible that the changes reflect recent efforts to improve AU. Continued AU surveillance and research are needed to optimize prescribing practices through appropriate antimicrobial stewardship.
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http://dx.doi.org/10.1016/j.ijid.2022.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8926437PMC
June 2022

Myalgic encephalomyelitis/chronic fatigue syndrome post coronavirus disease 2019.

Pediatr Int 2022 Jan;64(1):e14976

Department of Pediatrics, Hyogo Prefectural Amagasaki Medical Center, Hyogo, Japan.

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http://dx.doi.org/10.1111/ped.14976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9115412PMC
January 2022

Rapid progressive destruction of the cochleae in an infant due to pneumococcal meningitis.

J Infect Chemother 2022 Jun 22;28(6):806-809. Epub 2022 Jan 22.

Department of Pediatrics, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan.

The widespread adoption of pneumococcal conjugate vaccines has reduced the incidence of Streptococcus pneumoniae infections, but has also led to the emergence of infections due to non-vaccine serotypes. A 15-month-old girl was referred to our hospital with suspected meningitis. S. pneumoniae was isolated from her cerebrospinal fluid. She was initially treated with a combination of cefotaxime and vancomycin, followed by ampicillin and vancomycin. After 7 days, the patient's condition improved and she was transferred to the general ward; however, her mother noted signs of hearing difficulties. On the 16th day of admission, we performed an auditory brainstem response test, which suggested severe bilateral hearing impairment. This was confirmed using an auditory steady-state response test after consulting with otolaryngologists. Magnetic resonance imaging revealed fibrosis of both cochleae with labyrinthitis. The patient underwent emergency cochlear implantation at a different hospital. The S. pneumoniae isolate was later identified to be serotype 10A with a PBP2x mutation, which is not covered by the conjugate vaccine and has reduced cephalosporin susceptibility. This case was characterized by highly rapid cochlear destruction, and an earlier otolaryngologist consultation may have provided a more well-organized surgery plan. Pediatricians are urged to promptly consult with otolaryngologists for patients with similar indications.
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http://dx.doi.org/10.1016/j.jiac.2022.01.007DOI Listing
June 2022

The intended purpose and regional patterns of use of antibiotics for managing Clostridioides (Clostridium) difficile infections: An analysis of the National Database of Health Insurance Claims and Specific Health Checkups data of Japan.

J Infect Chemother 2022 Feb 13;28(2):356-358. Epub 2021 Dec 13.

AMR Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan; 1-21-1 Toyama Shinjuku-ku, Tokyo, 162-8655, Japan. Electronic address:

Introduction: We previously showed the trend of antimicrobial use (AMU) for Clostridioides (Clostridium) difficile infection (CDI) using sales data. However, the details of the prescribing medical institutions and regional characteristics are unknown. Therefore, the purpose of this study was to clarify the details of the medical institutions where antibiotics for CDI were prescribed, and evaluate the AMU for CDI and the regional characteristics.

Methods: Antibiotics for CDI, including oral vancomycin (VCM), oral metronidazole (MNZ), and intravenous (IV) MNZ, were collected from the National Database of Health Insurance Claims and Specific Health Checkups (NDB) between 2013 and 2016. The PID (patients/1000 inhabitants/day) was used as an evaluation index for AMU. The PID was calculated using the claim types: inpatient, outpatient, dental, and pharmacy. The PID of each prefecture was calculated for inpatient claims in 2016.

Results: The AMU of oral VCM and IV MNZ were observed mainly in the inpatient claims. For oral MNZ, the total AMU in the outpatient and pharmacy claims accounted for approximately 80% per year throughout the study period. For inpatient claims of each prefecture in 2016, the PID of the antibiotics used for CDIs was approximately 3.5 times the difference between the highest and lowest prefectures.

Conclusions: The AMU for CDI that takes into account the purpose of use was clarified by using the information of the prescribed medical institutions that were included in the NDB. Oral MNZ was used frequently in outpatients, and attention should be paid to the acquisition of resistance.
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http://dx.doi.org/10.1016/j.jiac.2021.12.004DOI Listing
February 2022

Effects of the cefazolin shortage on the sales, cost, and appropriate use of other antimicrobials.

BMC Health Serv Res 2021 Oct 19;21(1):1118. Epub 2021 Oct 19.

AMR Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan.

Background: Shortages of antimicrobials lead to treatment failures, increase medical costs, and accelerate the development of antimicrobial resistance. We evaluated the effects of the serious cefazolin shortage in 2019 in Japan on the sales, costs, and appropriate use of other antimicrobials.

Methods: We evaluated monthly defined daily doses/1000 inhabitants/day (DID) values of antimicrobial sales from January 2016 to December 2019 using wholesaler's sales databases. Using 2016-2018 sales data, we generated a prediction model of DID in 2019 under the assumption that the cefazolin shortage did not occur. We then compared the predicted DID and actual DID. Cefazolin, government-recommended alternatives, and government-not-recommended broad-spectrum alternatives were assessed. Antimicrobial groups according to the AWaRe classification were also assessed to evaluate the effect on appropriate antimicrobial use. In addition, we evaluated changes in costs between 9 months before and after the cefazolin shortage.

