The safety and efficacy of relebactam/imipenem/cilastatin in Japanese patients with complicated intra-abdominal infection or complicated urinary tract infection: A multicenter, open-label, noncomparative phase 3 study.

INTRODUCTION: Relebactam, a novel class A/C ß-lactamase inhibitor developed as a fixed-dose combination with imipenem/cilastatin, restores imipenem activity against imipenem-nonsusceptible gram-negative pathogens. METHODS: This phase 3, multicenter, open-label, noncomparative study (NCT03293485) evaluated relebactam/imipenem/cilastatin (250 mg/500 mg/500 mg) dosed every 6 h for 5-14 days in Japanese patients with complicated intra-abdominal infections (cIAIs) or complicated urinary tract infections (cUTIs), including those with secondary sepsis. Sepsis was defined as an infection-induced systemic inflammatory response syndrome, with a documented positive blood culture; patients meeting these protocol-defined criteria were evaluated for efficacy against sepsis. RESULTS: Of 83 patients enrolled, 81 patients (cIAI, n = 37; cUTI, n = 44) received ≥1 dose of study treatment. Escherichia coli was the most common baseline pathogen isolated in both patients with cIAI and cUTI. Adverse events (AEs) were reported in 74.1% (n = 60/81) of patients, and drug-related AEs occurred in 18.5% (n = 15/81). The most common AEs were diarrhea and nausea (8.6%). Serious AEs occurred in nine patients, including one death, but none were considered treatment related. The primary efficacy endpoint for patients with cIAI was clinical response at end of treatment (EOT) in the microbiologically evaluable (ME) population, and for patients with cUTI was microbiological response at EOT in the ME population. The proportion of cIAI and cUTI patients achieving favorable responses were 85.7% (n = 24/28) and 100.0% (n = 39/39), respectively. All patients with sepsis (cIAI, n = 1; cUTI, n = 5) achieved a favorable composite clinical and microbiological response at EOT. CONCLUSIONS: A favorable safety and efficacy profile for relebactam/imipenem/cilastatin was observed in Japanese patients with cIAI and cUTI.

The efficacy and safety of tazobactam/ceftolozane in Japanese patients with uncomplicated pyelonephritis and complicated urinary tract infection.

We report efficacy and safety results for a combination of a novel cephalosporin class antibiotic and a ß-Lactamase inhibitor, tazobactam/ceftolozane (1:2) at a dose of 1.5 g intravenously every 8 h in Japanese patients with uncomplicated pyelonephritis and complicated urinary tract infection. This study design was a nonrandomized, multicenter, open-label trial, and the treatment period was 7 days. Of 115 patients enrolled in this study, 114 received tazobactam/ceftolozane, and 90 were included in the efficacy analyses. Ninety-nine isolates (bacterial count ≥105 CFU/mL) were identified by urine culture. The main baseline uropathogens were Escherichia coli (80 isolates), Klebsiella pneumoniae (8 isolates), and Proteus mirabilis (3 isolates). Of these, 13 isolates were ESBL-producers. The favorable per-patient microbiological response rate at 7 days after the final administration of tazobactam/ceftolozane was 80.7% (71/88). The response rate in uncomplicated pyelonephritis was 90.0% (36/40), complicated pyelonephritis 63.6% (14/22), and complicated cystitis 80.8% (21/26). The favorable clinical response rate was 96.6% (86/89), and composite response rate (based on microbiological and clinical response) was 80.7% (71/88). The eradication rate by uropathogen was 83.5% (66/79) in E. coli, 42.9% (3/7) in K. pneumoniae, and 100% (3/3) in P. mirabilis. The incidence of drug-related adverse events was 17.5% (20/114 patients). The most common drug-related adverse events were diarrhea and alanine aminotransferase increased in 5.3% (6/114 patients each). Drug-related serious adverse events and deaths were not observed. These results support the safety and efficacy of tazobactam/ceftolozane and suggest it will be a useful treatment for uncomplicated pyelonephritis and complicated urinary tract infection.

The effect of bezlotoxumab for prevention of recurrent Clostridium difficile infection (CDI) in Japanese patients.

