Oren Zusman

Multicentre open-label randomised controlled trial to compare colistin alone with colistin plus meropenem for the treatment of severe infections caused by carbapenem-resistant Gram-negative infections (AIDA): a study protocol

Introduction The emergence of antibiotic-resistant bacteria has driven renewed interest in older antibacterials, including colistin. Previous studies have shown that colistin is less effective and more toxic than modern antibiotics. In vitro synergy studies and clinical observational studies suggest a benefit of combining colistin with a carbapenem. A randomised controlled study is necessary for clarification. Methods and analysis This is a multicentre, investigator-initiated, open-label, randomised controlled superiority 1:1 study comparing colistin monotherapy with colistin–meropenem combination therapy for infections caused by carbapenem-resistant Gram-negative bacteria. The study is being conducted in 6 centres in 3 countries (Italy, Greece and Israel). We include patients with hospital-associated and ventilator-associated pneumonia, bloodstream infections and urosepsis. The primary outcome is treatment success at day 14, defined as survival, haemodynamic stability, stable or improved respiratory status for patients with pneumonia, microbiological cure for patients with bacteraemia and stability or improvement of the Sequential Organ Failure Assessment (SOFA) score. Secondary outcomes include 14-day and 28-day mortality as well as other clinical end points and safety outcomes. A sample size of 360 patients was calculated on the basis of an absolute improvement in clinical success of 15% with combination therapy. Outcomes will be assessed by intention to treat. Serum colistin samples are obtained from all patients to obtain population pharmacokinetic models. Microbiological sampling includes weekly surveillance samples with analysis of resistance mechanisms and synergy. An observational trial is evaluating patients who met eligibility requirements but were not randomised in order to assess generalisability of findings. Ethics and dissemination The study was approved by ethics committees at each centre and informed consent will be obtained for all patients. The trial is being performed under the auspices of an independent data and safety monitoring committee and is included in a broad dissemination strategy regarding revival of old antibiotics. Trial registration number NCT01732250 and 2012-004819-31; Pre-results.

Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial

BACKGROUNDnColistin-carbapenem combinations are synergistic in vitro against carbapenem-resistant Gram-negative bacteria. We aimed to test whether combination therapy improves clinical outcomes for adults with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria.nnnMETHODSnA randomised controlled superiority trial was done in six hospitals in Israel, Greece, and Italy. We included adults with bacteraemia, ventilator-associated pneumonia, hospital-acquired pneumonia, or urosepsis caused by carbapenem-non-susceptible Gram-negative bacteria. Patients were randomly assigned (1:1) centrally, by computer-generated permuted blocks stratified by centre, to intravenous colistin (9-million unit loading dose, followed by 4·5 million units twice per day) or colistin with meropenem (2-g prolonged infusion three times per day). The trial was open-label, with blinded outcome assessment. Treatment success was defined as survival, haemodynamic stability, improved or stable Sequential Organ Failure Assessment score, stable or improved ratio of partial pressure of arterial oxygen to fraction of expired oxygen for patients with pneumonia, and microbiological cure for patients with bacteraemia. The primary outcome was clinical failure, defined as not meeting all success criteria by intention-to-treat analysis, at 14 days after randomisation. This trial is registered at ClinicalTrials.gov, number NCT01732250, and is closed to accrual.nnnFINDINGSnBetween Oct 1, 2013, and Dec 31, 2016, we randomly assigned 406 patients to the two treatment groups. Most patients had pneumonia or bacteraemia (355/406, 87%), and most infections were caused by Acinetobacter baumannii (312/406, 77%). No significant difference between colistin monotherapy (156/198, 79%) and combination therapy (152/208, 73%) was observed for clinical failure at 14 days after randomisation (risk difference -5·7%, 95% CI -13·9 to 2·4; risk ratio [RR] 0·93, 95% CI 0·83-1·03). Results were similar among patients with A baumannii infections (RR 0·97, 95% CI 0·87-1·09). Combination therapy increased the incidence of diarrhoea (56 [27%] vs 32 [16%] patients) and decreased the incidence of mild renal failure (37 [30%] of 124 vs 25 [20%] of 125 patients at risk of or with kidney injury).nnnINTERPRETATIONnCombination therapy was not superior to monotherapy. The addition of meropenem to colistin did not improve clinical failure in severe A baumannii infections. The trial was unpowered to specifically address other bacteria.nnnFUNDINGnEU AIDA grant Health-F3-2011-278348.