Results: DID values of total antimicrobials increased sharply 1 month before the decrease in cefazolin. Actual DIDs were higher than predicted DIDs for ceftriaxone, flomoxef, clindamycin, cefotiam, piperacillin/tazobactam, and meropenem. Actual DID values were higher than the predicted DID values in the Watch group. The costs of antimicrobials between pre- and post- cefazolin shortage were unchanged.

Conclusion: The cefazolin shortage brought confusion to the antimicrobial market and led to a setback in the appropriate use of antimicrobials. Early recognition and structures for prompt reactions to antimicrobial shortages are needed. Moreover, development of a system to secure the supply of essential antimicrobials is required.
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http://dx.doi.org/10.1186/s12913-021-07139-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523201PMC
October 2021

The Use of Topical Antibiotics Based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) Open Data in 2017.

Jpn J Infect Dis 2022 Mar 30;75(2):177-182. Epub 2021 Sep 30.

Department of Clinical Pharmacoepidemiology, Kyoto Pharmaceutical University, Japan.

The national action plan on antimicrobial resistance (AMR) in Japan emphasizes the importance of understanding antimicrobial use (AMU). Some studies have been conducted on oral and parenteral AMU in Japan. However, there are few studies on the use of topical antimicrobials, such as in dermatology and ophthalmology. Therefore, the purpose of this study was to investigate the use of topical AMU in Japan. Data on AMU in dermatology and ophthalmology were obtained from the 2017 National Database of Health Insurance Claims and Specific Health Checkups of Japan Open Data. The number of dermatological products used was 58,396,530 in 2017. The proportions of betamethasone/gentamicin and gentamicin used were 50.5% and 16.7%, respectively, whereas that of the ingredient quantity in gentamicin was 7.8%. It has been suggested that topical AMU should be evaluated based on the number of products being used. The number of ophthalmological products used was 24,655,653 in 2017, and the proportion of quinolones used was 95.9%. The high prescription rate of quinolones may cause an increase in quinolone resistance in the ophthalmologic field. Topical AMU, which is a potential "blind spot" in the measures against AMR, needs to be continuously monitored, together with systemic AMU.
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http://dx.doi.org/10.7883/yoken.JJID.2021.450DOI Listing
March 2022

Trends in healthcare visits and antimicrobial prescriptions for acute infectious diarrhea in individuals aged 65 years or younger in Japan from 2013 to 2018 based on administrative claims database: a retrospective observational study.

BMC Infect Dis 2021 Sep 21;21(1):983. Epub 2021 Sep 21.

AMR Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.

Background: The inappropriate use of antimicrobials for acute infectious diarrhea is widespread and leads to the problem of antimicrobial resistance. To improve the use of antimicrobials, it is first necessary to understand the actual situation of diarrheal disease and to identify potential targets for intervention. This study aimed to investigate the recent epidemiological characteristics of and antimicrobial prescriptions for acute infectious diarrhea in Japan.

Methods: This was a retrospective observational study of outpatients aged 0-65 years, separated into children (age 0-17 years) and adults (age 18-65 years), diagnosed with acute infectious diarrhea, using the administrative claims database of the Japan Medical Data Center from 2013 to 2018. We evaluated the number of eligible visits/number of database registrants (defined as the visit rate). The analysis of the antimicrobial prescription rate was restricted to otherwise healthy individuals diagnosed with acute infectious diarrhea alone by excluding patients with multiple disease diagnoses and with medical backgrounds of chronic bowel diseases or immunocompromised conditions. We further classified them by diagnosis of bacterial or nonbacterial acute infectious diarrhea.

Results: The total number of eligible visits for acute infectious diarrhea was 2,600,065. The visit rate, calculated based on the number of eligible visits by database registrants, was higher in children (boys, 0.264; girls, 0.229) than in adults (men, 0.070; women, 0.079), with peaks in early summer and winter. The peaks for visits in adults lagged those of children. In total, 482,484 visits were analyzed to determine the antimicrobial prescription rate; 456,655 (94.6%) were diagnosed with nonbacterial acute infectious diarrhea. Compared with children (boys, 0.305; girls, 0.304), the antimicrobial prescription rate was higher in adults, and there were differences between sexes in adults (men, 0.465; women, 0.408). Fosfomycin and fluoroquinolone were most frequently used for nonbacterial acute infectious diarrhea in children (44.1%) and adults (50.3%), respectively.

Conclusions: These results revealed overprescription of antimicrobials for acute infectious diarrhea in this administrative claims database in Japan and contribute to the development of antimicrobial stewardship strategies and the identification of targets for efficiently reducing inappropriate antimicrobial use.
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http://dx.doi.org/10.1186/s12879-021-06688-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8454076PMC
September 2021

Difficulty of morphological diagnosis in Gram staining.

BMJ Case Rep 2021 Aug 20;14(8). Epub 2021 Aug 20.

Department of Pediatrics, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Hyogo, Japan.

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http://dx.doi.org/10.1136/bcr-2021-245349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381292PMC
August 2021

Trends in Antipseudomonal Agent Use Based on the 2006 to 2015 Sales Data in Japan.

