The effects of antibiotic cycling and mixing on acquisition of antibiotic resistant bacteria in the ICU: A post-hoc individual patient analysis of a prospective cluster-randomized crossover study.

BACKGROUND: Repeated rotation of empiric antibiotic treatment strategies is hypothesized to reduce antibiotic resistance. Clinical rotation studies failed to change unit-wide prevalence of antibiotic resistant bacteria (ARB) carriage, including an international cluster-randomized crossover study. Unit-wide effects may differ from individual effects due to "ecological fallacy". This post-hoc analysis of a cluster-randomized crossover study assesses differences between cycling and mixing rotation strategies in acquisition of carriage with Gram-negative ARB in individual patients. METHODS: This was a controlled cluster-randomized crossover study in 7 ICUs in 5 European countries. Clinical cultures taken as routine care were used for endpoint assessment. Patients with a first negative culture and at least one culture collected in total were included. Community acquisitions (2 days of admission or less) were excluded. Primary outcome was ICU-acquisition of Enterobacterales species with reduced susceptibility to: third- or fourth generation cephalosporins or piperacillin-tazobactam, and Acinetobacter species and Pseudomonas aeruginosa with reduced susceptibility for piperacillin-tazobactam or carbapenems. Cycling (altering first-line empiric therapy for Gram-negative bacteria, every other 6-weeks), to mixing (changing antibiotic type every empiric antibiotic course). Rotated antibiotics were third- or fourth generation cephalosporins, piperacillin-tazobactam and carbapenems. RESULTS: For this analysis 1,613 admissions were eligible (855 and 758 during cycling and mixing, respectively), with 16,437 microbiological cultures obtained. Incidences of acquisition with ARB during ICU-stay were 7.3% (n = 62) and 5.1% (n = 39) during cycling and mixing, respectively (p-value 0.13), after a mean of 17.7 (median 15) and 20.8 (median 13) days. Adjusted odds ratio for acquisition of ARB carriage during mixing was 0.62 (95% CI 0.38 to 1.00). Acquired carriage with ARB were Enterobacterales species (n = 61), Pseudomonas aeruginosa (n = 38) and Acinetobacter species (n = 20), with no statistically significant differences between interventions. CONCLUSIONS: There was no statistically significant difference in individual patients' risk of acquiring carriage with Gram-negative ARB during cycling and mixing. These findings substantiate the absence of difference between cycling and mixing on the epidemiology of Gram-negative ARB in ICU. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, registered 10 January 2011, NCT01293071.

Gender-related outcome difference is related to course of sepsis on mixed ICUs: a prospective, observational clinical study.

INTRODUCTION: Impact of gender on severe infections is in highly controversial discussion with natural survival advantage of females described in animal studies but contradictory to those described human data. This study aims to describe the impact of gender on outcome in mixed intensive care units (ICUs) with a special focus on sepsis. METHODS: We performed a prospective, observational, clinical trial at Charité University Hospital in Berlin, Germany. Over a period of 180 days, patients were screened, undergoing care in three mainly surgical ICUs. In total, 709 adults were included in the analysis, comprising the main population ([female] n = 309, [male] n = 400) including 327 as the sepsis subgroup ([female] n = 130, [male] n = 197). RESULTS: Basic characteristics differed between genders in terms of age, lifestyle factors, comorbidities, and SOFA-score (Sequential Organ Failure Assessment). Quality and quantity of antibiotic therapy in means of antibiotic-free days, daily antibiotic use, daily costs of antibiotics, time to antibiotics, and guideline adherence did not differ between genders. ICU mortality was comparable in the main population ([female] 10.7% versus [male] 9.0%; P = 0.523), but differed significantly in sepsis patients with [female] 23.1% versus [male] 13.7% (P = 0.037). This was confirmed in multivariate regression analysis with OR = 1.966 (95% CI, 1.045 to 3.701; P = 0.036) for females compared with males. CONCLUSIONS: No differences in patients' outcome were noted related to gender aspects in mainly surgical ICUs. However, for patients with sepsis, an increase of mortality is related to the female sex.

The effects of antibiotic cycling and mixing on antibiotic resistance in intensive care units: a cluster-randomised crossover trial.

