Absorption, Metabolism, and Excretion of [14C]-Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) in Healthy Male Subjects.

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral prodrug of pharmacologically active moiety tebipenem (TBP), which is a carbapenem with activity against multidrug-resistant Gram-negative pathogens. Conversion from the prodrug to the active moiety, namely, TBP, occurs in the enterocytes of the gastrointestinal tract via intestinal esterases. The absorption, metabolism, and excretion in humans were evaluated, following the administration of a single oral dose of [14C]-TBP-PI-HBr. Healthy male subjects (n = 8) received a single 600 mg oral dose of TBP-PI-HBr containing approximately 150 µCi of [14C]-TBP-PI-HBr. Blood, urine, and fecal samples were collected to determine the total radioactivity, concentrations of TBP (plasma only), and metabolite profiling and identification. The overall mean recovery of the total radioactivity in urine (38.7%) and feces (44.6%) combined was approximately 83.3% of the administered dose, with individual recoveries ranging from 80.1% to 85.0%. Plasma TBP LC-MS/MS and metabolite profiling data suggest that TBP was the main circulating component in plasma and that it accounts for approximately 54% of the total plasma radioactivity, based on the plasma AUC ratio of TBP/total radioactivity. The ring-open metabolite LJC 11562 was another major component in plasma (>10%). TBP (M12), LJC 11562, and four trace to minor metabolites were identified/characterized in the urine. TBP-PI, TBP (M12), and 11 trace to minor metabolites were identified/characterized in the feces. The renal and fecal routes are major clearance pathways in the elimination of [14C]-TBP-PI-HBr, with a mean combined recovery of 83.3%. TBP and its inactive ring-open metabolite LJC 11562 were the major circulating metabolites in the plasma.

Plasma and Intrapulmonary Concentrations of Tebipenem following Oral Administration of Tebipenem Pivoxil Hydrobromide to Healthy Adult Subjects.

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem prodrug being developed for the treatment of serious bacterial infections. The active moiety, tebipenem, has broad-spectrum activity against common Enterobacterales pathogens, including extended-spectrum-ß-lactamase (ESBL)-producing multidrug-resistant strains. This study evaluated the intrapulmonary pharmacokinetics (PK) and epithelial lining fluid (ELF) and alveolar macrophage (AM) concentrations of tebipenem relative to plasma levels in nonsmoking, healthy adult subjects. Thirty subjects received oral TBP-PI-HBr at 600 mg every 8 h for five doses. Serial blood samples were collected following the last dose. Each subject underwent one standardized bronchoscopy with bronchoalveolar lavage (BAL) 1, 2, 4, 6, or 8 h after the fifth dose of TBP-PI-HBr. The tebipenem area under the concentration-time curve for the 8-h dosing interval (AUC0-8) values in plasma, ELF, and AMs were calculated using the mean concentration at each BAL sampling time. Ratios of AUC0-8 values for total ELF and AMs to those for unbound plasma were determined, using a plasma protein binding value of 42%. Mean values ± standard deviations (SD) of tebipenem maximum (Cmax) and minimum (Cmin) total plasma concentrations were 11.37 ± 3.87 mg/L and 0.043 ± 0.039 mg/L, respectively. Peak tebipenem concentrations in plasma, ELF, and AMs occurred at 1 h and then decreased over 8 h. Ratios of tebipenem AUC0-8 values for ELF and AMs to those for unbound plasma were 0.191 and 0.047, respectively. Four (13.3%) subjects experienced adverse events (diarrhea, fatigue, papule, and coronavirus disease 2019 [COVID-19]); all resolved, and none were severe or serious. Tebipenem is distributed into the lungs of healthy adults, which supports the further evaluation of TBP-PI-HBr for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT04710407.).

The gap between stated importance of and clinical work in promoting healthy lifestyle habits by healthcare professionals in a Swedish hospital setting: A cross-sectional survey.

The objective of this study was to explore the stated importance of promoting healthy lifestyle habits (alcohol, eating habits, physical activity and tobacco) by healthcare professionals, and to what extent these attitudes were translated into clinical work. In 2014, healthcare professionals (n = 251) from cardiology departments in two hospitals in Stockholm, Sweden, participated in a cross-sectional descriptive questionnaire-based survey. The questionnaire included topics regarding stated importance and clinical work undertaken to promote healthy lifestyle habits. Personal and organisational factors of potential importance, expectations and future work were also explored. To analyse differences in stated importance and clinical work within and between lifestyle factors, comparisons of proportions were performed with 99% confidence intervals (CI). Relationships between stated importance and clinical work were investigated using logistic regression. The majority of healthcare professionals stated that it was 'very important' to promote healthy lifestyle habits among patients in general (69%-94%) and in their own clinical work (63%-80%). Despite this, always asking questions (18%-41%) or providing counselling (11%-23%) regarding lifestyle habits was reported to be rare. Overall, tobacco cessation was considered the most important behavioural change and was more often included in clinical work compared to promoting physical activity, healthy eating habits and limiting alcohol use. Clinical work was mainly influenced by to what extent the healthcare professional perceived clear organisational routines and objectives. In conclusion, we observed a gap between stated importance and clinical work in the promotion of healthy lifestyle habits among healthcare professionals. There were differences between lifestyle factors, indicating that work with tobacco cessation is the most established. Our results suggest that in order to promote patients' lifestyle habits in line with evidence-based guidelines, healthcare management should focus on and improve organisational routines and objectives.