Biol Pharm Bull 2021 ;44(6):816-821

Department of Clinical Pharmacoepidemiology, Kyoto Pharmaceutical University.

Pseudomonas aeruginosa resistance is a major issue worldwide. Drug resistance is related to inappropriate antibiotic use. Because antipseudomonal agents have a wide spectrum, they must be used appropriately. The purpose of this study was to clarify the trends in antipseudomonal agent use in Japan based on sales data from 2006 to 2015. The total antipseudomonal agent use was increased significantly (r = 0.10, P = 0.00040). The proportion of fluoroquinolones use was the highest throughout the year, accounting for 88.6-91.4%. The use of piperacillin/tazobactam significantly increased. The increased use of these drugs may be due to the launch of higher doses and additional indications. On the other hand, for antipseudomonal agents, parenteral carbapenems use was 2.7-3.7%, but it has remained unchanged over the years. In Japan, permit and notification systems have been introduced to prevent the inappropriate use of parenteral carbapenems in medical institutions. It was speculated that these efforts suppressed the inappropriate use of parenteral carbapenems. This study clarified the trend of antipseudomonal agent use in Japan from 2006 to 2015. It is important to continue monitoring antipseudomonal agents use to conduct appropriate antimicrobial resistance measures.
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http://dx.doi.org/10.1248/bpb.b21-00004DOI Listing
November 2021

Characteristics and limitations of national antimicrobial surveillance according to sales and claims data.

PLoS One 2021 11;16(5):e0251299. Epub 2021 May 11.

AMR Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan.

Purpose: Antimicrobial use (AMU) is estimated at the national level by using sales data (S-AMU) or insurance claims data (C-AMU). However, these data might be biased by generic drugs that are not sold through wholesalers (direct sales) and therefore not recorded in sales databases, or by claims that are not submitted electronically and therefore not stored in claims databases. We evaluated these effects by comparing S-AMU and C-AMU to ascertain the characteristics and limitations of each kind of data. We also evaluated the interchangeability of these data by assessing their relationship.

Methods: We calculated monthly defined daily doses per 1,000 inhabitants per day (DID) using sales and claims data from 2013 to 2017. To assess the effects of non-electronic claim submissions on C-AMU, we evaluated trends in the S-AMU/C-AMU ratio (SCR). To assess the effects of direct sales of S-AMU, we divided AMU into generic and branded drugs and evaluated each SCR in terms of oral versus parenteral drugs. To assess the relationship between S-AMU and C-AMU, we created a linear regression and evaluated its coefficient.

Results: Median annual SCRs from 2013 to 2017 were 1.046, 0.993, 0.980, 0.987, and 0.967, respectively. SCRs dropped from 2013 to 2015, and then stabilized. Differences in SCRs between branded and generic drugs were significant for oral drugs (0.820 vs 1.079) but not parenteral drugs (1.200 vs 1.165), suggesting that direct sales of oral generic drugs were omitted in S-AMU. Coefficients of DID between S-AMU and C-AMU were high (generic, 0.90; branded, 0.84) in oral drugs but relatively low (generic, 0.32; branded, 0.52) in parenteral drugs.

Conclusions: The omission of direct sales information and non-electronically submitted claims have influenced S-AMU and C-AMU information, respectively. However, these data were well-correlated, and it is considered that both kinds of data are useful depending on the situation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251299PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112693PMC
October 2021

Nationwide cross-sectional study of antimicrobial stewardship and antifungal stewardship programs in inpatient settings in Japan.

BMC Infect Dis 2021 Apr 16;21(1):355. Epub 2021 Apr 16.

Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.

Background: To prevent antimicrobial resistance, both antimicrobial stewardship (AMS) and antifungal stewardship (AFS) in inpatient settings are needed in small/middle-sized hospitals as well as large hospitals.

Methods: We conducted the web-based, self-administered, nationwide cross-sectional study regarding AMS and AFS in inpatient settings in Japan, targeting hospitals that participated in a hospital epidemiology workshop conducted in July 2018. The questionnaire was composed of intervention protocols for use of broad-spectrum antimicrobials and antifungals within 7 or 28 d of beginning usage. These broad-spectrum antimicrobial and antifungal protocols were compared between large (≥501beds) and small/middle-sized (≤500 beds) hospitals.

Results: Of 240 hospitals surveyed, 39 (16%; 18 large and 21 small/middle-sized) responded. The number of hospitals that intervened in the use of broad-spectrum antimicrobials within 7 and 28 d were 17 (44%) and 34 (87%), respectively; those that intervened for antifungals were 3 (8%) and 10 (26%), respectively. Interventions for use of broad-spectrum antimicrobials within 7 d were significantly more frequent in small/middle-sized hospitals compared to large hospitals [13 (61. 9%) vs. 4 (22. 2%), odds ratio = 5.7, 95% confidence interval = 1.4-23.3, p = 0.023].

Conclusions: Small/middle-sized hospitals had more frequent interventions within 7 d of broad-spectrum antimicrobial use than large hospitals. More effort to improve AFS is needed among all hospitals.
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http://dx.doi.org/10.1186/s12879-021-06035-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050890PMC
April 2021

National database study of trends in bacteraemia aetiology among children and adults in Japan: a longitudinal observational study.

