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

This study aimed to clarify other diseases claimed simultaneously with acute upper respiratory infection (URI), antibiotic prescriptions, and examinations associated with infectious diseases in pediatric patients with acute URI insurance claims at otorhinolaryngology outpatient visits. Pediatric patients who visited an otolaryngology department between 2019 and 2021 and were definitively diagnosed with URI were selected using a large Japanese medical claims database. Patient backgrounds, antibiotic use, and examinations were descriptively evaluated. In total, 8010 patients were included in the analysis. The median number (interquartile range) of diseases claimed in the same month as acute URI was 4 (3–6). Only 519 (6.5 %) patients were claimed as acute URI alone. Regardless of the prescription of antibiotics, the most commonly redundantly claimed disease in these patients was allergic rhinitis, followed by acute bronchitis, acute sinusitis, and earwax impaction. The frequently prescribed antibiotics were third-generation cephalosporins, macrolides, and penicillins with extended-spectrum, including amoxicillin which was recommended by the Japanese manual; the proportion of patients with examinations was low (2.9–21.7 %). Among patients with acute URI, diagnoses requiring antibiotics were also claimed; therefore, when evaluating acute URI using the Japanese medical claims database, care must be taken in patient selection. Moreover, the implementation rate of examinations necessary for diagnosis was low, so there is an urgent need to develop an environment where examinations can be conducted in outpatient settings. [ABSTRACT FROM AUTHOR]

Objectives: Although amoxicillin is the first‐line prophylactic drug for impacted mandibular third molar extraction, third‐generation cephalosporins are widely prescribed in Japan. The lack of real‐world evidence may be one reason for this inappropriate use. We evaluated differences in the incidence of surgical site infection between amoxicillin and third‐generation cephalosporins for impacted mandibular third molar extraction. Methods: Using the JMDC Claims Database, we identified dental visits with fully or horizontally impacted mandibular third molar extraction from April 2015 to March 2020. One‐to‐one propensity‐score matching was conducted between amoxicillin and third‐generation cephalosporin groups. The incidence of surgical site infection following extraction was compared in the matched pairs using McNemar's test. Results: We identified 109,266 dental visits, including 39,514 (36.2%) patients who received amoxicillin and 69,752 (63.8%) patients who received third‐generation cephalosporins. In the 39,514 matched pairs, the incidence of surgical site infection was 3.5% (n = 1399) for amoxicillin group and 3.7% (n = 1467) for third‐generation cephalosporin group (p = 0.003). Conclusions: Amoxicillin was associated with a lower incidence of surgical site infection after impacted mandibular third molar extraction compared with third‐generation cephalosporins. This result supports current guidelines and strengthens the importance of disseminating and implementing antimicrobial resistance control in dentistry. [ABSTRACT FROM AUTHOR]

Background The choice of prophylactic antibiotics for use in endonasal transsphenoidal surgery (ETSS) lacks universal standards. This study aimed to investigate the effectiveness of cefazolin, ampicillin and third-generation cephalosporins for preventing postoperative meningitis and secondary outcomes (in-hospital death and the combination of pneumonia and urinary tract infection) in patients who have undergone ETSS. Methods The study used data from the Diagnosis Procedure Combination database in Japan. Data from 10 688 patients who underwent ETSS between April 2016 and March 2021 were included. Matching weight analysis based on propensity scores was conducted to compare the outcomes of patients receiving cefazolin, ampicillin or third-generation cephalosporins as prophylactic antibiotics. Results Of the 10 688 patients, 9013, 102 and 1573 received cefazolin, ampicillin and third-generation cephalosporins, respectively. The incidence of postoperative meningitis did not significantly differ between the cefazolin group and the ampicillin group (OR, 1.02; 95% CI, 0.14–7.43) or third-generation cephalosporins group (OR, 0.81; 95% CI, 0.10–6.44). Similarly, in-hospital death and the composite incidence of pneumonia and urinary tract infection did not differ between the cefazolin group and the ampicillin or third-generation cephalosporins group. Conclusions Cefazolin, ampicillin and third-generation cephalosporins as perioperative prophylactic antibiotics for ETSS do not differ significantly in terms of preventing meningitis. [ABSTRACT FROM AUTHOR]

Introduction: Antimicrobial resistance (AMR) is a major global health threat. While antimicrobial consumption (AMC) in Japan substantially decreased after implementation of the AMR National Action Plan, the disease burden due to AMR seems to be unchanged. The main objective of this study is to examine the relationship between AMC and the disease burden due to AMR in Japan. Methods: We estimated the annual population-standardized AMC from 2015 to 2021 using defined daily doses (DDDs) per 1000 inhabitants per day (DIDs) and the disease burden due to bloodstream infections caused by nine major antimicrobial-resistant bacteria (AMR-BSIs) from 2015 to 2021 using disability-adjusted life years (DALYs). We then examined the correlation between AMC and DALYs using Spearman's rank correlation coefficient and cross-correlation function. Spearman's ρ > 0.7 was considered to indicate a strong correlation. Results: The sales amounts of third-generation cephalosporins, fluoroquinolones, and macrolides were 3.82 DIDs, 2.71 DIDs, and 4.59 DIDs, respectively, in 2015, but 2.11, 1.48, and 2.72 in 2021. This corresponded to reductions of 44.8%, 45.4%, and 40.7% during the study period. DALYs due to AMR-BSIs were 164.7 per 100,000 population in 2015 but 195.2 per 100,000 in 2021. Spearman's rank correlation coefficients between AMC and DALYs were − 0.37 (total antibiotics), − 0.50 (oral antibiotics), − 0.43 (third-generation cephalosporins), − 0.5 (fluoroquin,olones) and − 0.5 (macrolides). No obvious cross-correlations were found. Conclusions: Our results reveal that changes in AMC are not associated with DALYs caused by AMR-BSIs. AMR countermeasures besides efforts to reduce inappropriate AMC might be necessary to mitigate the disease burden due to AMR. [ABSTRACT FROM AUTHOR]

