The importance of meropenem resistance, rather than imipenem resistance, in defining carbapenem-resistant Enterobacterales for public health surveillance: an analysis of national population-based surveillance.

BACKGROUND: In Japan, carbapenem-resistant Enterobacterales (CRE) infections were incorporated into the National Epidemiological Surveillance of Infectious Diseases (NESID) in 2014, necessitating mandatory reporting of all CRE infections cases. Subsequently, pathogen surveillance was initiated in 2017, which involved the collection and analysis of CRE isolates from reported cases to assess carbapenemase gene possession. In this surveillance, CRE is defined as (i) minimum inhibitory concentration (MIC) of meropenem ≥2 mg/L (MEPM criteria) or (ii) MIC of imipenem ≥2 mg/L and MIC of cefmetazole ≥64 mg/L (IPM criteria). This study examined whether the current definition of CRE surveillance captures cases with a clinical and public health burden. METHODS: CRE isolates from reported cases were collected from the public health laboratories of local governments, which are responsible for pathogen surveillance. Antimicrobial susceptibility tests were conducted on these isolates to assess compliance with the NESID CRE definition. The NESID data between April 2017 and March 2018 were obtained and analyzed using antimicrobial susceptibility test results. RESULTS: In total, 1681 CRE cases were identified during the study period, and pathogen surveillance data were available for 740 (44.0%) cases. Klebsiella aerogenes and Enterobacter cloacae complex were the dominant species, followed by Klebsiella pneumoniae and Escherichia coli. The rate of carbapenemase gene positivity was 26.5% (196/740), and 93.4% (183/196) of these isolates were of the IMP type. Meanwhile, 315 isolates were subjected to antimicrobial susceptibility testing. Among them, 169 (53.7%) fulfilled only the IPM criteria (IPM criteria-only group) which were susceptible to meropenem, while 146 (46.3%) fulfilled the MEPM criteria (MEPM criteria group). The IPM criteria-only group and MEPM criteria group significantly differed in terms of carbapenemase gene positivity (0% vs. 67.8%), multidrug resistance rates (1.2% vs. 65.8%), and mortality rates (1.8% vs 6.9%). CONCLUSION: The identification of CRE cases based solely on imipenem resistance has had a limited impact on clinical management. Emphasizing resistance to meropenem is crucial in defining CRE, which pose both clinical and public health burden. This emphasis will enable the efficient allocation of limited health and public health resources and preservation of newly developed antimicrobials.

Comparative effectiveness of cefmetazole versus carbapenems and piperacillin/tazobactam as initial therapy for bacteremic acute cholangitis: A retrospective study.

INTRODUCTION: Carbapenems and piperacillin/tazobactam (PIPC/TAZ) are commonly used as the initial therapy to treat extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales in acute cholangitis. However, the overuse of these antibiotics contributes to the spread of antimicrobial resistance. Cefmetazole (CMZ) is stable to hydrolysis by ESBLs, so it may be an alternative to carbapenems and PIPC/TAZ. However, the effectiveness of CMZ compared with that of carbapenems and PIPC/TAZ as the initial therapy for acute cholangitis is unknown. METHODS: We conducted a retrospective cohort study at a university hospital between April 1, 2014, and December 31, 2022. Patients with bacteremic acute cholangitis who received CMZ, carbapenems, or PIPC/TAZ as the initial therapy were included. The patients were divided into a CMZ group and a carbapenems or PIPC/TAZ (CP) group to compare patient outcomes. RESULTS: A total of 99 patients (54 in the CMZ group and 45 in the CP group) were analyzed. The baseline characteristics of the patients were similar and 30-day mortality did not differ between groups (4% vs. 7%, P = 0.66). However, the CMZ group had a shorter length of stay (LOS) (8 days vs. 15 days, P < 0.001) and lower mean antibiotic cost (98.92 USD vs. 269.49 USD, P < 0.001) than the CP group. CONCLUSIONS: In bacteremic acute cholangitis, initial therapy with CMZ may contribute to a shorter LOS and lower antibiotic costs than treatment with carbapenems and PIPC/TAZ, without worsening patient outcomes.

Efficacy of cefmetazole in immunocompetent patients with uncomplicated colonic diverticulitis: A propensity score matching analysis.