BMJ Open 2021 03 30;11(3):e043774. Epub 2021 Mar 30.

AMR Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan.

Objectives: Domestic epidemiological studies are needed to ascertain the disease burden of bacteraemia in individual countries. This study aimed to evaluate the domestic trends in paediatric and adult bacteraemia in Japan.

Setting: Laboratory-based surveillance was used to obtain data from 592 hospitals located throughout Japan.

Participants: The study was conducted using the results of 827 780 and 3 512 524 blood culture tests obtained from children and adults, respectively, between January 2010 and December 2016.

Outcome Measures: We analysed the temporal trends in specific bacterial species (, , , , , , , , and ) detected from the blood cultures of children and adults. For children aged ≤2 years, the data were analysed for each year of age. The proportions of bacteraemia-positive results among the patients were also evaluated.

Results: The number of bacteraemia-positive samples over the study period was 47,125/827,855 (5.7%) in children and 959,765/3,513,885 (27.3%) in adults. was the most frequent cause of bacteraemia in children in 2010. However, after 2011, bacteraemia was the most frequent, followed by and bacteraemia showed significant increases in both children and adults. In children, and bacteraemia decreased from 2010 to 2013. However, bacteraemia case numbers stabilised from 2013, whereas bacteraemia cases continued to decrease until 2016.

Conclusion: The results suggest that the introduction of the 13-valent pneumococcal conjugate vaccine did not substantially affect disease occurrence. In contrast to the decreasing trends in and bacteraemia, , and bacteraemia showed increasing trends. These findings shed light on recent temporal trends in bacteraemia in both children and adults in Japan.
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http://dx.doi.org/10.1136/bmjopen-2020-043774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011712PMC
March 2021

Effect of population inflow and outflow between rural and urban areas on regional antimicrobial use surveillance.

PLoS One 2021 18;16(3):e0248338. Epub 2021 Mar 18.

AMR Clinical Reference Center, National Center for Global Health and Medicine, Tokyo, Japan.

Purpose: Regional-level measures can complement national antimicrobial stewardship programs. In Japan, sub-prefectural regions called secondary medical areas (SMAs) provide general inpatient care within their borders, and regional antimicrobial stewardship measures are frequently implemented at this level. There is therefore a need to conduct antimicrobial use (AMU) surveillance at this level to ascertain antimicrobial consumption. However, AMU estimates are generally standardized to residence-based nighttime populations, which do not account for population mobility across regional borders. We examined the impact of population in/outflow on SMA-level AMU estimates by comparing the differences between standardization using daytime and nighttime populations.

Methods: We obtained AMU information from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. AMU was quantified at the prefectural and SMA levels using the number of defined daily doses (DDDs) divided by (a) 1,000 nighttime population per day or (b) 1,000 daytime population per day. We identified and characterized the discrepancies between the two types of estimates at the prefectural and SMA levels.

Results: The national AMU was 17.21 DDDs per 1,000 population per day. The mean (95% confidence interval) prefectural-level DDDs per 1,000 nighttime and daytime population per day were 17.27 (14.10, 20.44) and 17.41 (14.30, 20.53), respectively. The mean (95% confidence interval) SMA-level DDDs per 1,000 nighttime and daytime population per day were 16.12 (9.84, 22.41) and 16.41 (10.57, 22.26), respectively. The nighttime population-standardized estimates were generally higher than the daytime population-standardized estimates in urban areas, but lower in the adjacent suburbs. Large differences were observed in the main metropolitan hubs in eastern and western Japan.

Conclusion: Regional-level AMU estimates, especially of smaller regions such as SMAs, are susceptible to the use of different populations for standardization. This finding indicates that AMU standardization based on population values is not suitable for AMU estimates in small regions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248338PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971456PMC
October 2021

An alternative index for evaluating AMU and anti-methicillin-resistant Staphylococcus aureus agent use: A study based on the National Database of Health Insurance Claims and Specific Health Checkups data of Japan.

J Infect Chemother 2021 Jul 19;27(7):972-976. Epub 2021 Feb 19.

Department of Clinical Pharmacoepidemiology, Kyoto Pharmaceutical University, 5 Misasagi-Nakauchi-cho, Yamashina-ku, Kyoto-shi, Kyoto, 607-8414, Japan. Electronic address:

Introduction: Anti-methicillin-resistant Staphylococcus aureus (MRSA) agents have different doses and administration periods. Thus, it is difficult to evaluate antimicrobial use (AMU) of anti-MRSA agents using defined daily doses per 1000 inhabitants per day (DID) or days of therapy per 1000 inhabitants per day (DOTID). This study aimed to evaluate the relationship between anti-MRSA agent use and resistant bacteria using the number of patients per 1000 inhabitants per day (PID) as an alternative index of AMU.