In recent years, antimicrobial resistance （AMR） has become a health problem worldwide. In Japan, the Ministry of Health, Labour and Welfare （MHLW） has presented an action plan for AMR countermeasures. Although the standard duration of antimicrobial therapy for dental infections has been shown to vary depending on type of infection and patient's condition, three-day therapy is considered the basic duration. Inappropriate or prolonged administration of antimicrobial agents results in the emergence of drug-resistant bacteria. Particularly, prolonged use of empiric antimicrobial agents may lead to the emergence of drug-resistant bacteria. Therefore, in this study, we evaluated the use and duration of antimicrobial administration in dental practice. The results showed that more than 80 ％ of prescriptions were for 3 days or less, with a decreasing trend in the number of prescriptions of cephalosporins, （particularly, the third-generation. In addition, there were an increasing number of prescriptions of penicillins. However, since the reduction rate of cephalosporins has not reached that reduction rate set forth in the Action Plan for AMR control, the hospital Infection Control Team （ICT） and Antimicrobial Stewardship Team （AST）, which are currently expected to carry out few interventions in dental practice, should significantly limit antimicrobial use and ensure the use of firstline drugs for treatment. The significance of these interventions in the dental field could be effective. [ABSTRACT FROM AUTHOR]

• This is the first multicenter study on extended-spectrum beta-lactamase–related febrile urinary tract infections in Japanese children. • Risk factors include previous history of febrile urinary tract infections and recent antibiotic use. • Most patients who started on discordant antibiotics experienced clinical improvement. The incidence of infections caused by extended-spectrum beta-lactamase (ESBL)–producing bacteria has increased. This study aimed to clarify the risk factors and treatment strategies for febrile urinary tract infection (fUTI) caused by ESBL-producing bacteria in Japanese children. A retrospective observational study was conducted in 21 hospitals among children aged <16 years diagnosed with an fUTI between 2008 and 2017. Clinical data of children with fUTI caused by ESBL-producing and non-ESBL–producing bacteria were compared. Of the 2049 cases of fUTI, 147 (7.2%) were caused by ESBL-producing bacteria. Children in the ESBL group were more likely to have a history of recent antibiotic use or prophylactic antibiotic use, and experience recurrent UTIs (P <0.001) compared with those in the non-ESBL group. Of the 124 cases of fUTI due to ESBL-producing bacteria that were reviewed, 20 and 100 had concordant and discordant antibiotic use, respectively, and four had unknown antibiotic susceptibility. The median time from the start of treatment to fever resolution was 24 hours and did not differ significantly by therapy group (P = 0.39). ESBL-producing bacteria should be considered in children with recurrent UTIs and recent antibiotic use. Most children with fUTI experience clinical improvement regardless of the choice of antibiotic. [ABSTRACT FROM AUTHOR]

What is known and objective: Third‐generation oral cephalosporins, especially cefcapene‐pivoxil (CFPN‐PI), have been used frequently in the Japanese dental field. In December 2014 and April 2016, the newly published clinical guidelines recommended the use of amoxicillin (AMPC). Thus, it is important to evaluate the impact of these guidelines on the prescription profiles of prophylactic antibiotics, clinical outcomes and cost‐effectiveness of antibiotics. Methods: We conducted a retrospective study to analyse an interrupted time series analysis from April 2013 to March 2020 at the Department of Dentistry of Hokkaido University Hospital. A segmented regression model was used to estimate the changes in the incidence of infectious complications following tooth extraction. Prescribed antibiotic data were evaluated via days of therapy (DOT). Antibiotic costs were calculated in terms of the Japanese yen (JPY). Results and Discussion: We identified 17,825 eligible patients. The incidence rates of infectious complications (SSI + dry socket) and SSI after tooth extraction were 3.2% and 2.2%, respectively, during the entire period. The extraction of impacted third molars corresponded to 5.0% and 3.4%, respectively. However, their incidence rates were not significantly different during this period. The use of prophylactic antibiotics and antibiotic cost showed consistent trends following the implementation of guidelines. The mean DOT of CFPN‐PI decreased (ranging from 4893.6 DOTs/1000 patients [March 2013 to November 2014] to 3856.4 DOTs/1000 patients [December 2014 to March 2016]; p < 0.001, and from 3856.4 DOTs/1000 patients [December 2014 to March 2016] to 2293.9 DOTs/1000 patients [April 2016 to March 2020]; p < 0.001). In contrast, the mean DOT of AMPC was found to be increased (ranging from 1379.7 DOTs/1000 patients [March 2013 to November 2014] to 3236.3 DOTs/1000 patients [December 2014 to March 2016]; p < 0.001, and from 3236.3 DOTs/1000 patients [December 2014 to March 2016] to 4597.8 DOTs/1000 patients [April 2016 to March 2020]; p < 0.001). The mean monthly cost was decreased (ranging from 905.3 JPY [March 2013 to November 2014] to 788.7 JPY [December 2014 to March 2016]; p = 0.003, and from 788.7 JPY [December 2014 to March 2016] to 614.0 JPY [April 2016 to March 2020]; p < 0.001). What is new and conclusion: After December 2014, prophylactic antibiotics were switched from CFPN‐PI to AMPC, and the incidence rate of infectious complications was not significantly different over time. However, changing antibiotics is useful from a cost‐effectiveness perspective. [ABSTRACT FROM AUTHOR]