Recurrent Clostridium difficile infection is considered as a significant health care burden. The global study (MODIFY II) of antibody treatment (bezlotoxumab) for the prevention of recurrent C. difficile infection includes Japanese patients (95 subjects); The aim of this subgroup analysis is to report the data obtained from Japanese patients. Patients with C. difficile infection receiving standard of care antibiotic treatment and a single infusion of bezlotoxumab 10 mg/kg, actoxumab 10 mg/kg + bezlotoxumab 10 mg/kg or placebo. Recurrent C. difficile infection through Week 12 was evaluated. In the Full Analysis Set (93 subjects), 91% were older than 65 years of age and 93% were hospitalized at the time of study entry. The standard of care antibiotic for C. difficile infection was metronidazole for 57 subjects and vancomycin for 36 subjects. The recurrent C. difficile infection rate was 46% in the placebo, 21% in the bezlotoxumab (p = 0.0197) and 28% in the actoxumab + bezlotoxumab group. No additive recurrent C. difficile infection-reducing effect with the addition of actoxumab was demonstrated. There were no events representing safety concern in bezlotoxumab. Among 54 clinical isolates of C. difficile as a baseline culture in Japanese patients, the common ribotypes were 052 (28%), 018 (19%), 002 (15%) and 369 (9%). It showed distinctly different distribution from that in the United States and Europe. The superior effect of bezlotoxumab 10 mg/kg in the prevention of recurrent C. difficile infection suggests that the agent will be useful in the rapidly aging Japanese society.

Low intake of vegetables and fruits and risk of colorectal cancer: the Japan Collaborative Cohort Study.

BACKGROUND: The evidence for an association between low intake of vegetables and fruits and increased colorectal cancer risk is inconclusive. Evaluating the colorectal cancer risk associated with continued low intake is important. METHODS: We used data of 45 516 and 14 549 subjects aged 40-79 years obtained in the baseline and interim surveys, respectively, from the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study). The intake frequency of vegetables and fruits as assessed by a self-administered questionnaire was classified into tertiles of low, middle, and high groups, and the low group was subdivided into 2 equal groups (lower low and higher low groups). Colorectal cancer incidence determined from follow-up was used. Cox's proportional hazard model was employed to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for covariates. RESULTS: During 598 605 person-years of subject follow-up after baseline, we identified 806 colorectal cancer cases. HRs for the lower low versus the middle and high intake frequencies of vegetables and fruits at baseline were 0.95 (95% CI 0.77-1.16) and 1.08 (95% CI 0.90-1.29), respectively. During 125 980 person-years of subject follow-up after the interim survey, 197 colorectal cancer cases were identified. HRs for the low versus middle and high intake frequencies of vegetables and fruits in both baseline and interim surveys were 0.91 (95% CI 0.61-1.37) and 0.87 (95% CI 0.59-1.27), respectively. CONCLUSIONS: Our results suggest that low intake and continued low intake of vegetables and fruits are not strongly associated with colorectal cancer risk.

Coffee consumption and risk of colorectal cancer: the Japan Collaborative Cohort Study.

BACKGROUND: Epidemiologic studies have reported coffee consumption to be associated with various health conditions. The purpose of this study was to examine the relationship of coffee consumption with colorectal cancer incidence in a large-scale prospective cohort study in Japan. METHODS: We used data from the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study). Here, we analyzed a total of 58 221 persons (23 607 men, 34 614 women) followed from 1988 to the end of 2009. During 738 669 person-years of follow-up for the analysis of colorectal cancer risk with coffee consumption at baseline, we identified 687 cases of colon cancer (355 males and 332 females) and 314 cases of rectal cancer (202 males and 112 females). We used the Cox proportional-hazard regression model to estimate hazard ratio (HR). RESULTS: Compared to those who consumed less than 1 cup of coffee per day, men who consumed 2-3 cups of coffee per day had an HR of 1.26 (95% confidence interval [CI] 0.93-1.70), and men who consumed more than 4 cups of coffee per day had an HR of 1.79 (95% CI 1.01-3.18). A statistically significant increase in the risk of colon cancer was associated with increasing coffee consumption among men (P for trend = 0.03). On the other hand, coffee consumption in women was not associated with incident risk of colon cancer. Coffee consumption was also not associated with rectal cancer incidence in men or women. CONCLUSIONS: This large-scale population-based cohort study showed that coffee consumption increases the risk of colon cancer among Japanese men.