The past decade has brought a significant rise in antimicrobial resistance, and the ESKAPE pathogens have become a significant threat to public health. Three epidemiological features that negatively ...impact patients, which are consistently seen with the ESKAPE pathogens, are the following: 1) there has been a rise in incidence of these organisms as causative human pathogens, 2) there has been a significant increase in antimicrobial resistance in these bacterial species, and 3) the infections caused by these resistant strains are associated with worse outcomes when compared with infections caused by their susceptible counterparts. Significant delays in time to appropriate antimicrobial therapy of up to 5 days have been reported in infections due to these organisms and this is the strongest predictor of mortality with ESKAPE pathogens, particular in critically ill patients, where every hour delay has an incremental survival disadvantage for patients. Strategies to decrease these delays are urgently needed. Although routine broad-spectrum empiric coverage for these organisms would ideally limit this delay, agents with activity against these organisms are sometimes less effective, have significant toxicity risk, and their use can result in the development of resistance. Therefore, strategies to optimize therapy, although limiting unnecessary use of broad-spectrum antimicrobials, are urgently needed. This review will discuss potential strategies to optimize empiric therapy in the age of multi-drug resistance, the limitations of these strategies, and will discuss future directions and opportunities.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Polymyxins have remained the drug of choice for treatment due to carbapenem-resistant Gram-negative bacilli. Unfortunately, the utility of these agents has been limited by a lack of pharmacokinetic ...understanding, a high toxicity rate, and an extremely narrow therapeutic index. Significant advancements have been achieved in the understanding of the polymyxins over the past decade, and have led to the recognition of several differences between available intravenous formulations. The purpose of this review is to discuss the implications of these differences, assess comparative efficacy and safety of the polymyxins, and provide recommendations for polymyxin dosing and selection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aims
The objectives of this study were to determine the association of waist circumference (WC) and waist-to-hip ratio (WHR) with the risk of incident cardiovascular disease (CVD) events and to ...determine whether the strength of association of WC and WHR with CVD risk is different.
Methods and results
This meta-regression analysis used a search strategy of keywords and MeSH terms to identify prospective cohort studies and randomized clinical trials of CVD risk and abdominal obesity from the Medline, Embase, and Cochrane databases. Fifteen articles (n = 258 114 participants, 4355 CVD events) reporting CVD risk by categorical and continuous measures of WC and WHR were included. For a 1 cm increase in WC, the relative risk (RR) of a CVD event increased by 2% (95% CI: 1-3%) overall after adjusting for age, cohort year, or treatment. For a 0.01 U increase in WHR, the RR increased by 5% (95% CI: 4-7%). These results were consistent in men and women. Overall risk estimates comparing the extreme quantiles of each measure suggested that WHR was more strongly associated with CVD than that for WC (WHR: RR = 1.95, 95% CI: 1.55-2.44; WC: RR = 1.63, 95% CI: 1.31-2.04), although this difference was not significant. The strength of association for each measure was similar in men and women.
Conclusion
WHR and WC are significantly associated with the risk of incident CVD events. These simple measures of abdominal obesity should be incorporated into CVD risk assessments.
Oral anticoagulation therapy reduces risk of vascular events in patients with atrial fibrillation. However, long-term monitoring is necessary and many patients cannot achieve optimum anticoagulation. ...We assessed whether clopidogrel plus aspirin was non-inferior to oral anticoagulation therapy for prevention of vascular events.
Patients were enrolled if they had atrial fibrillation plus one or more risk factor for stroke, and were randomly allocated to receive oral anticoagulation therapy (target international normalised ratio of 2·0–3·0; n=3371) or clopidogrel (75 mg per day) plus aspirin (75–100 mg per day recommended; n=3335). Outcome events were adjudicated by a blinded committee. Primary outcome was first occurrence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death. Analyses were by intention-to-treat. This study is registered with
ClinicalTrials.gov, number NCT00243178.