Background: Urinary tract infections (UTIs) are the most common bacterial infections in children. This study aimed to review characteristics of causative bacteria and the effectiveness of antimicrobial therapy in children with febrile UTIs. Methods: Clinical records of 108 patients (130 episodes) with febrile UTIs admitted to the Kawasaki Medical School Hospital between July 2009 and October 2016 were retrospectively reviewed. The characteristics of the causative bacteria, antibacterial therapy, and therapeutic effect were verified. Results: Patients were aged between 0 and 183 months (median age: 3 months). Seventy‐three (67.6%) were males. Sixty‐three episodes (48.5%) were diagnosed with complicated UTIs. Forty‐seven episodes (36.2%) were observed in patients aged <3 months; 15 of them had complicated UTIs. Escherichia coli (E. coli) was the most common pathogen, followed by Enterococcus faecalis (E. faecalis). Blood cultures were positive in three episodes. Among the 130 episodes, 62 (47.7%) were treated with a combination of ampicillin and third‐generation cephalosporins, followed by third‐generation cephalosporins (31 episodes, 23.8%) and sulbactam sodium / ampicillin sodium (15 episodes, 11.5%). In case of patients with uncomplicated/complicated UTIs and patients aged <3 and ≥3 months, the most common pathogen was E. coli, followed by E. faecalis. There was no difference in therapeutic effects between "combination ampicillin and third‐generation cephalosporins" and "third‐generation cephalosporin monotherapy" administered for the treatment of UTIs caused by E. coli. Conclusions: Escherichia coli is the most common pathogen among pediatric UTIs. For antibacterial therapy, third‐generation cephalosporin monotherapy is effective and may not require combination therapy with ampicillin. [ABSTRACT FROM AUTHOR]

Oral antibiotic therapy is routinely administered when a third molar (M3) is extracted to prevent infectious complications after surgery. Oral third-generation cephalosporins are frequently used after M3 extraction in Japan but at the expense of an increased risk of antimicrobial resistance. Therefore, the infection control team (ICT) at our institution recommended a reduction in use of these agents after M3 extraction. In this study, we compared the types of antibiotic agents prescribed for patients undergoing M3 extraction before and after this recommendation. We investigated the relationship between type of antibiotic used and the likelihood of infectious complications as well as cost savings in patients who underwent M3 extraction in the 6 months before and after the ICT recommendation in July 2018. There was a marked reduction in use of oral third-generation cephalosporins after M3 extraction (P < 0.0001) and increased use of oral penicillins and first-generation cephalosporins after the ICT recommendation. Moreover, surgical site infection (SSIs) were significantly less common after the ICT recommendation (P = 0.0099); however, the SSI rate was higher in patients who received a third-generation cephalosporin than in those who received penicillin (8.8% vs 0.5%). There was also a significant saving in per-patient antibiotic costs after the ICT recommendation (269.5 ± 282.0 JPY vs 454.7 ± 376.6 JPY; P < 0.0001). These findings suggest that collaboration with an ICT promotes appropriate antibiotic use, decreases the risk of an SSI, and improves the cost-benefit ratio in patients undergoing M3 extraction. [ABSTRACT FROM AUTHOR]

Background: In this age of antimicrobial resistance, unnecessary use of antibiotics to treat non-bacterial acute respiratory tract infections (ARTIs) and inappropriate use of antibiotics in treating bacterial ARTIs are public health concerns.Purpose: Our aim is to identify the pattern of oral antibiotic prescriptions for outpatients with ARTIs in Japan.Methods: We analysed health insurance claims data of patients (aged ≤74 years) from 2013 to 2015, to determine the pattern of antibiotic prescriptions for outpatient ARTIs and calculated the proportion of each antibiotic.Results: Data on 4.6 million antibiotic prescriptions among 1559394 outpatients with ARTIs were analysed. The most commonly prescribed classes of antibiotics included cephalosporins (41.9%), macrolides (32.8%) and fluoroquinolones (14.7%). The proportion of first-, second- and third-generation cephalosporins was 1.0%, 1.7% and 97.3%, respectively. Fluoroquinolones accounted for a quarter of the prescriptions for ARTIs in patients aged >20 years. In contrast, penicillins accounted for just 8.0% of the total number of antibiotic prescriptions for ARTIs.Conclusions: According to clinical guidelines, penicillins are first-line antibiotics against ARTIs. However, third-generation cephalosporins, macrolides and fluoroquinolones are more frequently prescribed in Japan. Although we could not assess the extent to which appropriate antibiotics are selected, our results support the necessity of improving antibiotic choices in the treatment of ARTIs. [ABSTRACT FROM AUTHOR]

• The National Action Plan on Antimicrobial Resistance significantly reduced antimicrobial use in Japan. • The plan resulted in both an immediate and accelerated reduction in antimicrobial use. • These changes were observed for total and broad-spectrum oral antimicrobials. • Parenteral antimicrobial use did not decrease after implementation of the plan. 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. [ABSTRACT FROM AUTHOR]