Empirical Antibiotic Treatment Does Not Improve Outcomes in Catheter-Associated Urinary Tract Infection: Prospective Cohort Study

BackgroundnCatheter associated urinary tract infection (CAUTI) is the most common healthcare-associated acquired infection. We aimed to describe the short- and long-term survival of patients with CAUTI and the impact of the empirical antibiotic treatment on survival rates.nnnMethodsnIn this prospective observational study we included consecutive adult patients with a chronic indwelling catheter-associated UTI and sepsis hospitalized in medical departments. The primary outcomes were 30-days all-cause mortality and long-term survival at end of the follow-up. A multivariate analysis using logistic regression and Cox proportional hazard model was performed to identify independent risk factors for an adverse outcome. A propensity-score model for receiving appropriate empirical antibiotic therapy was constructed and used to match patients.nnnResultsnOverall, 315 consecutive patients with CAUTI were enrolled. The cohort consisted of elderly to very old patients (mean age 79.2 ± 11.5). The crude 30-day all-cause mortality rate was 30.8% (97/315). The median survival time was 82 days (interquartile range [IQR] 22-638). Appropriate early empirical treatment had no statistically significant association with 30-day mortality, propensity score-matched odds ratio (OR) 1.39 (0.76-2.55). Similarly, in the propensity-matched cohort, appropriate empirical treatment was not statistically associated with long-term survival (hazard ratio [HR] = 0.99, 95% confidence interval [CI] 0.75-1.3).nnnConclusionsnIn our setting, patients with CAUTI had poor short- and long-term prognosis regardless of appropriate empirical antibiotic treatment. Avoiding empirical antibiotics for CAUTI might be an important antibiotic stewardship intervention in hospitals.

Trimethoprim/sulfamethoxazole versus vancomycin in the treatment of healthcare/ventilator-associated MRSA pneumonia: a case-control study.

Objectives: Therapeutic options available to treat MRSA pneumonia are limited. Trimethoprim/sulfamethoxazole is an attractive treatment because of its bactericidal anti-MRSA activity, oral and parenteral formulations and good penetration to the lung tissue. We aimed to compare the efficacy and safety of trimethoprim/sulfamethoxazole with vancomycin in the treatment of healthcare/ventilator-associated MRSA pneumonia. Methods: We carried out a retrospective case–control study of all consecutive hospitalized adult patients diagnosed with MRSA pneumonia at Beilinson Hospital during 2010–15 and treated with either vancomycin or trimethoprim/sulfamethoxazole. The primary outcomes were all-cause mortality at 30u2005days and clinical failure at the end of treatment. In order to reduce bias affecting the decision to use a specific antibiotic and as a sensitivity analysis, a propensity-score model for choosing between vancomycin and trimethoprim/sulfamethoxazole was used. Results: We identified 42 patients with MRSA pneumonia treated with trimethoprim/sulfamethoxazole and 39 treated with vancomycin. There were no significant differences in the baseline characteristics between the groups. Vancomycin-treated patients showed significantly higher 30u2005day mortality on both multivariate analysis (HRu2009=u20095.28; 95% CIu2009=u20091.50–18.60; Pu2009<u20090.05) and sensitivity analysis with propensity score [vancomycin 13/24 (54.1%) versus trimethoprim/sulfamethoxazole 4/24 (16.7%); Pu2009<u20090.05], and higher clinical failure rates [vancomycin 23/39 (59%) versus trimethoprim/sulfamethoxazole 15/42 (35.7%); Pu2009<u20090.05], also in the sensitivity analysis with propensity score [vancomycin 14/24 (58.3%) versus trimethoprim/sulfamethoxazole 6/24 (25%); Pu2009<u20090.05]. The rates of side effects in both arms were comparable. Conclusions: Trimethoprim/sulfamethoxazole appears to be superior to vancomycin in the treatment of MRSA pneumonia. A large-scale randomized controlled trial is needed to evaluate these findings.