The study was stopped early because of clear evidence of superiority of oral anticoagulation therapy. There were 165 primary events in patients on oral anticoagulation therapy (annual risk 3·93%) and 234 in those on clopidogrel plus aspirin (annual risk 5·60%; relative risk 1·44 (1·18–1.76; p=0.0003). Patients on oral anticoagulation therapy who were already receiving this treatment at study entry had a trend towards a greater reduction in vascular events (relative risk 1·50, 95% CI 1·19–1·89) and a significantly (p=0·03 for interaction) lower risk of major bleeding with oral anticoagulation therapy (1.30; 0.94–1.79) than patients not on this treatment at study entry (1·27, 0·85–1·89 and 0·59, 0·32–1·08, respectively).
Oral anticoagulation therapy is superior to clopidogrel plus aspirin for prevention of vascular events in patients with atrial fibrillation at high risk of stroke, especially in those already taking oral anticoagulation therapy.
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DOBA, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SIK, UILJ, UKNU, UL, UM, UPCLJ, UPUK, VSZLJ
Background. Colistin, originally abandoned due to high rates of nephrotoxicity, has been recently reintroduced due to activity against carbapenem-resistant Gram-negative organisms. Recent literature, ...largely obtained from outside the United States, suggests a lower rate of nephrotoxicity than historically reported. Methods. A retrospective cohort of all patients who received colistin for ≥48 hours at the Detroit Medical Center over a 5-year period was performed to determine the rate of colistin-associated nephrotoxicity as defined by the RIFLE criteria. Results. Fifty-four (43%) patients in the cohort developed nephrotoxicity. Patients who experienced nephrotoxicity after colistin administration were in the Risk (13%), Injury (17%), or Failure (13%) categories per RIFLE criteria. Patients who developed nephrotoxicity received significantly higher mean doses than those who did not (5.48 mg/kg per day vs 3.95 mg/kg per day; P <.001), and the toxicity occurred in a dose-dependent fashion. Independent predictors for nephrotoxicity were a colistin dose of ≥5.0 mg/kg per day of ideal body weight (odds ratio OR, 23.41; 95% confidence interval CI, 5.3—103.55), receipt of concomitant rifampin (OR, 3.81; 95% CI, 1.42—10.2), and coadministration of ≥3 concomitant nephrotoxins (OR, 6.80; 95% CI, 1.42—32.49). Conclusions. In this retrospective cohort, nephrotoxicity (as defined by RIFLE criteria) occurred among 43% of treated patients in a dose-dependent manner. Higher colistin doses, similar to those commonly used in the United States, led to a relatively high rate of nephrotoxicity. These data raise important questions regarding the safe use of colistin in the treatment of multidrug-resistant pathogens.
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BFBNIB, NUK, PNG, UL, UM, UPUK
Background
This post hoc analysis aimed to determine whether neuraxial block was associated with a composite of cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal cardiac arrest ...within 30 days of randomization in POISE trial patients.
Methods
A total of 8351 non-cardiac surgical patients at high risk of cardiovascular complications were randomized to β-blocker or placebo. Neuraxial block was defined as spinal, lumbar or thoracic epidural anaesthesia. Logistic regression, with weighting using estimated propensity scores, was used to determine the association between neuraxial block and primary and secondary outcomes.
Results
Neuraxial block was associated with an increased risk of the primary outcome 287 (7.3%) vs 229 (5.7%); odds ratio (OR), 1.24; 95% confidence interval (CI), 1.02–1.49; P=0.03 and MI 230 (5.9%) vs 177 (4.4%); OR, 1.32; 95% CI, 1.07–1.64; P=0.009 but not stroke 23 (0.6%) vs 32 (0.8%); OR, 0.76; 95% CI, 0.44–1.33; P=0.34, death 96 (2.5%) vs 111 (2.8%); OR, 0.87; 95% CI, 0.65–1.17; P=0.37 or clinically significant hypotension 522 (13.4%) vs 484 (12.1%); OR, 1.13; 95% CI, 0.99–1.30; P=0.08. Thoracic epidural with general anaesthesia was associated with a worse primary outcome than general anaesthesia alone 86 (12.1%) vs 119 (5.4%); OR, 2.95; 95% CI, 2.00–4.35; P<0.001.