Cefiderocol is an injectable siderophore cephalosporin discovered and being developed by Shionogi & Co., Ltd., Japan. As with other β-lactam antibiotics, the principal antibacterial/bactericidal activity of cefiderocol occurs by inhibition of Gram-negative bacterial cell wall synthesis by binding to penicillin binding proteins; however, it is unique in that it enters the bacterial periplasmic space as a result of its siderophore-like property and has enhanced stability to β-lactamases. The chemical structure of cefiderocol is similar to both ceftazidime and cefepime, which are third- and fourth-generation cephalosporins, respectively, but with high stability to a variety of β-lactamases, including AmpC and extended-spectrum β-lactamases (ESBLs). Cefiderocol has a pyrrolidinium group in the side chain at position 3 like cefepime and a carboxypropanoxyimino group in the side chain at position 7 of the cephem nucleus like ceftazidime. The major difference in the chemical structures of cefiderocol, ceftazidime and cefepime is the presence of a catechol group on the side chain at position 3. Together with the high stability to β-lactamases, including ESBLs, AmpC and carbapenemases, the microbiological activity of cefiderocol against aerobic Gram-negative bacilli is equal to or superior to that of ceftazidime-avibactam and meropenem, and it is active against a variety of Ambler class A, B, C and D β-lactamases. Cefiderocol is also more potent than both ceftazidime-avibactam and meropenem versus Acinetobacter baumannii, including meropenem non-susceptible and multidrug-resistant (MDR) isolates. Cefiderocol's activity against meropenem-non-susceptible and Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriales is comparable or superior to ceftazidime-avibactam. Cefiderocol is also more potent than both ceftazidime-avibactam and meropenem against all resistance phenotypes of Pseudomonas aeruginosa and against Stenotrophomonas maltophilia. The current dosing regimen being used in phase III studies is 2 g administered intravenously every 8 h (q8 h) using a 3-h infusion. The pharmacokinetics of cefiderocol are best described by a three-compartment linear model. The mean plasma half-life (t½) was ~ 2.3 h, protein binding is 58%, and total drug clearance ranged from 4.6-6.0 L/h for both single- and multi-dose infusions and was primarily renally excreted unchanged (61-71%). Cefiderocol is primarily renally excreted unchanged and clearance correlates with creatinine clearance. Dosage adjustment is thus required for both augmented renal clearance and in patients with moderate to severe renal impairment. In vitro and in vivo pharmacodynamic studies have reported that as with other cephalosporins the pharmacodynamic index that best predicts clinical outcome is the percentage of time that free drug concentrations exceed the minimum inhibitory concentration (%fT > MIC). In vivo efficacy of cefiderocol has been studied in a variety of humanized drug exposure murine and rat models of infection utilizing a variety of MDR and extremely drug resistant strains. Cefiderocol has performed similarly to or has been superior to comparator agents, including ceftazidime and cefepime. A phase II prospective, multicenter, double-blind, randomized clinical trial assessed the safety and efficacy of cefiderocol 2000 mg q8 h versus imipenem/cilastatin 1000 mg q8 h, both administered intravenously for 7-14 days over 1 h, in the treatment of complicated urinary tract infection (cUTI, including pyelonephritis) or acute uncomplicated pyelonephritis in hospitalized adults. A total of 452 patients were initially enrolled in the study, with 303 in the cefiderocol arm and 149 in the imipenem/cilastatin arm. The primary outcome measure was a composite of clinical cure and microbiological eradication at the test-of-cure (TOC) visit, that is, 7 days after the end of treatment in the microbiological intent-to-treat (MITT) population. Secondary outcome measures included microbiological response per pathogen and per patient at early assessment (EA), end of treatment (EOT), TOC, and follow-up (FUP); clinical response per pathogen and per patient at EA, EOT, TOC, and FUP; plasma, urine and concentrations of cefiderocol; and the number of participants with adverse events. The composite of clinical and microbiological response rates was 72.6% (183/252) for cefiderocol and 54.6% (65/119) for imipenem/cilastatin in the MITT population. Clinical response rates per patient at the TOC visit were 89.7% (226/252) for cefiderocol and 87.4% (104/119) for imipenem/cilastatin in the MITT population. Microbiological eradication rates were 73.0% (184/252) for cefiderocol and 56.3% (67/119) for imipenem/cilastatin in the MITT population. Additionally, two phase III clinical trials are currently being conducted by Shionogi & Co., Ltd., Japan. The two trials are evaluating the efficacy of cefiderocol in the treatment of serious infections in adult patients caused by carbapenem-resistant Gram-negative pathogens and evaluating the efficacy of cefiderocol in the treatment of adults with hospital-acquired bacterial pneumonia, ventilator-associated pneumonia or healthcare-associated pneumonia caused by Gram-negative pathogens. Cefiderocol appears to be well tolerated (minor reported adverse effects were gastrointestinal and phlebitis related), with a side effect profile that is comparable to other cephalosporin antimicrobials. Cefiderocol appears to be well positioned to help address the increasing number of infections caused by carbapenem-resistant and MDR Gram-negative bacilli, including ESBL- and carbapenemase-producing strains (including metallo-β-lactamase producers). A distinguishing feature of cefiderocol is its activity against resistant P. aeruginosa, A. baumannii, S. maltophilia and Burkholderia cepacia. [ABSTRACT FROM AUTHOR]

Objectives: We examined four clinical strains of Neisseria gonorrhoeae (GU030113, GU110095, GU110332 and GU110362) isolated between 2000 and 2014 in Japan, exhibiting ceftriaxone MICs of 0.5 mg/L, for mutations of the genes associated with penicillin resistance.Methods: The penA, mtrR, porB1b (penB), ponA and pilQ genes of the strains were sequenced. PBP2s of the strains were aligned to the PBP2s associated with decreased susceptibility to oral cephalosporins, and PBP2s of previously reported strains with decreased susceptibility to ceftriaxone.Results: GU030113 had PBP2 pattern X with an additional substitution of A502T. GU110095 had PBP2 pattern XXVII. GU110332 had PBP2 pattern XXXIV with an additional substitution of P552S. GU110362 had PBP2 composed of pattern X (amino acid positions 1-291) and pattern V (amino acid positions 292-576). GU030113, GU110095 and GU110332 had deletion of A in the mtrR promoter, G120K and A121D or A121N in PorB1b and L421P in PBP1. GU110362 had A40D in the repressor of MtrR and L421P in PBP1. The strains did not have mutations of pilQ1 and pilQ2.Conclusions: Addition of A502T to PBP2 pattern X in GU030113 and of P552S to PBP2 pattern XXXIV in GU110332 would possibly contribute to decreased susceptibility to ceftriaxone. In GU110095 and GU110362, it was suggested that, in addition to their altered PBP2s, the enhanced efflux pump, reduced permeability in the outer membrane, another altered target of β-lactams and/or other mechanisms not identified in the present study might contribute to decreased susceptibility. [ABSTRACT FROM AUTHOR]