BACKGROUND: Whether antibiotic rotation strategies reduce prevalence of antibiotic-resistant, Gram-negative bacteria in intensive care units (ICUs) has not been accurately established. We aimed to assess whether cycling of antibiotics compared with a mixing strategy (changing antibiotic to an alternative class for each consecutive patient) would reduce the prevalence of antibiotic-resistant, Gram-negative bacteria in European intensive care units (ICUs). METHODS: In a cluster-randomised crossover study, we randomly assigned ICUs to use one of three antibiotic groups (third-generation or fourth-generation cephalosporins, piperacillin-tazobactam, and carbapenems) as preferred empirical treatment during 6-week periods (cycling) or to change preference after every consecutively treated patient (mixing). Computer-based randomisation of intervention and rotated antibiotic sequence was done centrally. Cycling or mixing was applied for 9 months; then, following a washout period, the alternative strategy was implemented. We defined antibiotic-resistant, Gram-negative bacteria as Enterobacteriaceae with extended-spectrum ß-lactamase production or piperacillin-tazobactam resistance, and Acinetobacter spp and Pseudomonas aeruginosa with piperacillin-tazobactam or carbapenem resistance. Data were collected for all admissions during the study. The primary endpoint was average, unit-wide, monthly point prevalence of antibiotic-resistant, Gram-negative bacteria in respiratory and perineal swabs with adjustment for potential confounders. This trial is registered with ClinicalTrials.gov, number NCT01293071. FINDINGS: Eight ICUs (from Belgium, France, Germany, Portugal, and Slovenia) were randomly assigned and patients enrolled from June 27, 2011, to Feb 16, 2014. 4069 patients were admitted during the cycling periods in total and 4707 were admitted during the mixing periods. Of these, 745 patients during cycling and 853 patients during mixing were present during the monthly point-prevalence surveys, and were included in the main analysis. Mean prevalence of the composite primary endpoint was 23% (168/745) during cycling and 22% (184/853) during mixing (p=0·64), yielding an adjusted incidence rate ratio during mixing of 1·039 (95% CI 0·837-1·291; p=0·73). There was no difference in all-cause in-ICU mortality between intervention periods. INTERPRETATION: Antibiotic cycling does not reduce the prevalence of carriage of antibiotic-resistant, Gram-negative bacteria in patients admitted to the ICU. FUNDING: European Union Seventh Framework Programme.

Tributyltin (TBT) induces ultra-rapid caspase activation independent of apoptosome formation in human platelets.

Activation of caspases has been demonstrated to be involved in thrombocytopenia and prolonged storage of platelet concentrates. Platelets represent enucleate cells that comprise all elements of the mitochondrial apoptosis pathway. However, no apoptotic stimuli capable of activating the endogenous caspase cascade have been identified so far. Using tributyltin (TBT) we could identify a compound that is capable of activating caspase-9 and -3 in platelets. Recent studies implicate that TBT induces apoptosis via the mitochondrial signaling pathway that is characterized by the formation of a high-molecular-weight complex (apoptosome) containing the adapter protein Apaf-1 and active caspase-9. Interestingly, addition of TBT induced the activation of caspase-9 in an ultra-rapid kinetic within the first 2 min. In addition, size exclusion chromatography revealed that TBT-mediated processing of caspase-9 occurs in the absence of the apoptosome. Thus, these data implicate that TBT induces the activation of caspase-9 by a mechanism not involving the formation of the apoptosome.

Peripheral intravenous cannulation with support of infrared laser vein viewing system in a pre-operation setting in pediatric patients.

