Elimination of Doripenem during Dialysis and Pharmacokinetic Evaluation of Posthemodialysis Dosing for Patients Undergoing Intermittent Renal Replacement Therapy.

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa and Enterobacteriaceae Current dosing regimens recommend the administration of 0.25 to 0.5 g once daily in patients undergoing intermittent renal replacement therapy. As patients are usually dialyzed thrice weekly, we aimed to investigate a 1-g posthemodialysis regimen, thus reducing treatment costs and enhancing patient compliance. A second objective of this trial was to describe the pharmacokinetics of intradialytic doripenem. Ten oliguric or anuric patients in need of intermittent renal replacement therapy were included in this trial. All patients suffered from a septic episode. The mean hemofilter clearance was 123.46 ± 42.03 ml/min, and the total body clearance between hemodialysis sessions was 16.79 ± 6.02 ml/min. The average prehemodialysis trough concentration was 2.4 ± 1.3 mg/liter, while the EUCAST resistance breakpoint for Enterobacteriaceae is set at 2 mg/liter. The interpatient variability was considerably higher than the intrapatient variability. Apart from one patient who suffered an allergic reaction, doripenem was tolerated well by all patients. Our data indicate that posthemodialysis administration of 1 g of doripenem results in sufficient plasma levels in anuric but not oliguric patients during the entire dosing interval. (This trial was registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.).

Doripenem Treatment during Continuous Renal Replacement Therapy.

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa. While the initial dosing recommendation for renally competent patients and patients undergoing continuous renal replacement therapy (cRRT) was 500 mg every 8 h (q8h), the dose for renally competent patients was updated to 1 g q8h in June 2012. There are no updated data for the dosing of patients on continuous renal replacement therapy. The original dosing regimen for cRRT patients was based on nonseptic patients, while newer publications chose comparatively low target concentrations for a carbapenem. Thus, there is an urgent need for updated recommendations for dosing during cRRT. In the trial presented here, we included 13 oliguric septic patients undergoing cRRT in an intensive care setting. Five patients each were treated with hemodiafiltration or hemodialysis, while three patients received hemofiltration treatment. All patients received 1 g doripenem every 8 h. Doripenem concentrations in the plasma and ultrafiltrate were measured over 48 h. The mean hemofilter clearance was 36.53 ml/min, and the mean volume of distribution was 59.26 liters. The steady-state trough levels were found at 8.5 mg/liter, with no considerable accumulation. Based on pharmacokinetic and pharmacodynamic considerations, we propose a regimen of 1 g q8h, which may be combined with a loading dose of 1.5 to 2 g for critically ill patients. (This study has been registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.).

A pilot study on reparixin, a CXCR1/2 antagonist, to assess safety and efficacy in attenuating ischaemia-reperfusion injury and inflammation after on-pump coronary artery bypass graft surgery.

Reparixin, a CXCR 1/2 antagonist, has been shown to mitigate ischaemia-reperfusion injury (IRI) in various organ systems in animals, but data in humans are scarce. The aim of this double-blinded, placebo-controlled pilot study was to evaluate the safety and efficacy of reparixin to suppress IRI and inflammation in patients undergoing on-pump coronary artery bypass grafting (CABG). Patients received either reparixin or placebo (n = 16 in each group) after induction of anaesthesia until 8 h after cardiopulmonary bypass (CPB). We compared markers of systemic and pulmonary inflammation, surrogates of myocardial IRI and clinical outcomes using Mann-Whitney U- and Fisher's exact tests. Thirty- and 90-day mortality was 0% in both groups. No side effects were observed in the treatment group. Surgical revision, pleural and pericardial effusion, infection and atrial fibrillation rates were not different between groups. Reparixin significantly reduced the proportion of neutrophil granulocytes in blood at the beginning [49%, interquartile range (IQR) = 45-57 versus 58%, IQR = 53-66, P = 0·035], end (71%, IQR = 67-76 versus 79%, IQR = 71-83, P = 0·023) and 1 h after CPB (73%, IQR = 71-75 versus 77%, IQR = 72-80, P = 0·035). Reparixin patients required a lesser positive fluid balance during surgery (2575 ml, IQR = 2027-3080 versus 3200 ml, IQR = 2928-3778, P = 0·029) and during ICU stay (2603 ml, IQR = 1023-4288 versus 4200 ml, IQR = 2313-8160, P = 0·021). Numerically, more control patients required noradrenaline ≥ 0·11 µg/kg/min (50 versus 19%, P = 0·063) and dobutamine (50 versus 25%, P = 0·14). Therefore, administration of reparixin in CABG patients appears to be feasible and safe. It concurrently attenuated postoperative granulocytosis in peripheral blood.

All-cause mortality in hospitalized patients with infectious diarrhea: Clostridium difficile versus other enteric pathogens in Austria from 2008 to 2010.

BACKGROUND: Clostridium difficile infection is the leading cause of gastroenteritis-associated deaths in the industrialized world, followed by infection with norovirus. METHODS: Using a cohort study design, we compared 90 inpatients with diarrhea due to C. difficile infection (CDI) with 180 inpatients with diarrhea due to other infectious agents (including 55% with norovirus infection) with respect to complications and all-cause mortality. The effects of age, severity of underlying diseases and additional infections were assessed by stratified analyses. RESULTS: Diarrhea recurrence occurred 8.9 (95%CI: 2.9-27.3) times more often in CDI independent of age and severity of comorbidities. The all-cause mortality in CDI patients pre-discharge and at 30 and 180 days, respectively, was 20.0%, 17.0% and 42.3% versus 7.2%, 6.7% and 22.5% in non-CDI diarrhea patients. Among those patients with low comorbidities, who were younger than 65 years and without additional infections, the all-cause pre-discharge, 30-day and 180-day mortality risks were significantly higher for the CDI diarrhea patients than the non-CDI diarrhea patients. This association was not observed among patients with an older age, more severe comorbidities or additional infections. CONCLUSION: CDI results in higher all-cause mortality than diarrhea due to other infectious agents in younger patients with low comorbidities.