In Japan, most tularemia cases occur after contact with hares (hunting, cooking) and involve the glandular or ulceroglandular form. Here, we present a case of typhoidal tularemia in a 72-year-old Japanese male farmer who presented with fever, fatigue, and right lower abdominal pain. Computed tomography revealed intestinal wall thickening at the ascending colon, pleural effusion, and ascites. Following an initial diagnosis of bacterial enteric infection, his symptoms deteriorated after a week-long cephalosporin treatment course. The patient lived in an area endemic for scrub typhus; the antibiotic was changed to a tetracycline on suspicion of scrub typhus infection. His symptoms rapidly improved after initiation of minocycline treatment. Later, blood tests revealed marked increases in serological tests against Francisella tularensis exclusively, and the patient was diagnosed with typhoidal tularemia. Typhoidal tularemia may be characterized by any combination of general symptoms, but does not exhibit the local manifestations associated with other forms of tularemia. The patient, in this case, had no direct contact with hares or other wild animals and did not present with local manifestations of tularemia. Physicians should consider this disease, especially when tick-borne disease is suspected in the absence of local wounds, eschar, ulcers, or lymphadenopathy. [ABSTRACT FROM AUTHOR]

Extended-spectrum β-lactamase (ESBL)-producing Salmonella are one of the most important public health problems in developed countries. ESBL-producing Salmonella strains have been isolated from humans in Asian countries neighboring Japan, along with strains harboring the plasmid-mediated extended-spectrum cephalosporin (ESC)-resistance gene, ampC (pAmpC). However, only a few studies have investigated the prevalence of ESC-resistant Salmonella in chicken products in Japan, which are the main vehicle of Salmonella transmission. The aim of this study was to investigate the prevalence of ESBL-producing, pAmpC-harboring, or carbapenem-resistant Salmonella in chicken products in Japan. In total, 355 out of 779 (45.6%) chicken product samples collected from 1996–2010 contained Salmonella, resulting in 378 distinct isolates. Of these isolates, 373 were tested for resistance to ESCs, cephamycins, or carbapenems. Isolates that showed resistance to one or more of these antimicrobials were then examined by PCR and DNA sequence analysis for the presence of the blaCMY, blaCTX-M, blaTEM, and blaSHV resistance genes. Thirty-five resistant isolates were detected, including 26 isolates that contained pAmpC (blaCMY-2), and nine ESBL-producing isolates harboring blaCTX-M (n = 4, consisting of two blaCTX-M-2 and two blaCTX-M-15 genes), blaTEM (n = 4, consisting of one blaTEM-20 and three blaTEM-52 genes), and blaSHV (n = 1, blaSHV-12). All pAmpC-harboring and ESBL-producing Salmonella isolates were obtained from samples collected after 2005, and the percentage of resistant isolates increased significantly from 0% in 2004 to 27.9% in 2010 (P for trend = 0.006). This increase was caused in part by an increase in the number of Salmonella enterica subsp. enterica serovar Infantis strains harboring an approximately 280-kb plasmid containing blaCMY-2 in proximity to ISEcp1. The dissemination of ESC-resistant Salmonella containing plasmid-mediated blaCMY-2 in chicken products indicates the need for the development of continuous monitoring strategies in the interests of public health. [ABSTRACT FROM AUTHOR]

The article discusses a reports about the colistin-resistant Escherichia coli isolates from Japan, including a global-spreading pathogenic lineage. E. coli isolates obtained from clinical specimens taken at Sapporo Clinical Laboratory Inc. and Sapporo Medical University Hospital in Japan were tested and four E. coli isolates exceeded the colistin resistance breakpoint. The colistin-resistant isolates reported were resistant to fluoroquinolones, and one (SME296) was resistant to cephalosporins.

Resistance to broad-spectrum cephalosporins (BSCs) in Enterobacteriaceae in companion animals has become a great concern for public health. To estimate the dissemination of BSC-resistant bacteria between dog and human, we examined the BSC-resistance determinants of and genetic similarities between 69 BSC-resistant Escherichia coli isolates derived from canine rectal swabs (n = 28) and human clinical samples (n = 41). Some E. coli isolates possessed blaTEM-1b (14 canine and 16 human isolates), blaCTx-M-2 (6 human isolates), blaCTx-M-14 (3 canine and 14 human isolates), blaCTx-M-27 (1 canine and 15 human isolates), and blaCMY-2 (11 canine and 3 human isolates). The possession of CTX-M-type β-lactamases was significantly more frequent in human isolates, whereas CMY-2 was more common in canine isolates. Bacterial typing methods (phylogenetic typing, O-antigen serotyping, and pulsed-field gel electrophoresis) showed little clonal relationship between canine isolates and human isolates. Plasmid analysis and Southern blotting indicated that the plasmids encoding CMY-2 were similar among canine and human isolates. Based on the differences in the major β-lactamase and the divergence of bacterial types between canine and human isolates, it seems that clonal dissemination of BSC-resistant E. coli between canines and humans is limited. The similarity of the CMY-2-encoding plasmid suggests that plasmid-mediated β-lactamase gene transmission plays a role in interspecies diffusion of BSC-resistant E. coli between dog and human. [ABSTRACT FROM AUTHOR]