INTRODUCTION: The incidence of colonic diverticulitis is increasing in Japan. Although antimicrobial chemotherapy is a treatment option, Japanese guidelines for diverticulosis do not recommend any antibiotic in particular and antibiotic selection is left to the discretion of the prescribing physician, who often selects antibiotics with anti-pseudomonal activity. Therefore, this study compared the efficacy of cefmetazole (CMZ) with that of tazobactam/piperacillin (TAZ/PIPC) in hospitalized Japanese immunocompetent patients with uncomplicated colonic diverticulitis. PATIENTS AND METHODS: This retrospective study included Japanese immunocompetent patients hospitalized for colonic diverticulitis between April 2019 and March 2022. Participants were divided into the CMZ and TAZ/PIPC groups. After propensity score matching, the intergroup differences in clinical outcomes, including adverse events, mortality, and re-admission rate, were ascertained. RESULTS: During the study period, 142 Japanese patients were hospitalized with community-onset colonic diverticulitis; 124 of these patients were immunocompetent. Of the 124 patients, 42 were excluded, and the CMZ and TAZ/PIPC groups comprised 62 and 20 patients, respectively. After propensity score matching, there were 16 patients in each group. There was no significant intergroup difference in the mortality and re-admission rates; however, the incidence of liver dysfunction was significantly higher (p = 0.018) in the TAZ/PIPC group. CONCLUSION: In patients with colonic diverticulitis, CMZ therapy should be selected because of the adequate clinical outcomes and lower incidence of adverse events, as this would reduce broad-spectrum antibiotic use and minimize antibiotic-resistant bacteria.

Risk factors for cefmetazole-non-susceptible bacteremia in acute cholangitis.

INTRODUCTION: Cefmetazole (CMZ), an antibiotic with limited international distribution, is recommended by the Tokyo Guidelines 2018 (TG18) for non-severe cases of acute cholangitis (AC). However, the risk factors for CMZ-non-susceptible (CMZ-NS) bacteremia in AC remain unclear. Here, we aimed to investigate the risk factors for CMZ-NS bacteremia and evaluate mortality in patients with AC. METHODS: This single-center, retrospective, observational study included all patients diagnosed with definite bacteremic AC, based on TG18, from April 2019 to March 2023. Risk factors for CMZ-NS bacteremia were analyzed by univariate, and age- and sex-adjusted, logistic regression analyses. Mortality was compared by cause of obstruction, CMZ-susceptible/CMZ-NS bacteremia, and initial treatment. RESULTS: In total, 165 patients were enrolled. CMZ-NS bacteremia was diagnosed in 46 (27.9 %) patients. Histories of diabetes mellitus, hepato-biliary-pancreatic cancer, malignant biliary obstruction, and endoscopic sphincterotomy were identified as significant factors associated with the risk of CMZ-NS bacteremia. Thirteen patients died within 30 days of hospital admission. The mortality of patients with AC and malignant biliary obstruction was statistically higher than that of patients with bile duct stones. No patients with AC and bile duct stones died in the group with CMZ-NS bacteremia and inappropriate initial antibiotics. CONCLUSIONS: In AC, a history of diabetes mellitus, hepato-biliary-pancreatic cancer, malignant biliary obstruction, and endoscopic sphincterotomy are associated with an increased risk of CMZ-NS bacteremia. Therefore, the choice of empiric therapy for AC should be based on the etiology and patient background, rather than on the severity.

In vitro Activity of Cefmetazole and Flomoxef among Extended-Spectrum Beta-Lactamase producing Enterobacterales.

In this age of antimicrobial resistance (AMR), improving treatment using existing antibiotics is desirable. Extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales (ESBL-E) are high priority AMR pathogens according to the World Health Organization. Cephamycin-class beta- lactams are tolerant to hydrolysis by ESBL activity and have bactericidal effects on ESBL-E. The aim of the present study was to compare the in vitro minimum inhibitory concentration (MIC) of cefmetazole (CMZ) and flomoxef (FMOX) among ESBL-E strains. This was a retrospective study using microbiology laboratory data from Okayama University Hospital (Japan) from January 2014 to June 2022. The MIC was determined by broth microdilution method and the ESBL phenotypes were determined by double-disk method. Antimicrobial use density (AUD) data for CMZ and FMOX were also gathered. Annual proportions of ESBL-producing organisms in Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae complex were 20.4-30.6%, 3.5-13.7%, and 0-3.1%, respectively. The ESBL-producing bacteria with MIC levels ≤1 µg/mL for CMZ and FMOX ranged from 57 to 84% and 97 to 100%, respectively, for E. coli, and from 50 to 92% and 80 to 100%, respectively, for K. pneumoniae. E. cloacae strains showed MIC levels ≥32 µg/mL for both agents. The AUD ratio for CMZ to FMOX ranged from 5.31 to 12.27, with no apparent upward or downward trend. Proportions of ESBL-producing E. coli and K. pneumoniae strains with MIC ≤1 µg/mL were greater in FMOX than in CMZ. To corroborate the clinical superiority of FMOX in treating ESBL-E infections, a randomized controlled study, as well as pharmacokinetic/pharmacodynamic analysis, is required.