Conclusions
In patients at high risk of cardiovascular morbidity, neuraxial block was associated with an increased risk of adverse cardiovascular outcomes, which could be causal or because of residual confounding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Acinetobacter baumannii-Acinetobacter calcoaceticus complex (referred to herein as A. baumannii) treatment guidelines contain numerous older antimicrobial agents with susceptibility test interpretive ...criteria (STIC, also known as susceptibility breakpoints) set using only epidemiological data. We utilized a combination of
surveillance data, preclinical murine thigh and lung infection models, population pharmacokinetics, simulation, and pharmacokinetic/pharmacodynamic (PK/PD) target attainment analyses to evaluate A. baumannii STIC for four commonly recommended antimicrobials from different classes (amikacin, ceftazidime, ciprofloxacin, and minocycline). Antimicrobial
surveillance data were based on 1,647 clinical A. baumannii isolates obtained from 109 centers in the United States and Europe. Among these isolates, 5 were selected for evaluation in murine infection models based on fitness and MIC variability. PK and dose-ranging studies were conducted using neutropenic murine thigh and lung infection models The MIC ranges for the 5 isolates evaluated were as follows: amikacin, 2 to 32 μg/mL; ceftazidime, 4 to 16 μg/mL; ciprofloxacin, 0.12 to 2 μg/mL; minocycline, 0.25 to 4 μg/mL. All organisms grew ≥1.5 log
CFU in both models in untreated controls. Plasma and epithelial lining fluid (ELF) pharmacokinetics for all drugs were determined in mice using liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. For each isolate, 5 dose levels of each drug were tested individually in the thigh and lung infection model. The inoculum ranged from 7.9 to 8.4 and 6.8 to 7.7 log
CFU/mL for the lung and thigh models, respectively. PK/PD targets associated with net bacterial stasis and 1- and 2-log
CFU reductions from baseline were identified for each organism/infection model using Hill-type models. Population pharmacokinetic models for each agent were identified from the literature. Using demographic variables for simulated patients with hospital-acquired or ventilator-associated bacterial pneumonia or urinary tract infections (including acute pyelonephritis) who were administered maximal dosing regimens of each agent, estimates of protein binding, and ELF penetration ratios based on data from the literature, free-drug plasma and total-drug concentration-time profiles were generated, and PK/PD indices by MIC were calculated. Percent probabilities of attaining median and randomly assigned PK/PD targets associated with the above-described endpoints were determined. Recommended susceptible breakpoints for each agent were those representing the highest MIC at which the percent probabilities of achieving PK/PD targets associated with a 1-log
CFU reduction from baseline approached or were ≥90%. The following susceptible breakpoints for A. baumannii were identified: amikacin, ≤8 μg/mL for pneumonia; ceftazidime, ≤32 and ≤8 μg/mL for pneumonia; ciprofloxacin, ≤1 μg/mL; and minocycline, ≤0.5/≤1 μg/mL which correspond to the standard and high minocycline dosing regimens of 200 mg per day and 200 mg every 12 h, respectively. Implementation of appropriate STIC will help clinicians optimally use the above-described agents and improve the likelihood of successful patient outcomes.
Emerging data suggest that different indices of glycaemia are risk factors for clinical events. The aim of this analysis was to investigate the relationship between fasting plasma glucose or glycated ...haemoglobin (GHb) levels and incident cardiovascular (CV) outcomes, death, heart failure and overt nephropathy in diabetic and non-diabetic individuals enrolled in the Heart Outcomes Prevention Evaluation (HOPE) study.
The adjusted 4.5-year risk of CV events (myocardial infarction or stroke or CV death), heart failure, death and overt nephropathy was analysed in relation to baseline and updated GHb levels (in 3,529 diabetic HOPE study participants) and baseline fasting plasma glucose levels (in 1,937 non-diabetic and 1,013 diabetic participants).
In diabetic participants, a 1% absolute rise in the updated GHb predicted future CV events (relative risk RR=1.07, 95% CI 1.01-1.13; p=0.014), death (RR=1.12, 95% CI 1.05-1.19; p=0.0004), heart failure (RR=1.20, 95% CI 1.08-1.33; p=0.0008) and overt nephropathy (RR=1.26, 95% CI 1.17-1.36; p<0.0001) after adjusting for age, sex, diabetes duration, blood pressure, WHR, hyperlipidaemia and ramipril. Similarly, a 1 mmol/l rise in fasting plasma glucose was related to an increased risk of CV outcomes (RR=1.09, 95% CI 1.05-1.13; p<0.0001), death (RR=1.06, 95% CI 1.01-1.12; p=0.017), heart failure (RR=1.16, 95% CI 1.06-1.13; p=0.0007) and overt nephropathy (RR=1.34, 95% CI 1.23-1.45; p<0.0001) in the group composed of diabetic and non-diabetic individuals. The significant relationship between fasting plasma glucose and CV outcomes persisted after adjustment for diabetes status (RR=1.06, 95% CI 1.00-1.12; p=0.043).