Methods: AMU data for anti-MRSA agents were collected from the National Database of Health Insurance Claims and Specific Health Checkups (NDB) in 2016. The relationship between PID and DID or DOTID was evaluated. The number of patients with MRSA isolated was obtained from Japan Nosocomial Infections Surveillance, and their correlation with PID was analyzed. The rate of anti-MRSA agent use in each prefecture was investigated.

Results: PID showed a significant linear relationship with both DID and DOTID (all p < 0.0001). PID was significantly correlated with the number of patients with MRSA isolated. Additionally, the rate of anti-MRSA agent use was markedly different in each region.

Conclusions: PID is not affected by doses and administration periods, and thus may be an alternative index for the selective pressure of antibiotics. Evaluating AMU using PID based on NDB data will help in the development of effective antimicrobial resistance measures.
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http://dx.doi.org/10.1016/j.jiac.2021.02.009DOI Listing
July 2021

Effects of a nudge-based antimicrobial stewardship program in a pediatric primary emergency medical center.

Eur J Pediatr 2021 Jun 8;180(6):1933-1940. Epub 2021 Feb 8.

AMR Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine Hospital, 1-21-1 Toyama Shinjuku-ku, Tokyo, 162-8655, Japan.

Outpatient medical facilities tend to have high antimicrobial prescription rates and are therefore major targets for antimicrobial stewardship programs (ASPs). Pediatric primary emergency medical centers in Japan have difficulties in implementing conventional ASPs due to the low continuity of stewardship. Accordingly, there is a need to develop effective ASP models for these facilities. We conducted a single-center, quasi-experimental study to evaluate the effects of a nudge-based ASP in reducing unnecessary third-generation cephalosporin (3GC) prescriptions in a pediatric primary emergency care center (PEC). The implemented ASP utilizes monthly newsletters that report current antimicrobial use patterns and prescribing targets. We compared the monthly 3GC prescription numbers and proportions of unnecessary prescriptions before and after the ASP was implemented. The trends in 3GC prescriptions were examined using an interrupted time-series analysis. The numbers of patients before and after ASP implementation were 129,156 and 28,834, respectively. The number of unnecessary 3GC prescriptions decreased by 67.2% in the year after ASP implementation. The interrupted time-series analysis showed that the ASP was significantly associated with a reduction in 3GC prescriptions (regression coefficient - 0.58, P < 0.001).Conclusion: The nudge-based ASP was effective in reducing 3GC use in a Japanese PEC. This simple and inexpensive approach may have applications in other outpatient facilities. What is Known: • Outpatient medical facilities tend to have high antimicrobial prescription rates. Despite the development of several strategies for outpatient antimicrobial stewardship programs, these approaches have not sufficiently reduced antimicrobial use. What is New • Our nudge-based antimicrobial stewardship program using newsletters was shown to be a simple, inexpensive, and feasible method for reducing unnecessary antimicrobial use in a pediatric primary emergency care center. This may represent an effective antimicrobial stewardship strategy in Japanese outpatient facilities.
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http://dx.doi.org/10.1007/s00431-021-03979-3DOI Listing
June 2021

The first national survey of antimicrobial use among dentists in Japan from 2015 to 2017 based on the national database of health insurance claims and specific health checkups of Japan.

PLoS One 2020 28;15(12):e0244521. Epub 2020 Dec 28.

AMR Clinical Reference Center, National Center for Global Health and Medicine, Tokyo, Japan.

Purpose: To counter the global health threat of antimicrobial resistance, effective antimicrobial stewardship programs are needed to improve antimicrobial use (AMU) among dentists in addition to physicians. This study aimed to investigate the nationwide epidemiology of AMU among Japanese dentists to facilitate the development of dentist-centered programs.

Methods: We conducted a retrospective population-based study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan to analyze the AMU among Japanese dentists between 2015 and 2017. AMU was quantified as the defined daily doses per 1,000 inhabitants per day (DID). The trends in dentist-prescribed AMU were examined according to antimicrobial category and administration route. We also compared outpatient oral AMU between dentists and physicians as well as between on-site and off-site dispensing.

Results: The DID values of dentist-prescribed AMU were 1.23 in 2015, 1.22 in 2016, and 1.21 in 2017. During this study period, outpatient oral antimicrobials comprised the majority (approximately 99%) of dentist-prescribed AMU, and cephalosporins were the most frequently prescribed antimicrobials (>60% of all antimicrobials). The DID values of outpatient oral AMU were 1.21 for dentists and 12.11 for physicians. The DID value for on-site dispensing was 0.89 in 2017, in which cephalosporins were the predominantly used antimicrobials (DID: 0.60).

Conclusions: Interventions that target dentists in Japan should focus on on-site dispensing of oral antimicrobials (especially cephalosporins) for outpatients. Further studies are needed to ascertain the underlying factors of oral cephalosporin prescriptions to guide the development of effective antimicrobial stewardship programs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244521PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769482PMC
March 2021

SARS-CoV-2 infection among returnees on charter flights to Japan from Hubei, China: a report from National Center for Global Health and Medicine.

Glob Health Med 2020 Apr;2(2):107-111

Department of Infectious Diseases, Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan.