In vitro efficacy of humanized regimen of flomoxef against extended-spectrum ß-lactamase-producing Escherichia coli and Klebsiella pneumoniae.

This study compared the efficacy of flomoxef with other ß-lactam antibiotics against extended-spectrum ß-lactamases (ESBL)-producing bacteria of clinical relevance. First, the prevalence and ß-lactamase genotypes of ESBL-producing strains among Escherichia coli and Klebsiella pneumoniae isolates collected in Japan from 2004 to 2018 were investigated. High MIC90 values (>64 µg/mL) of ceftriaxone, cefepime, and ceftazidime and low MIC90 values (≤0.06-2 µg/mL) of flomoxef, cefmetazole, and meropenem against both species were observed. Second, a chemostat model was used to analyze the efficacy of humanized regimens of three oxacephem/cephamycin antibiotics (flomoxef, cefmetazole, cefoxitin) and two other antibiotics (meropenem and piperacillin/tazobactam) in suppressing the growth of five ESBL-producing E. coli and two K. pneumoniae strains. Flomoxef, piperacillin/tazobactam, and meropenem showed good bactericidal effects with >4 log10 CFU/mL reduction without bacterial regrowth at 24 h even when the MIC of test isolates was >MIC90. Cefmetazole and cefoxitin resulted in regrowth of test isolates with MIC ≥MIC90 at 24 h. Cefmetazole, cefoxitin, flomoxef, and meropenem showed increased MICs for regrown samples. A clear relationship between the proportion of time that the free drug concentration exceeded the MIC (%fT>MIC) and antibiotic efficacy was found for flomoxef, cefoxitin, and cefmetazole, and flomoxef had the highest %fT>MIC, whereas discrepancies between Clinical and Laboratory Standards Institute breakpoint and bactericidal activity were observed for cefmetazole. Flomoxef was effective in preventing the growth of all ESBL-producing strains, even those with an MIC eight times the MIC90. Thus, flomoxef may be a good alternative to meropenem in context of carbapenems sparing stewardship.

Effectiveness of cefmetazole versus meropenem for invasive urinary tract infections caused by extended-spectrum ß-lactamase-producing Escherichia coli.

Cefmetazole is active against extended-spectrum ß-lactamase-producing Escherichia coli (ESBLEC) and is a potential candidate for carbapenem-sparing therapy. This multicenter, observational study included patients hospitalized for invasive urinary tract infection due to ESBLEC between March 2020 and November 2021 at 10 facilities in Japan, for whom either cefmetazole or meropenem was initiated as a definitive therapy within 96 h of culture collection and continued for at least 3 d. Outcomes included clinical and microbiological effectiveness, recurrence within 28 d, and all-cause mortality (14 d, 30 d, in-hospital). Outcomes were adjusted for the inverse probability of propensity scores for receiving cefmetazole or meropenem. Eighty-one and forty-six patients were included in the cefmetazole and meropenem groups, respectively. Bacteremia accounted for 43% of the cefmetazole group, and 59% of the meropenem group. The crude clinical effectiveness, 14 d, 30 d, and in-hospital mortality for patients in the cefmetazole and meropenem groups were 96.1% vs 90.9%, 0% vs 2.3%, 0% vs 12.5%, and 2.6% vs 13.3%, respectively. After propensity score adjustment, clinical effectiveness, the risk of in-hospital mortality, and the risk of recurrence were similar between the two groups (P = 0.54, P = 0.10, and P = 0.79, respectively). In all cases with available data (cefmetazole : n = 61, meropenem : n = 22), both drugs were microbiologically effective. In all isolates, bla CTX-M was detected as the extended-spectrum ß-lactamase gene. The predominant CTX-M subtype was CTX-M-27 (47.6%). Cefmetazole showed clinical and bacteriological effectiveness comparable to meropenem against invasive urinary tract infection due to ESBLECs.