Subjective reports of physical activity levels and sedentary time prior to hospital admission can predict utilization of hospital care and all-cause mortality among patients with cardiovascular disease.

BACKGROUND: In prevention, sedentary behaviour and physical activity have been associated with risk of cardiovascular disease and mortality. Less is known about associations with utilization of hospital care. AIM: To investigate whether physical activity level and sedentary behaviour prior to cardiac ward admission can predict utilization of hospital care and mortality among patients with cardiovascular disease. METHODS: Longitudinal observational study including 1148 patients admitted and treated in cardiac wards in two hospitals. Subjective reports of physical activity levels and sedentary time prior to admission were collected during inpatient care and categorized as low, medium or high. The associations between physical activity level and sedentary time with hospital stay, readmission and mortality were analysed using linear, logistic and Cox regressions. RESULTS: Median hospital stay was 2.1 days. One higher step in the physical activity level, or lower sedentary time, was related to an approximately 0.9 days shorter hospital stay. Sixty per cent of patients were readmitted to hospital. The risk of being readmitted was lower for individuals reporting high physical activity and low sedentary time (odds ratios ranging between 0.44 and 0.91). A total of 200 deaths occurred during the study. Mortality was lower among those with high and medium physical activity levels and low sedentary time (hazard ratios ranging between 0.36 and 0.90). CONCLUSION: Both physical activity level and sedentary time during the period preceding hospitalization for cardiac events were predictors of hospital utilization and mortality. This highlights the prognostic value of assessing patients' physical activity and sedentary behaviour.

Physical inactivity and smoking after myocardial infarction as predictors for readmission and survival: results from the SWEDEHEART-registry.

BACKGROUND: Physical activity (PA) and smoking cessation are included in the secondary prevention guidelines after myocardial infarction (MI), but they are still underutilised. This study aims to explore how PA level and smoking status (6-10 weeks post-MI) were associated with 1-year readmission and mortality during full follow-up time, and with the cumulative 5-year mortality. METHODS: A population-based cohort of all hospitals providing MI-care in Sweden (SWEDEHEART-registry) in 2004-2014. PA was expressed as the number of exercise sessions of ≥ 30 min in the last 7 days: 0-1 (low), 2-4 (medium) and 5-7 (high) sessions/week. Individuals were categorised as smokers, former smokers or never-smokers. The associations were analysed by unadjusted and adjusted logistic and Cox regressions. RESULTS: During follow-up (M = 3.58 years), a total of 1702 deaths occurred among 30 644 individuals (14.1 cases per 1000 person-years). For medium and high PA, the hazard ratios (HRs) for mortality were 0.39 and 0.36, respectively, compared with low PA. For never-smokers, the HR was 0.45 and former smokers 0.56 compared with smokers. Compared with low PA, the odds ratios (ORs) for readmission in medium PA were 0.65 and 0.59 for CVD and non-CVD causes, respectively. For high PA, the corresponding ORs were 0.63 and 0.55. The association remained in adjusted models. There were no associations between smoking status and readmission. CONCLUSIONS: The PA level and smoking status are strong predictors of mortality post-MI and the PA level also predicts readmission, highlighting the importance of adherence to the secondary prevention guidelines.

Increased Physical Activity Post-Myocardial Infarction Is Related to Reduced Mortality: Results From the SWEDEHEART Registry.

Background With increasing survival rates among patients with myocardial infarction ( MI ), more demands are placed on secondary prevention. While physical activity ( PA ) efforts to obtain a sufficient PA level are part of secondary preventive recommendations, it is still underutilized. Importantly, the effect of changes in PA after MI is largely unknown. Therefore, we sought to investigate the effect on survival from changes in PA level, post- MI . Methods and Results Data from Swedish national registries were combined, totaling 22 227 patients with MI . PA level was self-reported at 6 to 10 weeks post- MI and 10 to 12 months post- MI . Patients were classified as constantly inactive, increased activity, reduced activity, and constantly active. Proportional hazard ratios were calculated. During 100 502 person-years of follow-up (mean follow-up time 4.2 years), a total of 1087 deaths were recorded. Controlling for important confounders (including left ventricular function, type of MI , medication, smoking, participation in cardiac rehabilitation program, quality of life, and estimated kidney function), we found lower mortality rates among constantly active (hazard ratio: 0.29, 95% confidence interval: 0.21-0.41), those with increased activity (0.41, 95% confidence interval: 0.31-0.55), and those with reduced activity (hazard ratio: 0.56, 95% confidence interval: 0.45-0.69) during the first year post- MI , compared with those being constantly inactive. Stratified analyses indicated strong effect of PA level among both sexes, across age, MI type, kidney function, medication, and smoking status. Conclusions The present article shows that increasing the PA level, compared with staying inactive the first year post- MI , was related to reduced mortality.