Due to the significant spread of a new type of coronavirus (SARS-CoV-2) infection (COVID-19) in China, the Chinese government blockaded several cities in Hubei Province. Japanese citizens lost a means of transportation to return back to Japan. The National Center for Global Health and Medicine (NCGM) helped the operation of charter flights for evacuation of Japanese residents from Hubei Province, and this article outlines our experiences. A total of five charter flights were dispatched, and the majority of returnees (793/829 [95.7%]) were handled at NCGM. A large number of personnel from various departments participated in this operation; 107 physicians, 115 nurses, 110 clerical staff, and 45 laboratory technicians in total. Several medical translators were also involved. In this operation, we conducted airborne precautions in addition to contact precautions. Eye shields were also used. The doctors collecting the pharyngeal swab used a coverall to minimize the risk of body surface contamination from secretions and droplets. Enhanced hand hygiene using alcohol hand sanitizer was performed. Forty-eight persons were ultimately hospitalized after the triage at NCGM operation, which was more than the number of persons triaged at the airport ( = 34). Of those hospitalized after NCGM triage, 8.3% (4/48 patients) ultimately tested positive for SARS-CoV-2, significantly higher than the positive rate among subjects not triaged (4/48 [8.3%] 9/745 [1.2%]: = 0.0057). NCGM participated in a large-scale operation to evacuate Japanese nationals from the COVID-19 epidemic area. We were able to establish a scheme through this experience that can be used in the future.
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http://dx.doi.org/10.35772/ghm.2020.01036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731067PMC
April 2020

Trends of the Use of Anti-methicillin-Resistant Staphylococcus aureus Agents in Japan Based on Sales Data from 2006 to 2015.

Biol Pharm Bull 2020 ;43(12):1906-1910

Department of Clinical Pharmacoepidemiology, Kyoto Pharmaceutical University.

Patterns of the use of anti-methicillin-resistant Staphylococcus aureus (MRSA) agents in Japan might be influenced by the launch of new anti-MRSA agents, the publication of relevant guidelines, and the increase in the number of generic medicines. However, as anti-MRSA agents are included in multiple anatomical therapeutic chemical classifications, such as glycopeptides and aminoglycosides, the trends of the use of individual anti-MRSA agents remain unclear. Here, we aimed to clarify the trends of anti-MRSA agent use in Japan from 2006 to 2015 based on sales data. Total anti-MRSA agent use was found to have significantly increased from 2006 to 2015 (P = 0.027, r = 0.00022). Individual trends for vancomycin (VCM), daptomycin, and linezolid (LZD) use showed significant increases, while those for arbekacin (ABK) and teicoplanin (TEIC) showed decreases. In addition, oral LZD use significantly increased, while there was no significant change in intravenous LZD use. The ratio of oral LZD use to total LZD use increased from 25.5% in 2006 to 39.9% in 2015. Meanwhile, TEIC and ABK use decreased, while VCM use increased, following the launch of generic medicines. These results might reflect the status of guideline compliance, the launch of new anti-MRSA agents, and the decline in the sales promotion of the original medicines. It is extremely important to investigate trends for the use of not only different antibiotic groups but also individual antibiotics to develop and implement antimicrobial resistance countermeasures.
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http://dx.doi.org/10.1248/bpb.b20-00605DOI Listing
August 2021

A Matched Case-Case-Control Study of the Impact of Clinical Outcomes and Risk Factors of Patients with IMP-Type Carbapenemase-Producing Carbapenem-Resistant in Japan.

Antimicrob Agents Chemother 2021 02 17;65(3). Epub 2021 Feb 17.

Disease Control and Prevention Center, National Centre for Global Health and Medicine, Tokyo, Japan.

IMP-type carbapenemase, found in various Gram-negative bacteria, has been increasingly detected worldwide. We aimed to study the outcomes and risk factors for acquisition of IMP-type carbapenemase-producing carbapenem-resistant (IMP-CRE), as this has not been evaluated in detail. We conducted a matched case-case-control study of patients from whom IMP-CRE isolates were obtained. All patients who tested positive for IMP-CRE were included; they were matched with patients with carbapenem-susceptible (CSE) and with controls at a ratio of 1:1:2. The risk factors for acquisition for the CRE and CSE groups and mortality rates, which were calculated using multivariate logistic regression models with weighting according to the inverse probability of propensity scores, were compared. In total, 192 patients (96 patients each in the CRE and CSE groups, with 130 isolates and 62 sp. isolates) were included. The IMP-11 type was present in 43 patients, IMP-1 in 33, and IMP-60 and IMP-66 in 1 each; 31 patients with CRE (32.3%) and 34 with CSE (35.4%) developed infections. Multivariate analysis identified the following independent risk factors: gastrostomy, history of intravenous therapy or hemodialysis, and previous exposure to broad-spectrum β-lactam antibiotics, including penicillin with β-lactamase inhibitors, cephalosporins, and carbapenems. In propensity score-adjusted analysis, mortality rates for the CRE and CSE groups were similar (15.0% and 19.5%, respectively). We found that IMP-CRE may not contribute to worsened clinical outcomes, compared to CSE, and gastrostomy, previous intravenous therapy, hemodialysis, and broad-spectrum antimicrobial exposure were identified as risk factors for CRE isolation. Fluoroquinolone and aminoglycosides are potentially useful antibiotics for IMP-CRE infections.
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http://dx.doi.org/10.1128/AAC.01483-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092526PMC
February 2021

Secondary osteomyelitis from contiguous intrapelvic hematoma.