A prospective cohort study on hospital mortality due to Clostridium difficile infection.

PURPOSE: Although an increase in burden of disease has frequently been reported for Clostridium difficile infection (CDI), specific data on the effect of CDI on a patient's risk of death or overall hospital mortality are scarce. Therefore, we performed a prospective cohort study to analyse the effect of CDI on the risk of pre-discharge all-cause death in all inpatients with CDI compared to all inpatients without CDI during 2009 in a single hospital. METHODS: Clostridium difficile infection was defined as by the European Society of Clinical Microbiology and Infectious Diseases. Data were collected from the medical charts of CDI patients and from the hospital discharge data of non-CDI and CDI patients. The effect measures of CDI used to compute the risk of pre-discharge all-cause death were risk ratio, attributable risk, mortality fraction (%) and population attributable risk percentage. Co-morbidity was categorized using the Charlson co-morbidity score in which a value of ≤2 was defined as low co-morbidity and that of >2 as moderate/severe co-morbidity. A stratified analysis and a Poisson regression model were applied to adjust for the effects of the risk factors sex, age and severity of co-morbidity. RESULTS: A total of 185 hospitalized patients with CDI were compared to 38,644 other hospitalized patients without CDI admitted between 1 January 2009 and 31 December 2009. The mean age of the CDI and non-CDI patients was 74.3 (range 72.3-76.4) and 51.9 (range 51.6-52.1) years, respectively. Of the 185 CDI, 136 (73.5%) and 49 (26.5%) were categorized with low and high co-morbidity, respectively, versus 32,107 (83.4%) and 6,352 (16.5%), respectively, in non-CDI patients. Overall, 24 of the 185 CDI patients (13%) versus 1,021 of the 38,459 non-CDI patients (2.7%) died during their hospital stay, resulting in a relative risk of pre-discharge death of 4.89 [95% confidence interval (CI) 3.35-7.13] for CDI patients, a CDI attributable risk of death of 10.3 per 100 patients and a CDI attributable fraction of 79.5 % (95% CI 70.1-86 %). After adjustment for age, sex and co-morbidity the relative risk of pre-discharge death was 2.74 (95% CI 1.82-4.10; p < 0.0001) for patients with CDI, and the proportion of hospital deaths due to CDI was 1.72 (95% CI 1.22-2.05). CONCLUSION: The results of this study lead to the conclusion that hospitalized patients with CDI are--independent of age, sex and co-morbidity severity--2.74-fold more likely to die during their hospital stay than all other hospitalized patients. The eradication of CDI in the hospital could have prevented 1.72% of in-hospital deaths in our study population during the 1 year of the study.

Hospital-acquired Clostridium difficile infection: determinants for severe disease.

Risk factors of severity (need for surgical intervention, intensive care or fatal outcome) were analysed in hospital-acquired Clostridium difficile infection (CDI) in a 777-bed community hospital. In a prospective analytical cross-sectional study, age (≥ 65 years), sex, CDI characteristics, underlying diseases, severity of comorbidity and PCR ribotypes were tested for associations with severe CDI. In total, 133 cases of hospital-acquired CDI (mean age 74.4 years) were identified, resulting in an incidence rate of 5.7/10,000 hospital-days. A recurrent episode of diarrhoea occurred in 25 cases (18.8%) and complications including toxic megacolon, dehydration and septicaemia in 69 cases (51.9%). Four cases (3.0%) required ICU admission, one case (0.8%) surgical intervention and 22 cases (16.5%) died within the 30-day follow-up period. Variables identified to be independently associated with severe CDI were severe diarrhoea (odds ratio [OR] 3.64, 95% confidence interval [CI] 1.19-11.11, p=0.02), chronic pulmonary disease (OR 3.0, 95% CI 1.08-8.40, p=0.04), chronic renal disease (OR 2.9, 95% CI 1.07-7.81, p=0.04) and diabetes mellitus (OR 4.30, 95% CI 1.57-11.76, p=0.004). The case fatality of 16.5% underlines the importance of increased efforts in CDI prevention, in particular for patients with underlying diseases.

Independent magnetization behavior of a ferromagnetic metal-semiconductor hybrid system.

We report the discovery of an effect where two ferromagnetic materials, one semiconductor [(Ga,Mn)As] and one metal (Permalloy), can be directly deposited on each other and still switch their magnetization independently. We use this independent magnetization behavior to create various resistance states dependent on the magnetization direction of the individual layers. At zero magnetic field a two layer device can reach up to four nonvolatile resistance states.

Control of magnetic anisotropy in (Ga,Mn)as by lithography-induced strain relaxation.

We report control of magnetic anisotropy in epitaxial (Ga,Mn)As by anisotropic strain relaxation in patterned structures. The strain in the structures is characterized using reciprocal space mapping by x-ray techniques. The magnetic anisotropy before patterning of the layer, which shows biaxial easy axes along [100] and [010], is replaced by a hard axis in the direction of large elastic strain relaxation and a uniaxial easy axis in the direction where pseudomorphic conditions are retained.