The use of extended-spectrum cephalosporins in food animals has been suggested to increase the risk of spread of Enterobacteriaceae carrying extended-spectrum β-lactamases to humans. However, evidence that selection of extended-spectrum cephalosporin–resistant bacteria owing to the actual veterinary use of these drugs according to criteria established in cattle has not been demonstrated. In this study, we investigated the natural occurrence of cephalosporin-resistant Escherichia coli in dairy cattle following clinical application of ceftiofur. E. coli isolates were obtained from rectal samples of treated and untreated cattle (n = 20/group) cultured on deoxycholate-hydrogen sulfide-lactose agar in the presence or absence of ceftiofur. Eleven cefazoline-resistant isolates were obtained from two of the ceftiofur-treated cattle; no cefazoline-resistant isolates were found in untreated cattle. The cefazoline-resistant isolates had mutations in the chromosomal ampC promoter region and remained susceptible to ceftiofur. Eighteen extended-spectrum cephalosporin–resistant isolates from two ceftiofur-treated cows were obtained on ceftiofur-supplemented agar; no extended-spectrum cephalosporin–resistant isolates were obtained from untreated cattle. These extended-spectrum cephalosporin–resistant isolates possessed plasmid-mediated β-lactamase genes, including blaCTX-M-2 (9 isolates), blaCTX-M-14 (8 isolates), or blaCMY-2 (1 isolate); isolates possessing blaCTX-M-2 and blaCTX-M-14 were clonally related. These genes were located on self-transmissible plasmids. Our results suggest that appropriate veterinary use of ceftiofur did not trigger growth extended-spectrum cephalosporin–resistant E. coli in the bovine rectal flora; however, ceftiofur selection in vitro suggested that additional ceftiofur exposure enhanced selection for specific extended-spectrum cephalosporin–resistant β-lactamase-expressing E. coli clones [ABSTRACT FROM AUTHOR]

The administration of ceftriaxone is known to be associated with biliary pseudolithiasis, although the development of urolithiasis has only rarely been reported. We treated a young male with bacterial meningitis complicated by urinary precipitates composed of ceftriaxone-calcium salt, which prompted us to study whether ceftriaxone administration predisposes children to the formation of urinary precipitates. The case-control study reported here included 83 children with bacterial pneumonia aged from 3 months to 8.9 years. The children were divided into one group of 43 children who received ceftriaxone (group A) and a second group of 40 children who received amoxicillin (group B). Paired samples of serum and urine before and after treatment were obtained from the patients in each group. There were no significant differences in demographic characteristics and blood biochemistry between the groups. However, the mean urinary calcium to creatinine ratio (uCa/Cr; mg/mg) was significantly higher in group A patients than in group B patients after treatment (0.19 vs. 0.09, respectively; p < 0.001), and analysis of the paired urine samples revealed that the uCa/Cr significantly increased after treatment only in group A patients( p < 0.001). There was a weak but non-significant relationship between the dose of ceftriaxone and the uCa/Cr in group A ( p = 0.10, r = 0.24). Our results are the first to demonstrate that ceftriaxone has the potential to significantly increase urinary excretion of calcium, which may be linked to ceftriaxone-related urolithiasis or sludge. We therefore suggest that it is worthwhile monitoring the uCa/Cr levels in patients on ceftriaxone as they may be at greater risk for developing large stones and renal damage. [ABSTRACT FROM AUTHOR]

Staphylococcus pseudintermedius strains were isolated from healthy dogs and dogs with pyoderma in 2000-2002 and 2009. All the isolates from dogs with pyoderma in 1999-2000 and from healthy dogs in 2000-2002 and 2009 were susceptible to cefalexin and/or other cephalosporins and oxacillin. However, 7.1-12.5 and 11.4% of S. pseudintermedius isolates from dogs with pyoderma in 2009 were resistant to cephalosporins and oxacillin, respectively. All S. pseudintermedius isolates from dogs with pyoderma in 1999-2000 and those from healthy dogs in 2000-2002 were susceptible to fluoroquinolones; however, 50% of the S. pseudintermedius strains isolated from dogs with pyoderma in 2009 and 30% of the S. pseudintermedius strains isolated from healthy dogs in 2009 were resistant to fluoroquinolones. Of the 21 oxacillin-resistant S. pseudintermedius (MRSP) isolates, 11 carried SCC mec type V and 10 carried hybrid SCC mec types II-III. Staphylococcus pseudintermedius strains that were resistant to only one of three fluoroquinolones had a mutation in the quinolone resistance determination region of grlA, whereas S. pseudintermedius strains that were resistant to two or more fluoroquinolones had mutations in the quinolone resistance determination regions of both grlA and gyrA. [ABSTRACT FROM AUTHOR]

Bacterial meningitis is a serious problem in pediatric clinics and, therefore, needs urgent and empirical chemotherapy. We investigated 1,116 cases of empirical chemotherapy of patients aged older than 4 months from 1997 through 2008 by sending questionnaires. A single antibiotic treatment was carried out in less than 30% of the cases throughout the years, whereas the combination of two antibiotics had been practiced in more than 70% of the cases. The main antibiotics used were cephalosporins, carbapenems, and ampicillin. Combinatory use of ampicillin and cephalosporin was carried out in 74.7-82.7% of cases in 1997-2000, but sharply declined thereafter to 0-13.8% in 2004-2008. However, the combination of carbapenem and cephalosporin compensated for the decline, increasing from 3.8-6.6% in 1998-1999 to 79.5-89.9% in 2005-2008. The breakdown in the use of cephalosporins, carbapenems, and ampicillin in two-drug combinatory therapy was as follows. (i) Use of cefotaxime was 61.8-75.3% in 1997-2001, but decreased to nearly 50%, equivalent to the level of ceftriaxone use in 2003-2008. (ii) Use of ampicillin dropped from 74.7-92.3% in 1997-2000 to 4.6% in 2008, and this decreased level was compensated for by the use of carbapenems. Overall, combinatory chemotherapy of the third-generation cephalosporins and carbapenems seems to be practical. The discussion in this report includes the difference between Japan and the United States in the prevalence of the causative agents and the use of antibiotics. These studies provide information on trends in the treatment of children's meningitis in Japan and will be useful for the design of future empirical chemotherapy. [ABSTRACT FROM AUTHOR]