Pediatr Int 2020 Nov;62(11):1301-1303

Department of Infectious Diseases, Medical Mycology Research Center, Chiba University, Chiba, Japan.

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http://dx.doi.org/10.1111/ped.14338DOI Listing
November 2020

The effects of Japan's National Action Plan on Antimicrobial Resistance on antimicrobial use.

Int J Infect Dis 2021 Feb 20;103:154-156. Epub 2020 Nov 20.

AMR Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo, Japan; Collaborative Chairs Emerging and Reemerging Infectious Diseases, National Center for Global Health and Medicine, Graduate School of Medicine, 1-1, Seriryo-tyo, Aoba-ku, Sendai, Miyagi, Japan; Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo, Japan. Electronic address:

The aim of this study was to estimate the effects of Japan's National Action Plan on Antimicrobial Resistance 2016-2020 (NAP) on antimicrobial use (AMU). Monthly AMU from January 2013 to December 2019 was calculated using sales data, and time-series charts of AMU were then created for the total antimicrobials and target drug categories shown in the NAP (oral cephalosporins, oral fluoroquinolones, oral macrolides, and parenteral antimicrobials). Twelve-month predictions were generated to evaluate AMU in 2020. The publication of the NAP was associated with an AMU reduction in total antimicrobials, cephalosporins, fluoroquinolones, and macrolides. Parenteral AMU showed an upward trend, although it was not significantly associated with the intervention effect. AMU reductions of 15.0% for total antimicrobials, 26.3% for cephalosporins, 23.5% for fluoroquinolones, and 24.6% for macrolides were predicted for 2020 relative to 2013. However, there was a predicted increase of 17.4% for parenteral AMU. While Japan's NAP has contributed to the reduction in national AMU over the past 5 years, sustained action is still needed to further improve antimicrobial stewardship and promote countermeasures to antimicrobial resistance.
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http://dx.doi.org/10.1016/j.ijid.2020.11.158DOI Listing
February 2021

Epidemiology of antibiotic treatment for uncomplicated cystitis in adults in Japan.

J Infect Chemother 2021 Jan 1;27(1):113-116. Epub 2020 Oct 1.

AMR Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan; Collaborative Chairs Emerging and Reemerging Infectious Diseases, National Center for Global Health and Medicine, Graduate School of Medicine, Tohoku University, 1-1, Seiryo-machi, Aobaku, Sendai-shi, Miyagi, 980-8574, Japan; Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.

Introduction: A large number of antibiotics are used for the treatment of uncomplicated cystitis owing to its high morbidity. As the administration of antibiotics for uncomplicated cystitis may be considered an example of inappropriate use, outpatient antimicrobial stewardship for this condition is important. We evaluated the current pharmacoepidemiology trends for the treatment of uncomplicated cystitis in Japan to predict stewardship strategies.

Methods: This descriptive observational study analyzed data from an anonymized claims database of employees and their family members covered by the employer's health insurance. We identified female outpatients diagnosed with acute cystitis (ICD-10 code N300) aged ≥15 years and extracted oral antibiotic prescription records between 2013 and 2016. We excluded prescriptions for >7 days.

Results: The most prescribed antibiotic category was fluoroquinolones (52.67%), followed by cephalosporins and penems (40.63%). Third-generation cephalosporins accounted for 90.91% of cephalosporin and penem prescriptions. The most common duration of antibiotic prescription was 5 days, except for first-generation cephalosporins, penem (7 days) and sulfamethoxazole and trimethoprim (3 days).

Conclusion: Fluoroquinolones and third-generation cephalosporins were prescribed to most uncomplicated cystitis cases in Japan. Although the lack of alternatives to quinolones and beta-lactams in Japan is an obstacle for antimicrobial stewardship for uncomplicated cystitis, promoting accurate diagnoses and establishing alternatives available in the Japanese market are important. Shortening the treatment duration is also an important strategy. Further research is needed on local antimicrobial resistance patterns to determine a fixed treatment strategy for uncomplicated cystitis.
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http://dx.doi.org/10.1016/j.jiac.2020.09.001DOI Listing
January 2021

Trends of Antifungal Use Based on Sales Data in Japan from 2006 to 2015.

Biol Pharm Bull 2020 ;43(8):1248-1252

AMR Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine.