Chi-square automatic interaction detector decision tree analysis model: Predicting cefmetazole response in intra-abdominal infection.

BACKGROUND: Cefmetazole is used as the first-line treatment for intra-abdominal infections. However, only a few studies have investigated the risk factors for cefmetazole treatment failure. AIMS: This study aimed to develop a decision tree-based predictive model to assess the effectiveness of cefmetazole in initial intra-abdominal infection treatment to improve the clinical treatment strategies. METHODS: This retrospective cohort study included adult patients who were unexpectedly hospitalized due to intra-abdominal infections between 2003 and 2020 and initially treated with cefmetazole. The primary outcome was clinical intra-abdominal infection improvement. The chi-square automatic interaction detector decision tree analysis was used to create a predictive model for clinical improvement after cefmetazole treatment. RESULTS: Among 2,194 patients, 1,807 (82.4%) showed clinical improvement post-treatment; their mean age was 48.7 (standard deviation: 18.8) years, and 1,213 (55.3%) patients were men. The intra-abdomせinal infections were appendicitis (n = 1,186, 54.1%), diverticulitis (n = 334, 15.2%), and pancreatitis (n = 285, 13.0%). The chi-square automatic interaction detector decision tree analysis identified the intra-abdominal infection type, C-reactive protein level, heart rate, and body temperature as predictive factors by categorizing patients into seven groups. The area under the receiver operating characteristic curve was 0.71 (95% confidence interval: 0.68-0.73). CONCLUSION: This predictive model is easily understandable visually and may be applied in clinical practice.

Pharmacokinetics of cefmetazole in plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue of patients scheduled for lower gastrointestinal surgery: Dosing considerations based on site-specific pharmacodynamic target attainment.

INTRODUCTION: Cefmetazole (CMZ) has gained interest as a carbapenem-sparing alternative to the epidemic of extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales (ESBL-E). In this study, we investigated the pharmacokinetics (PK) of CMZ in plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue to assess the dosing regimen needed to achieve pharmacodynamic (PD) goals at the target site. METHODS: Patients scheduled for elective lower gastrointestinal surgery were intravenously administered CMZ. Plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue samples were collected after CMZ infusion and during the surgery, and CMZ concentrations were measured. The non-compartmental and compartmental PK parameters were estimated and used to evaluate site-specific PD target attainment. RESULTS: A total of 38 plasma, 27 peritoneal fluid, 36 peritoneum, and 38 subcutaneous adipose tissue samples were collected from 10 patients. The non-compartmental PK analysis revealed the ratios of the mean area under the drug concentration-time curve (AUC0-3.5 h) of peritoneal fluid-to-plasma, peritoneum-to-plasma, and subcutaneous adipose tissue-to-plasma were 0.60, 0.36, and 0.11, respectively. The site-specific PD target attainment analyses based on the breakpoints for ESBL-E per the Japanese surgical site infection (SSI) surveillance (MIC90 = 8 mg/L) revealed that 2 g CMZ every 3.5 h achieved desired bactericidal effect at all sites and 2 g CMZ every 6 h achieved PD goals at peritoneum and peritoneal fluid. CONCLUSION: These findings clarify the PK of CMZ in abdominal tissues and could help decide optimal dosing regimens to treat intra-abdominal infection and prophylaxis of SSI.

Severe drug-induced immune hemolytic anemia due to cefmetazole: A case report.

OBJECTIVE: To report a case of drug-induced immune hemolytic anemia (DIIHA) that was suspected to have been caused by cefmetazole. CASE SUMMARY: A 93-year-old woman with no previous history of liver complications underwent a contrast-enhanced computed tomography scan, which resulted in a diagnosis of acute cholecystitis. The patient experienced intravascular hemolysis and rapid progression of anemia after being exposed to 2 g/day of cefmetazole. After 48 hours of cefmetazole administration, the patient was transferred to the intensive care unit (ICU) of our facility. In view of the severe autoimmune hemolytic anemia, the patient was started on steroid immunosuppression. The patient's condition further deteriorated for 13 hours after treatment and showed increased lactic acidosis and decreased consciousness, thus, the patient was intubated and managed on a ventilator. Lactic acidosis was not easily controlled, and the patient required continuous renal replacement therapy within 15 hours of ICU admission. Blood pressure was unable to be maintained even with the use of catecholamine, and the patient subsequently died 28 hours after ICU admission. Blood taken immediately after death was used to perform a drug-dependent antibody test where DIIHA due to cefmetazole was diagnosed. CONCLUSION: If there is rapid progression of anemia following drug administration, the possibility of DIIHA needs to be considered. If DIIHA is suspected, identification and immediate discontinuation of the causal drug are essential, and a drug-dependent antibody test should be considered.