BACKGROUND: Venous access, a prerequisite for anesthesiological and surgical intervention in pediatric patients, is often difficult to establish and potentially painful. AV300 uses near infrared laser light to improve visibility of peripheral veins and could help cannulating them. The aim of this study was to examine if use of Accuvein(®) AV300 vein viewer could facilitate venous cannulation in children. METHODS: From January to March 2011, 238 consecutive pediatric patients (0-17 years) preceding surgical interventions were included. All participants including newborns, infants and children were allocated to groups [control group (124 patients) and intervention group (114 patients)] in a non-random way. Randomization was not feasible because data was acquired retrospectively from a clinical quality management project. In control group, peripheral IV cannulation was performed without supporting device, in intervention group with support of AV300. Time and number of attempts until successful venous cannulation were defined as primary end points. RESULTS: Median time until successful cannulation was 2 min (range 0.1-20, quartiles: 25 %: 1; 75 %: 5) in the intervention group and 1 min (range 0.1-18, quartiles: 25 %: 0.2; 75 %: 2) in the control group (p < 0.01). Median number of attempts was higher in the intervention group (2; range 1-6, quartiles: 25 %: 1; 75 %: 3) than in the control group (1; range 1-6, quartiles: 25 %: 1; 75 %: 2, p < 0.01). Rate of cannulations successful at first attempt was 0.45 (51 of 114, 95 % CI 0.35-0.54) in the intervention group and 0.73 (90 of 124, 95 % CI 0.65-0.81) in the control group (p < 0.01). CONCLUSIONS: In our study we were not able to reduce neither time nor number of attempts until a successful venous cannulation in children using the vein viewer. Given certain limitations of our study as the lack of randomization and no control for inter-operator variability, the conclusions drawn from it are also limited, but by our results laser-supported cannulation cannot be recommended for standard procedures. TRIAL REGISTRATION: ClinicalTrials.gov NCT01434537. Registered 29 July 2011.

Effect of blood-sugar limitation on intensive care mortality: Intragroup evaluation.

OBJECTIVE: To evaluate the safety profile of blood sugar limits in intensive care unit (ICU) patients. METHODS: Adult patients with ICU stay >36 h, more than two blood sugar measurements and antibiotic therapy concordant with locally adapted guidelines were included. For analyses, one study cohort was defined in two ways: as a narrow group, euglycaemic patients' blood sugar levels 80-150 mg/dl; as a moderate group, euglycaemic patients' blood sugar levels 80-180 mg/dl. Dysglycaemia was defined as blood sugar levels <80 mg/dl for >5% of measurements, and >150 mg/dl or >180 mg/dl (narrow or moderate groups, respectively) for >10% of measurements. The primary endpoint was ICU mortality (euglycaemia versus dysglycaemia). RESULTS: The study comprised 668 patients. When defined as a narrow group, ICU mortality was 3% (four of 135) euglycaemic versus 10% (54/533) dysglycaemic patients (odds ratio [OR] 3.692, 95% confidence interval [CI] 1.313, 10.382). When defined as a moderate group, ICU mortality was 6% (21/351) euglycaemic versus 12% (37/317) dysglycaemic patients (OR 2.077, 95% CI 1.188, 3.630). Frequency of severe hypoglycaemia (blood sugar <40 mg/dl) was not different between the narrow and moderate euglycaemic ranges. CONCLUSIONS: Euglycaemia was associated with lower ICU mortality than dysglycaemia, and incidence of hypoglycaemia was low overall in this study. Based on current published evidence, therapeutic targets should be defined according to individual patient characteristics.

Polymorphisms of the toll-like receptor 2 and 4 genes are associated with faster progression and a more severe course of sepsis in critically ill patients.

OBJECTIVE: To determine whether the Arg753Gln polymorphism of the toll-like receptor 2 (TLR2) gene and the Asp299Gly polymorphism of the TLR4 gene in critically ill patients affect their clinical outcomes. METHODS: Medical and surgical patients in three intensive care units (ICU) were enrolled in this prospective study. TLR2 and TLR4 gene polymorphisms were determined using restriction fragment length polymorphism analysis. RESULTS: A total of 145 patients were included in this study: 28 patients carried heterozygous mutations (10 in the TLR2 gene, 19 in the TLR4 gene, and one combined) and 117 patients were wild type. Severe sepsis was observed in 33% of wild types (n = 38), 60% of the TLR2 group (n = 6), and 63% of the TLR4 group (n = 12); the difference was significant between the TLR4 and wild type groups. Both TLR groups demonstrated a shorter time-to-onset of severe sepsis or septic shock. Only the TLR4 group demonstrated significant progression towards septic shock compared with the wild type group. Length of ICU stay was significantly prolonged in the TLR4 group compared with the wild type group, but not in the TLR2 group. CONCLUSIONS: Two common SNPs of the TLR2 and TLR4 genes--Arg753Gln and Asp299Gly--were associated with a shorter time-to-onset of severe sepsis or septic shock in patients admitted to the ICU.