This study evaluated the effect of prophylactic cefdinir (3 mg/kg given once daily) for the prevention of recurrent and complicated urinary tract infections (UTI) in pediatric patients. The study included 14 infants who were observed for at least 6 months following the first signs of infection (eight boys, six girls; mean age at admission [±SD]: 6.2 [±7.4] months). Twelve patients had vesico-ureteric reflux (grade I, two; grade II, three; grade III, six; grade IV, one), and two patients had ureteropelvic junction stenosis. No patients discontinued medication due to diarrhea or other adverse drug reactions. The patients had a 6-month recurrence-free rate of 93% (13/14); only one patient had recurrent UTI. The mean urinary cefdinir concentration was 16.3 [±11.7]µg/mL; there was considerable variability among individual measurements, even though the samples were collected at similar intervals after drug intake (mean 18.00 [±2.63] h after dose). However, the lowest measured urinary cefdinir concentration (1.16 µg/mL) was sufficient to eradicate Escherichia coli, one of the most significant causes of UTI. Fecal cultures, obtained at monthly clinic visits during the observation period, indicated that the patients' E. coli strains were very sensitive to cefdinir. No patients were infected with Pseudomonas aeruginosa or other non-fermenting Gram-negative bacilli or fungi. These results show that cefdinir given 3 mg/kg once daily is very effective and safe for preventing recurrent complicated UTI in infants. [ABSTRACT FROM AUTHOR]

Abstract??AKlebsiella pneumoniaestrain, KU6500, which showed resistance to extended-spectrum ?-lactams and produced the plasmid-encoded AmpC ?-lactamase CMY-4, was identified from clinical isolates in Japan. The aim of this study was to identify the mechanism of the high-level expression ofblaCMY-4. Sequence analysis indicated that the promoter element ofCitrobacter freundiiwas conserved, but the insertion sequence ISEcp1coding with the putative promoter element, was inserted into the AmpR binding site. We determined the influence of the promoter onblaCMY-4expression and ?-lactam resistance. Two recombinant plasmids containing the entireblaCMY-4gene, with or without the ISEcp1-mediated promoter sequences, were constructed and named pMWampC and pMWISEcp1, respectively.Escherichia coliDH5? (pMWISEcp1) was resistant to almost all ?-lactams tested andE. coliDH5? (pMWampC) was susceptible to all, except for cephalothin. In addition, the activity of each promoter was measured by subcloning the element into a promoterless luciferase plasmid pGL3-Basic vector. The expression of the putative promoter of ISEcp1was 18.9-fold higher than that ofC. freundii. These results suggest that the putative promoter element of ISEcp1is necessary for the high-level expression ofblaCMY-4to confer resistance to extended-spectrum cephalosporins. [ABSTRACT FROM AUTHOR]

Background To manage antimicrobial resistance, both antimicrobial stewardship (AMS) and antifungal stewardship (AFS) are needed. However, limited data show AMS and AFS practices among hospitals in Japan. Methods We conducted a cross-sectional nationwide study using a questionnaire distributed to hospitals that participated in a hospital epidemiology workshop in Japan in July 2018. The questions addressed activities of preauthorization, notification, and intervention within 7 or 28 days about broad-spectrum antibiotics (third- and fourth-generation cephalosporins and piperacillin–tazobactam, carbapenem, intravenous quinolone) and antifungals. Interventions to use broad-spectrum antibiotics and antifungals were compared between large (≥501 beds) and small/medium-sized (≤500 beds) hospitals. Results Of 240 hospitals, 39 (16%; 18 large and 21 small/medium-sized) responded. Preauthorization of using broad-spectrum antibiotics and antifungals was found in 4 (10%) and 1 (3%) hospital(s), respectively. Notification of broad-spectrum antibiotics and antifungals was found in 37 (95%) and 2 (5%) hospitals, respectively. The numbers of hospitals that intervened in the use of broad-spectrum antibiotics within 7 and 28 days were 17 (44%) and 34 (87%), respectively; those of antifungals were 3 (8%) and 10 (26%), respectively (Table 1). Interventions to use broad-spectrum antibiotics within 7 days were statistically more frequent in small-/medium-sized hospitals than in large hospitals [13 (61.9%) vs. 4 (22.2%),odds ratio = 5.7, 95% confidence interval = 1.4–23.3, p = 0.023]. All hospitals had less-frequent interventions to use antifungals within 7 days than those for antibiotics[3 (14.3%) vs. 0 (0%)] (Table 2). Conclusion Small-/middle-sized hospitals had more frequent interventions within 7 days of broad-spectrum antibiotics than those of large hospitals, possibly because small-/medium-sized hospitals are agile and have few barriers against interventions to use broad-spectrum antibiotics. Compared with broad-spectrum antibiotics, interventions of antifungals were less frequently conducted in all hospitals. We need to emphasize the importance of AFS in Japan. Further studies on related factors are needed. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background The surveillance of antimicrobial use (AMU) among medical doctors and dentists is a key component of the Japanese national plan on antimicrobial resistance (AMR). However, there are no epidemiological studies of AMU among dentists in Japan. We aimed to evaluate the epidemiology of AMU among dentists in Japan and investigate the factors affecting inappropriate prescribing. Methods Total AMU among dentists in Japan between 2015 and 2017 was analyzed by using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), from the Ministry of Health, Labor and Welfare of Japan, which accounted for 98% of total claim data in Japan. Antimicrobials were classified by the World Health Organization (WHO) Anatomical Therapeutic Chemical Classification. The WHO measures antimicrobial usage by using the Defined Daily Dose per 1,000 inhabitant-days (DID) parameter. The patterns of oral AMU in 2017 in outpatient settings were compared between in-house and outside prescriptions. Results DID values of total AMU in 2015, 2016, and 2017 were 1.23, 1.22, and 1.21, respectively (Figure 1). In 2017, the DID value of oral AMU in outpatient settings was 1.19 (98.4%), comprising cephalosporins (0.76, 63.6%), macrolides (0.23, 18.9%), penicillins (0.12, 10.2%), and quinolones (0.07, 5.5%). DID values of oral AMU in outpatient settings were compared for in-house (0.89, 74.4%) and outside (0.31, 25.6%) prescriptions; in-house resulted in a higher proportion of oral cephalosporins (0.60, 66.9% vs. 0.17, 54.1%), but a lower proportion of oral penicillins (0.08, 9.0% vs. 0.04, 13.8%) (Table 1). Conclusion Oral AMU in outpatient settings comprised the highest proportion of antibiotic prescribing by dentists in Japan (98.4%). Oral cephalosporins, the predominant drug type and thought to result from inappropriate prescribing in general, were more frequently prescribed in-house than outside. To tackle AMR, further studies are needed to determine the patient and dentist characteristics encouraging cephalosporin prescription. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