Differences in clinical and cost-effectiveness between cefmetazole and flomoxef for the prevention of surgical site infection in elective colorectal surgery: A single-center, retrospective cohort study.

INTRODUCTION: Surgical site infection (SSI) is associated with increased morbidity and mortality rates, postoperative length of stay (pLOS), and medical costs. In colorectal surgery, cefmetazole (CMZ) and flomoxef (FMOX) are predominantly used in Japan, and they have almost the same spectrum of antibiotic activity against SSI pathogens, and an approximately four-fold cost difference (CMZ: ∼4$, FMOX: ∼16$). However, the difference between these antibiotics in SSI prophylaxis in colorectal surgery remains poorly understood. METHODS: We performed a single-center retrospective cohort study to investigate the prophylactic effects of these antibiotics, pLOS, and hospitalization costs. Patients who underwent elective colorectal surgery between April 2016 and March 2020 were considered for this study. RESULTS: Of the 634 patients, 316 (49.8%) were eligible. The SSI rates in the CMZ and FMOX groups were 14.7% and 12.5%, respectively. The incidence of organ/space SSI was approximately two-fold lower in the CMZ group than in the FMOX group (4.4% vs. 9.4%). Multivariable regression analysis revealed that CMZ was not significantly related to SSI, with an adjusted odds ratio of 1.21 (95% confidence interval [CI]: 0.52-2.82) and did not induce a significant difference in pLOS (difference ratio: 0.951 [95% CI: 0.868-1.041]). Hospitalization costs were reduced in the CMZ group (difference ratio, 0.951 [95% CI: 0.907-0.998], p = 0.042). The sensitivity analysis also showed results similar to the above findings. CONCLUSION: Our study showed that CMZ could be a cost-effective antibiotic with similar efficacy for SSI prophylaxis in colorectal surgery, compared with FMOX.

Timing of re-dosing based on population pharmacokinetic-pharmacodynamics target attainment analysis of cefmetazole in subjects undergoing lower gastrointestinal surgery.

INTRODUCTION: This study was conducted to evaluate the population pharmacokinetics of prophylactic cefmetazole sodium (CMZ) based on the serum concentrations and establish a pharmacodynamics target concentration exceeding the minimum inhibitory concentration (MIC) to design the re-dosing interval. METHODS: Serum (n = 362) samples from 107 individuals were analyzed using a nonlinear mixed-effects model. The pharmacodynamics index obtained was regarded as the probability of maintaining CMZ serum trough exceeding the minimal inhibitory concentration (MIC) of 2 mg/L. This MIC was chosen to account for methicillin-susceptible Staphylococcus aureus (MSSA), E. coli, and Klebsiella pneumoniae RESULTS: The final population pharmacokinetic model was a two-compartment model with linear elimination. Creatinine clearance and body weight were identified as significant covariates influencing the central clearance and volume of distribution in the central compartment. The probability of achieving serum concentrations exceeding the MIC90 for MSSA, E. coli, and Klebsiella pneumoniae for a 1 g dose with a 10 min intravenous infusion was above 90% except for good renal function (CLcr â‰§ 95 mL/min) at 2 h after the initial dose. For patients with good renal function (CLcr â‰§ 95 mL/min), a CMZ of 2 g re-dosing interval seemed necessary to meet the achievement probability. In patients with impaired renal function (CLcr ≤20 mL/min), the probability of achievement exceeded 90% even when the dosing interval was extended to 8 h. CONCLUSIONS: We evaluated re-dosing intervals based on the population pharmacokinetics. Re-dosing intervals should be determined based on renal function.

Cefmetazole as an Alternative to Carbapenems Against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Infections Based on In Vitro and In Vivo Pharmacokinetics/Pharmacodynamics Experiments.