There is an independent progressive relationship between indices of glycaemia and incident CV events, renal disease and death. Clinical trials of glucose lowering to prevent these outcomes in diabetic and non-diabetic individuals are indicated.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We investigated the effects of candesartan (an angiotensin II antagonist) alone, enalapril alone, and their combination on exercise tolerance, ventricular function, quality of life (QOL), ...neurohormone levels, and tolerability in congestive heart failure (CHF).
Seven hundred sixty-eight patients in New York Heart Association functional class (NYHA-FC) II to IV with ejection fraction (EF) <0.40 and a 6-minute walk distance (6MWD) <500 m received either candesartan (4, 8, or 16 mg), candesartan (4 or 8 mg) plus 20 mg of enalapril, or 20 mg of enalapril for 43 weeks. There were no differences among groups with regard to 6MWD, NYHA-FC, or QOL. EF increased (P=NS) more with candesartan-plus-enalapril therapy (0.025+/-0.004) than with candesartan alone (0.015+/-0.004) or enalapril alone(0.015+/-0.005). End-diastolic (EDV) and end-systolic (ESV) volumes increased less with combination therapy (EDV 8+/-4 mL; ESV 1+/-4 mL; P<0.01) than with candesartan alone (EDV 27+/-4 mL; ESV 18+/-3 mL) or enalapril alone (EDV 23+/-7 mL; ESV 14+/-6 mL). Blood pressure decreased with combination therapy (6+/-1/4+/-1 mm Hg) compared with candesartan or enalapril alone (P<0.05). Aldosterone decreased (P<0.05) with combination therapy (23.2+/-5.3 pg/mL) at 17 but not 43 weeks compared with candesartan (0.7+/-7.8 pg/mL) or enalapril (-0.8+/-11. 3 pg/mL). Brain natriuretic peptide decreased with combination therapy (5.8+/-2.7 pmol/L; P<0.01) compared with candesartan (4. 4+/-3.8 pmol/L) and enalapril alone (4.0+/-5.0 pmol/L).
Candesartan alone was as effective, safe, and tolerable as enalapril. The combination of candesartan and enalapril was more beneficial for preventing left ventricular remodeling than either candesartan or enalapril alone.
Impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) are risk factors for diabetes, cardiovascular disease (CVD), and kidney disease. We determined the effects of ramipril and ...rosiglitazone on combined and individual CVD and renal outcomes in people with IGT and/or IFG in the Diabetes REduction Assessment With ramipril and rosiglitazone Medication (DREAM) trial.
A total of 5,269 people aged >or=30 years, with IGT and/or IFG without known CVD or renal insufficiency, were randomized to 15 mg/day ramipril versus placebo and 8 mg/day rosiglitazone versus placebo. A composite cardiorenal outcome and its CVD and renal components were assessed during the 3-year follow-up.
Compared with placebo, neither ramipril (15.7% 412 of 2,623 vs. 16.0% 424 of 2,646; hazard ratio HR 0.98 95% CI 0.84-1.13; P = 0.75) nor rosiglitazone (15.0% 394 of 2,635 vs. 16.8% 442 of 2,634; 0.87 0.75-1.01; P = 0.07) reduced the risk of the cardiorenal composite outcome. Ramipril had no impact on the CVD and renal components. Rosiglitazone increased heart failure (0.53 vs. 0.08%; HR 7.04 95% CI 1.60-31.0; P = 0.01) but reduced the risk of the renal component (0.80 0.68-0.93; P = 0.005); prevention of diabetes was independently associated with prevention of the renal component (P < 0.001).
Ramipril did not alter the cardiorenal outcome or its components. Rosiglitazone, which reduced diabetes, also reduced the development of renal disease but not the cardiorenal outcome and increased the risk of heart failure.
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