The detailed epidemiology of invasive mycoses and superficial mycoses has not been clarified in Japan. In addition, treatment options have increased because of novel antifungals and/or guidelines for fungal infection. In the present study, we aimed to clarify the trends of antifungal use in Japan from 2006 to 2015 based on sales data to serve as an alternative indicator of fungal infection trends. We found that the total antifungal use decreased over time (r = -0.057, P < 0.0001). Oral and parenteral use significantly decreased by 44.1% (r = -0.056, P < 0.0001) and 27.1% (r = -0.0012, P = 0.00061), respectively. The trend of antifungal use for superficial mycoses significantly decreased by 49.8% (r = -0.061, P < 0.0001). However, the trend of antifungal use for invasive mycoses was significantly increased by 19.9% (r = 0.0032, P = 0.00045). In Japan, the increase in the number of immunocompromised patients might be associated with the increase in the frequency of antifungal use for invasive mycoses. This is the first study to clarify the trends of antifungal use in Japan. Further research is needed to establish a continuous surveillance system to compare fungal infections between Japan and the world.
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http://dx.doi.org/10.1248/bpb.b20-00302DOI Listing
May 2021

Narrative Review: The Process of Expanding the Manual of Antimicrobial Stewardship by the Government of Japan.

Intern Med 2021 Jan 21;60(2):181-190. Epub 2020 Jul 21.

AMR Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine Hospital, Japan.

The Ministry of Health, Labour and Welfare has published the Manual of Antimicrobial Stewardship (1st edition) in June 2017 to improve the prescribing practice of antimicrobials for immunocompetent adult and pediatric (both school-aged and older children) patients. Due to the increasing demand for further promoting outpatient antimicrobial stewardship, we conducted a literature and national guideline review to identify the area of need. The results of our review revealed a high antimicrobial prescription rate in the Japanese pediatric population. Furthermore, although the Japanese clinical guidelines/guidance covered the fields of almost all infectious diseases, no system exists to estimate the incidence and treatment patterns of important infectious diseases such as asymptomatic bacteriuria, skin and soft tissue infections, and dental practices in Japan. Therefore, addressing the issues of both establishing surveillance systems and the implementation of guidelines/guidance can be the next step to promote further outpatient antimicrobial stewardship.
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http://dx.doi.org/10.2169/internalmedicine.4760-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872805PMC
January 2021

Impact of antimicrobial stewardship fee on prescribing for Japanese pediatric patients with upper respiratory infections.

BMC Health Serv Res 2020 May 11;20(1):399. Epub 2020 May 11.

Antimicrobial Resistance Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan.

Background: In 2018, the Japanese medical reimbursement system was revised to introduce a fee for the implementation of an antimicrobial stewardship (AS) fee for pediatric patients. The purpose of this study was to evaluate physicians' prescription behavior following this revision.

Methods: We conducted a retrospective observational study from January 1, 2017 to September 30, 2018 of pediatric (< 15 years) outpatients with upper respiratory tract infections (URIs). To assess the pattern of antibiotic prescription for the treatment of pediatric URIs before and after the introduction of the AS fee, we extracted data on pediatric URIs, diagnosed during the study period. Patients were divided based on whether medical facilities claimed AS fees. We defined antibiotic use as the number of antibiotics prescribed, and evaluated the proportion of each class to the total number of antibiotics prescribed. We also recorded the number of medical facilities that each patient visited during the study period.

Results: The frequency of antibiotic prescription decreased after AS fee implementation, regardless of whether the facility claimed the AS fee, but tended to be lower in facilities that claimed the fee. Additionally, the frequency of antibiotic prescription decreased in all age groups. Despite the reduced frequency of antibiotic prescription, consultation behavior did not change.

Conclusions: The AS fee system, which compensates physicians for limiting antibiotic prescriptions, helped to reduce unnecessary antibiotic prescription and is thus a potentially effective measure against antimicrobial resistance.
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http://dx.doi.org/10.1186/s12913-020-05288-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212615PMC
May 2020

Pharmacist-supported antimicrobial stewardship in a retirement home.

J Infect Chemother 2020 Aug 30;26(8):858-861. Epub 2020 Apr 30.

Disease Control and Prevention Center, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.

In an 80-bed fee-based retirement home with nursing care, the dispatched-pharmacist has provided prescription recommendations to visiting physicians based on pathogen identification using Gram staining as part of an antimicrobial stewardship program. Thus, we evaluated the effects of pharmacist-supported antimicrobial stewardship. We calculated the total number of all antimicrobials and macrolides, fluoroquinolones, and cephalosporins prescriptions per 100 residents per month at the retirement home from January 2013 to December 2017. Using log-transformed monthly resident numbers with an offset before and after the intervention, we performed Poisson regression analyses that adjusted for monthly mean age. Interrupted time series analyses (ITSA) were conducted to examine the changes in the incidence rate ratios for the baseline and slope before and after the intervention. The total number of all antimicrobial prescriptions per 100 residents per month from 2013 to 2017 was 14.10, 18.51, 10.59, 5.41, and 3.90, respectively. Although there was a significant pre-intervention increase in the total number of all antimicrobial prescriptions, the intervention was followed by a significant decrease. There was also a significant reduction in the slope. ITSA of the changes in the prescription of macrolides and fluoroquinolones showed that there were significant pre-intervention increase and followed by a significant post-intervention decrease in the slope. There was no significant change in cephalosporin prescriptions by the intervention. Our study shows that pharmacist-supported AS can reduce antimicrobial prescriptions in a retirement home. Nevertheless, further studies are needed to collect and analyse more data on similar interventions.
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http://dx.doi.org/10.1016/j.jiac.2020.04.008DOI Listing
August 2020
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