PURPOSE: Cefmetazole (CMZ) has received attention as a pharmaceutical intervention for extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) infections. This study aimed to investigate the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of CMZ against ESBL-EC. METHODS: The susceptibility and time-killing activity of CMZ against clinically isolated ESBL-EC (EC9 and EC19) were determined in vitro. The optimal PK/PD index and its target value were calculated based on the results of a PK study in healthy mice and PD study in neutropenic murine thigh infection model mice. RESULTS: The minimum inhibitory concentrations (MICs) of CMZ against EC9 and EC19 were 2.0 and 1.0 µg/mL, respectively. Time-kill studies showed that colony-forming units decreased in a time-dependent manner at CMZ concentrations in the range of 4-64 × MIC. In in vivo PK/PD studies, the antibacterial effect of CMZ showed the better correlation with the time that the free drug concentration remaining above the MIC (fT>MIC), with the target values for a static effect and 1 log10 kill reduction calculated as 57.6% and 69.6%, respectively. CONCLUSION: CMZ possesses time-dependent bactericidal activities against ESBL-EC and is required to achieve "fT>MIC" ≥ 69.6% for the treatment of ESBL-EC infections.

Septic shock due to Yersinia pseudotuberculosis infection in an adult immunocompetent patient: a case report and literature review.

BACKGROUND: Yersinia pseudotuberculosis infection can occur in an immunocompromised host. Although rare, bacteremia due to Y. pseudotuberculosis may also occur in immunocompetent hosts. The prognosis and therapeutic strategy, especially for immunocompetent patients with Y. pseudotuberculosis bacteremia, however, remains unknown. CASE PRESENTATION: A 38-year-old Japanese man with a mood disorder presented to our hospital with fever and diarrhea. Chest computed tomography revealed consolidation in the right upper lobe with air bronchograms. He was diagnosed with pneumonia, and treatment with intravenous ceftriaxone and azithromycin was initiated. The ceftriaxone was replaced with doripenem and the azithromycin was discontinued following the detection of Gram-negative rod bacteria in 2 sets of blood culture tests. The isolated Gram-negative rod bacteria were confirmed to be Y. pseudotuberculosis. Thereafter, he developed septic shock. Doripenem was switched to cefmetazole, which was continued for 14 days. He recovered without relapse. CONCLUSIONS: We herein report a case of septic shock due to Y. pseudotuberculosis infection in an adult immunocompetent patient. The appropriate microorganism tests and antibiotic therapy are necessary to treat patients with Y. pseudotuberculosis bacteremia.

Retrospective evaluation of appropriate dosing of cefmetazole for invasive urinary tract infection due to extended-spectrum ß-lactamase-producing Escherichia coli.

INTRODUCTION: The frequency of urinary tract infections (UTIs) caused by extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales is steadily increasing worldwide. Therefore, we aimed to evaluate the efficacy and appropriate dosing of cefmetazole (CMZ) in invasive urinary tract infection (iUTI) caused by ESBL-producing Escherichia coli (ESBLEC). METHODS: Patients who developed ESBLEC iUTI and received CMZ between January 2007 and December 2018 were identified, and their medical records were reviewed. The time above minimum inhibitory concentration (MIC) (TAM) was calculated using the MIC value obtained from each patient and its simulated CMZ concentration. RESULTS: Thirty-nine patients were included in the study. The median TAM was 92.6% (interquartile range [IQR], 67.6-100). CMZ was clinically efficacious in 38 (97.4%) patients overall and in 11 out of 12 (91.7%) patients with normal renal function who received CMZ at 1 g every 8 h. CONCLUSIONS: In normal renal function, 1 g CMZ infused for over 1 h every 8 h is an efficacious treatment for iUTI caused by ESBLEC with MIC =< 4 mg/L.

Efficacy of fosfomycin in the prevention of postoperative infection following transurethral resection of bladder tumor during periods of limited cefazolin, cefotiam, and cefmetazole supply.