Predictive Equations versus Measured Energy Expenditure by Indirect Calorimetry: A Retrospective Validation

BACKGROUND & AIMSnMeasuring resting energy expenditure (REE) via indirect calorimetry (IC) in intensive care unit (ICU) patient is the gold standard recommended by guidelines. However technical difficulties hinder its use and predictive equations are largely used instead. We sought to validate commonly used equations using a large cohort of patients.nnnMETHODSnPatients hospitalized from 2003 to 2015 in a 16-bed ICU at a university-affiliated, tertiary care hospital who had IC measurement to assess caloric targets were included. Data was drawn from a computerized system and included REE and other variables required by equations. Measurements were restricted to 5 REE per patient to avoid bias. Equation performance was assessed by comparing means, standard deviations, correlation, concordance and agreement, which was defined as a measurement within 85-115% of measured REE. A total of 8 equations were examined.nnnRESULTSnA total of 3573 REE measurements in 1440 patients were included. Mean patient age was 58 years and 65% were male. A total of 562 (39%) patients had >2 REE measurements. Standard deviation of REE ranged from 430 to 570xa0kcal. The Faisy equation had the least mean difference (90xa0Kcal); Harris-Benedict had the highest correlation (52%) and agreement (50%) and Jolliet the highest concordance (62%). Agreement within 10% of caloric needs was met only in a third of patients.nnnCONCLUSIONSnPredictive equations have low performance when compared to REE in ICU patients. We therefore suggest that predictive equations cannot wholly replace indirect calorimetry for the accurate estimation of REE in this population.

A decision support model to predict the presence of an acute infiltrate on chest radiograph

A chest infiltrate is needed to make a diagnosis of community-acquired pneumonia, but chest X-rays might be time consuming, entail radiation exposure, and demand resources that are not always available. We sought to derive a model to predict whether a patient will have an infiltrate on chest X-ray (CXR). This prospective observational study included patients visiting the Emergency Department of Beilinson Hospital in the years 2003–2004 (derivation cohort) and 2010–2011 (validation cohort), who had undergone a CXR, and were suspected of having a respiratory infection. We excluded all patients with possible healthcare associated infections. A logistic regression model was derived and applied to the validation cohort. A total of 1,555 patients met inclusion criteria: 993 in the derivation cohort and 562 in the validation cohort with 287 (29%) and 226 (40%) having an infiltrate, respectively. The derivation model area-under-the curve (AUC) was 0.79 (95% CI 0.76–0.82). We categorized the patients into three groups—presence or absence of infiltrate, or undetermined. In the validation cohort, 70 (12%) patients were classified as ‘no infiltrate’; 3 (4%) of them had an infiltrate, 367 (65%) were classified as ‘infiltrate’; 190 (52%) of them had an infiltrate on CXR, and 125 (46%) were classified as ‘undetermined’; 33 (26%) of them with an infiltrate on CXR. Using this prediction model for the evaluation of patients with suspected respiratory infection in an ED setting may help avoid over 10% of CXRs.

Transcatheter Aortic Valve Implantation Futility Risk Model Development and Validation Among Treated Patients With Aortic Stenosis

Risk-benefit assessment for transcatheter aortic valve implantation (TAVI) is still evolving. A sizeable group of patients do not fully benefit from intervention despite a technically successful procedure. All patients who underwent TAVI with device success and with no Valve Academic Research Consortium (VARC)-2 defined complications were included. Various demographic data, clinical details, and echocardiographic findings were examined. The outcome was defined as 1-year composite of mortality, stroke, lack of functional-class improvement (by New York Heart Association class), and readmissions (≥1 month after the procedure). Logistic regression was used to fit the prediction model. We used a 10-fold cross-validation to validate our results. Of 543 patients, 435 met the inclusion criteria. The mean age was 82 (±6.5) years, 43% were men, and the mean Society of Thoracic Surgeons score was 6.6 (±4.7). At 1 year, 66 of 435 patients (15%) experienced the study end point. The final logistic regression model included diabetes, baseline New York Heart Association functional class, diastolic dysfunction, need for diuretics, mean gradient, hemoglobin level, and creatinine level. The area under the curve was 0.73 and was reduced to 0.71 after validation, with a 97% specificity using a single cutoff. Dividing to low-, medium-, and high-risk groups for futility produced a corresponding prevalence of 6%, 19%, and 59% futility. A web application for the prediction model was developed and provided. In conclusion, this prediction score may provide an important insight and may facilitate identification of patients who, despite a technically successful and uncomplicated procedure, have risk that may outweigh the benefit of a contemplated TAVI.