From November 2000 to June 2001, Escherichia coli strains producing CTX-M-2 β-lactamase were isolated from 6 (1.5%) of 396 cattle fecal samples and 2 (0.7%) of 270 surface swabs of cattle carcasses in Japan. The bla[subCTX-M-2] gene responsible for CTX-M-2 production was encoded on transferable plasmids, and the gene was transferred to E. coli CSH2 with a very high frequency (2 x 10[sup-4] to 6 x 10[sup-1] per donor cells) by conjugation. Random amplified polymorphic DNA analysis of nine isolates showed at least five different patterns. These findings suggest that CTX-M-2 producers might have originated from cattle through the use of cephalosporins such as ceftiofur and that cattle could be a reservoir of CTX-M-2-producing E. coil Continuous and strategic surveillance of antimicrobial-resistant bacteria in livestock is essential to suppress further dissemination of these bacteria into society at large. [ABSTRACT FROM AUTHOR]

Background Antimicrobial resistance (AMR) is a global threat for both dentists and medical doctors. The Japanese national action plan on AMR targets a 50% reduction in the use of oral broad-spectrum antimicrobials by 2020 compared with its use in 2013. However, no study has compared the pattern of oral antimicrobial use (AMU) in outpatient settings between all dentists and medical doctors in Japan using the national database of health insurance claims and specific health checkups (NDB). Methods Data of oral AMU in outpatient settings prescribed by both all dentists (n = 104,533) and medical doctors (n = 319,480) in Japan in 2016 were evaluated using NDB collected by the Ministry of Health, Labor and Welfare of Japan; the data accounted for 98% of the total claim data in Japan. Antimicrobials were classified by the World Health Organization (WHO) defined Anatomical Therapeutic Chemicals Classification. WHO measures the number of AMU using defined daily dose per 1,000 inhabitant-days (DIDs). The pattern of oral AMU between all dentists and medical doctors in Japan in 2016 was compared. Results The values of oral AMU in outpatient settings among all dentists (n = 104,533) and medical doctors (n = 319,480) in Japan were 1.20 and 12.11, respectively. The proportions of AMU among dentists were cephalosporins, 65.1%; macrolides, 18.9%; quinolones, 5.5%; and penicillin, 8.7%. In contrast, the proportions of AMU among medical doctors were cephalosporins, 23.1%; macrolides, 36.9%; quinolones, 22.2%; and penicillin, 8.1%. There were differences in the pattern of oral AMU between dentists and medical doctors (P < 0.001) (Table 1). Conclusion Although the value of total oral AMU among dentists was 9.9% of medical doctors, the proportion of cephalosporin use, which was thought to be inappropriate prescribing, was higher among dentists than among medical doctors. Further studies that are adjusted to patients' characteristics are needed. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background Uncomplicated cystitis (UC) imposes a large burden on antimicrobial use due to its high morbidity. IDSA/ESCMID guidelines recommend nitrofurantoin, sulfamethoxazole/trimethoprim (SMX/TMP), fosfomycin trometamol, and pivmecillinam for treating UC, but only SMX/TMP and fosfomycin calcium (FOM-C) are available in Japan. Therefore, we examined the antibiotics use to treat UC in Japan. Methods We obtained data from the JMDC Inc. claims database, which includes data of corporate employees and their family members. We extracted all records of oral antibiotic prescriptions for the treatment of acute cystitis (ICD-10 code: N300) between 2013 and 2016, and excluded prescriptions for male individuals and inpatients because they were considered to have complicated cystitis. Prescriptions for durations >7 days were also excluded because they were potentially prophylactic. Furthermore, we defined treatment failure as cases that required re-prescription within 13 days after the first prescription and estimated the treatment failure rate (TFR) of each antibiotic. Results Cephalosporins and quinolones accounted for 41.5% and 53.2% of the total number of antibiotic prescriptions (48,678). SMX/TMP and FOM-C only accounted for 0.7% and 0.8%. Third-generation cephalosporins accounted for 93.8% of total cephalosporins. TFR was less than 10% across almost all antibiotic categories, with the only exception being FOM-C. Conclusion Cephalosporins and quinolones accounted for 94.7% of oral antibiotic treatment for UC in Japan between 2013 and 2016. To avoid spreading antimicrobial resistance, approval of new antibiotics with good efficacy or an official recommendation for the use of narrower-spectrum antibiotics for treating UC may be required. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

The article focuses on occupational contact urticaria syndrome from cefotiam hydrochloride. Cefotiam hydrochloride (CTM) is a cephalosporin and one of the most common parenteral antibiotics in Japan in the last 10 years. Contact urticaria is classified as an immediate type of contact reaction and is further divided into 3 etiologic groups - non-immunologic, immunologic, and unknown. Contact urticaria related to antibiotics is usually accompanied by systemic symptoms, such as hypersensitivity reaction and is thus called contact urticaria syndrome.

The author shows his concern regarding Neisseria gonorrhoea, a sexually transmitted disease common in humans. He states that several countries including Australia, France and Japan have reported that the case of gonorrhoea is untreatable as it is resistant to antibiotic cephalosporin. He also suggests that research for new alternatives regarding the treatment of gonorrhoea must be prioritized and public health agencies should organize safe-sex educational programmes.

Reports the prevalence of staphylococcus aureus infection in Japan. Resistance of the bacteria to methicillin; Effect of overusing cephalosporins in the treatment; Reason for overprescribing antibiotics.