INTRODUCTION: In March 2019, cefazolin availability was limited owing to the contamination of the drug substance. In addition, there was a difficulty in supplying drugs alternative to cefazolin, such as cefotiam and cefmetazole. In our Department of Nephro-urology, we used fosfomycin-based drugs to substitute cefazolin as perioperative preventive antibacterial drugs. In this study, we aimed to evaluate the usage status of perioperative prophylactic antibacterial drugs before and after the period of limited cefazolin supply and to investigate the efficacy and safety of fosfomycin sodium in preventing infections following transurethral resection of bladder tumor. METHODS: We enrolled 346 patients who underwent transurethral resection of bladder tumor in our department from April 2018 to August 2020. The patients received the following perioperative antibacterial agents: cefotiam (n = 146), fosfomycin (n = 166), and other antibacterial agents (n = 34). There was no significant difference in the median age or surgery time. RESULTS: The median length of hospital stay was 6, 5, and 5 days in the cefotiam, fosfomycin, and other antibacterial groups, respectively, with significant difference. The median maximum postoperative temperature was 37.1 °C in all groups, with no significant difference. There were no differences in C-reactive protein, aspartate aminotransferase, and alanine aminotransferase levels determined by postoperative blood tests; preoperative and postoperative urinary white blood cell counts; preoperative urine bacterial counts; and surgery-related infection requiring additional antibiotic treatments among the groups. CONCLUSIONS: The use of fosfomycin-based agents helped overcome the limited supply of cefazolin without worsening clinical outcomes.

Inflammation-Induced Attenuation of Prostaglandin D2 Elimination across Rat Blood-Brain Barrier: Involvement of the Downregulation of Organic Anion Transporter 3 and Multidrug Resistance-Associated Protein 4.

Prostaglandin (PG) D2 is a lipid mediator, and in the brain, overproduction of PGD2 is reportedly involved in the progression and exacerbation of neuroinflammation. The objective of this study was to elucidate PGD2 efflux transport, under normal and inflammatory conditions, across the blood-brain barrier (BBB), which is formed by brain capillaries. Elimination of [3H]PGD2 across the BBB of normal and lipopolysaccharide (LPS)-induced inflammatory rats was examined by the intracerebral microinjection technique. After intracerebral injection, the percentage of [3H]PGD2 remaining in the ipsilateral cerebrum decreased with time, with a half-life of 13 min. This [3H]PGD2 elimination across the BBB was significantly inhibited by the co-administration of unlabeled PGD2, which suggests carrier-mediated PGD2 efflux transport at the BBB. In isolated rat brain capillaries, mRNA expression of organic anion transporter (Oat) 3, organic anion-transporting polypeptide (Oatp) 1a4, and multidrug resistance-associated protein (Mrp) 4 was observed. In addition, co-administration of substrates/inhibitors for Oat3, Oatp1a4, and/or Mrp4, such as benzylpenicillin and cefmetazole, reduced [3H]PGD2 elimination across the BBB. Data suggest that Oat3 and Mrp4, but not Oatp1a4 are involved in PGD2 elimination across the BBB, as Oatp1a4-expressing Xenopus (X.) oocytes did not show the significant [3H]PGD2 uptake compared with water-injected X. oocytes. In LPS-treated rats, [3H]PGD2 elimination across the BBB and mRNA expression levels of Oat3 and Mrp4 were significantly decreased. Our data suggest that Oat3- and Mrp4-mediated PGD2 elimination across the BBB is attenuated under inflammatory conditions.

Cost-effectiveness analysis of initial nonoperative management versus emergency laparoscopic appendectomy for acute complicated appendicitis.

BACKGROUND: The evidence regarding the safety and efficacy of nonoperative management is growing. However, the best treatment strategy for acute complicated appendicitis remains controversial. We aimed to evaluate the cost-effectiveness of treatment strategies for complicated appendicitis patients. This study sought to determine the most cost-effective strategy from the health care-payer's perspective. METHODS: The primary outcome was an incremental cost effectiveness ratio (ICER) using nonoperative management with or without interval laparoscopic appendectomy (ILA) as the intervention compared with operative management with emergency laparoscopic appendectomy (ELA) alone as the control. Model variables were abstracted from a literature review, and from data obtained from the hospital records of Tochigi Medical Center. Cost-effectiveness was evaluated using an ICER. We constructed a Markov model to compare treatment strategies for complicated appendicitis in otherwise-healthy adults, over a time horizon of a single year. Uncertainty surrounding model parameters was assessed via one-way- and probabilistic-sensitivity analyses. Threshold analysis was performed using the willingness-to-pay threshold set at the World Health Organization's criterion of $107,690. RESULTS: Three meta-analysis were included in our analysis. Operative management cost $6075 per patient. Nonoperative management with interval laparoscopic appendectomy (ILA) cost $984 more than operative management and produced only 0.005 more QALYs, resulting in an ICER of $182,587. Nonoperative management without ILA cost $235 more than operative management, and also yielded only 0.005 additional QALYs resulting in an ICER of $45,123 per QALY. Probabilistic sensitivity analysis with 1000 draws resulted in average ICER of $172,992 in nonoperative management with ILA and $462,843 in Nonoperative management without ILA. The threshold analysis demonstrated that regardless of willingness-to-pay, nonoperative management without ILA would not be most cost-effective strategy. CONCLUSIONS: Nonoperative management with ILA and Nonoperative management without ILA were not cost-effective strategies compared with operative management to treat complicated appendicitis. Based on our findings, operative management remains the standard of care and nonoperative management would be reconsidered as a treatment option in complicated appendicitis from economic perspective.

Preoperative mechanical bowel preparation with oral antibiotics reduces surgical site infection after elective colorectal surgery for malignancies: results of a propensity matching analysis.

BACKGROUND: Surgical site infections (SSIs) are a major postoperative complication after colorectal surgery. Current study aims to evaluate prophylactic function of oral antibiotic (OA) intake in combination with mechanical bowel preparation (MBP) relative to MBP alone with respect to postoperative SSI incidence. METHODS: A retrospective analysis of eligible patients was conducted using the databases of the Gastrointestinal Surgery Centre, Third Affiliated Hospital of Sun Yat-sen University from 2011 to 2017. Data pertaining to postoperative hospital stay length, expenses, SSI incidence, anastomotic fistula incidence, and rates of other complications were extracted and compared. A propensity analysis was conducted to minimize bias associated with demographic characteristics. Subgroup analyses were performed to further explore protective effects of OA in different surgical sites. RESULTS: The combination of OAs and MBP was related to a significant decrease in the incidence of overall SSIs, superficial SSI, and hospitalization expenses. The MBP + OA modality was particularly beneficial for patients undergoing left-side colon or rectum resections, with clear prophylactic efficacy. The combination of MPB + OA did not exhibit significant prophylactic efficacy in patients undergoing right hemi-colon resection. Age, surgical duration, and application of OA were all independent factors associated with the occurrence of SSIs. CONCLUSION: These results suggest that the combination of OA + MBP should be recommended for patients undergoing elective colorectal surgery, particularly for operations on the left side of the colon or rectum. TRIAL REGISTRATION: NCT04258098. Retrospectively registered.

Increased community-acquired upper urinary tract infections caused by extended-spectrum beta-lactamase-producing Escherichia coli in children and the efficacy of flomoxef and cefmetazole.

BACKGROUND: Urinary tract infections caused by extended-spectrum beta-lactamase-producing bacteria are increasing worldwide. At our hospital, the number of pediatric patients hospitalized because of an upper urinary tract infection has dramatically increased since 2016. In total, 60.5% of urinary tract infections are caused by extended-spectrum beta-lactamase-producing Escherichia coli. Such a high prevalence of extended-spectrum beta-lactamase-producing E. coli has not been detected previously in Japan. Therefore, we evaluated the clinical and bacteriologic characteristics and efficacy of antibiotics against upper urinary tract infections caused by E. coli in children. METHODS: This retrospective study surveyed 152 patients who were hospitalized in the pediatric department of Shimane Prefectural Central Hospital because of upper urinary tract infections caused by E. coli. Medical records were reviewed to examine patient characteristics. O antigens, antibiotic susceptibility, gene typing, and pulse-field gel electrophoresis were studied at the Shimane Prefectural Institute of Public Health and Environmental Science. RESULTS: Urine sample analyses showed extended-spectrum beta-lactamase types such as CTX-M-9 and plural virulence genes. We changed the primary antibiotic treatment to flomoxef or cefmetazole to treat upper urinary tract infections caused by Gram-negative bacilli. After changing treatment, the time to fever alleviation was significantly shortened. CONCLUSION: Extended-spectrum beta-lactamase-producing E. coli should be suspected in community-acquired upper urinary tract infections. Therefore, when treating patients, it is necessary to focus on antibiotic susceptibility and the prevalence of extended-spectrum beta-lactamase-producing bacteria found in each area. Flomoxef and cefmetazole are useful primary treatments for upper urinary tract infections caused by extended-spectrum beta-lactamase-producing E. coli.