Factors Associated With Antimicrobial Resistance and Mortality in Pneumococcal Bacteremia

We conducted a multicenter, retrospective cohort study of patients with Streptococcus pneumoniae bacteremia to determine factors associated with antibiotic resistance and mortality. Risk factors were identified using multivariate logistic regression. 1,574 patients at 34 sites were enrolled. Compared to isolates from patients not receiving an antibiotic before the index blood culture, patients receiving an antibiotic were less likely to harbor an antibiotic susceptible organism. Susceptibility to penicillin decreased from 78% (95% confidence interval [CI], 75−80) to 49% (95%CI, 39−59); to cefotaxime/ceftriaxone, from 92% (95%CI, 90−93) to 82% (95%CI, 72−89); and to macrolide, from 84% (95%CI, 82−87) to 55% (95%CI, 41−68). Factors associated with macrolide non-susceptibility include: >24 hours of antibiotic therapy at time of the index culture (odds ratio [OR] 4.0), residing in southern U.S. (OR 1.7), and having an antibiotic allergy (OR 1.7). Harboring an antibiotic non-susceptible strain (OR 1.4) and male sex (OR 1.4) were associated with increased risk of mortality, whereas Black race (OR 0.6) and evidence of focal infection (OR 0.6) were associated with decreased risk

Time to Clinical Stability in Patients with Ventilator-Associated Pneumonia due to Methicillin-Resistant Staphylococcus aureus Treated with Linezolid versus Vancomycin: Results from the IMPACT-HAP Study

Background: Time to clinical stability is a well-defined early clinical outcome in hospitalized patients with community-acquired pneumonia, but it has not been evaluated in patients with ventilator-associated pneumonia (VAP). The objective of this study was to compare time to clinical stability in patients with MRSA VAP treated with linezolid versus vancomycin. Methods: This was a secondary analysis of the IMPACT-HAP study database. VAP was defined according to CDC criteria. MRSA VAP was considered when MRSA was isolated from a tracheal aspirate or bronchoalveolar lavage. A patient was considered to reach clinical stability the day that the following four criteria were met: 1) Afebrile for 24 hours, 2) Decrease in WBC \u3e10% or WBC within normal range, 3) Improving of PaO2/FiO2 ratio of \u3e 20%, or PaO2/FiO2 ratio \u3e 250, or extubation, or FiO2 ≤ 30% if extubated, and 4) Systolic blood pressure \u3e90 mmHg. Time to clinical stability for linezolid and vancomycin were compared using the Chi-Squared and Student’s t-tests. Results: A total of 89 patients treated with linezolid and 75 patients treated with vancomycin met study criteria. From the population of linezolid treated patients, 79% reached clinical stability, compared to 75% of the population of vancomycin treated patients (P=0.463). Median time to clinical stability was 6 days (IQR 8) for patients treated with linezolid, versus 7 days (IQR 12) for patients treated with vancomycin (P=0.490). Conclusions: This study failed to demonstrate a statistically significant difference in time to clinical stability in patients with MRSA VAP treated with linezolid or vancomycin. The number of days for patients to reach clinical stability can be used as an early clinical outcome in patients with VAP

Sepsis in Patients with Ventilator Associated Pneumonia due to Methicillin- Resistant Staphylococcus aureus: Incidence and Impact on Clinical outcomes

Background: Sepsis is a clinical syndrome associated with organ dysfunction due to a dysregulated host response to infection. Methicillin-resistant Staphylococcus aureus (MRSA) Ventilator-associated pneumonia (VAP) is a serious infection frequently associated with sepsis. The objectives of this study were to define the incidence of sepsis and clinical failure in patients with MRSA VAP. Methods: This was a secondary analysis of the Improving Medicine through Pathway Assessment of Critical Therapy in Hospital-Acquired Pneumonia (IMPACT-HAP) study database. VAP was defined according to CDC criteria. MRSA VAP was considered when MRSA was isolated from a tracheal aspirate or bronchoalveolar lavage. We used the 3rd International Consensus Definitions for sepsis. The presence of clinical failure was evaluated at the 14-day follow-up and defined as: 1) progression of baseline signs and symptoms of pneumonia, or 2) death. The Chi- Square Trend Test was utilized to determine the association between the level of organ dysfunction and clinical failure. Results: MRSA VAP was diagnosed in 205 patients with 138 (67%) presenting with sepsis. Clinical failure occurred in 14% (8/57) of patients without sepsis. Clinical failure occurred in 18% (13/73) of patients with sepsis and 1 organ dysfunction, in 28% (12/43) of patients with sepsis and 2 organ dysfunction, in 28% (5/18) of patients with sepsis and 3 organ dysfunction, and in 100% (4/4) of patients with sepsis and 4 organ dysfunction (p= 0.01). Conclusions: Sepsis is a frequent complication of MRSA VAP and the number of organ dysfunction correlates with clinical failure in these patients. Effective prevention and treatment of sepsis and associated organ dysfunction is essential to avoid cumulative burden of disease in MRSA VAP

FOCUS 1: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia

Objectives: Ceftaroline, the active form of the prodrug ceftaroline fosamil, is a novel cephalosporin with bactericidal activity against important pathogens associated with community-acquired pneumonia (CAP), including Streptococcus pneumoniae and common Gram-negative pathogens. FOCUS 1 is a randomized, double-blinded, Phase III study that was conducted to evaluate the efficacy and safety of ceftaroline fosamil in treating patients with CAP. The primary objective was to determine non-inferiority [lower limit of 95% confidence interval (CI) ≥ 210%] in clinical cure rates achieved with ceftaroline fosamil compared with those achieved with ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations. Methods: Patients hospitalized in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV requiring intravenous (iv) therapy were randomized (1:1) to receive 600 mg of ceftaroline fosamil iv every 12 h or 1 g of ceftriaxone iv every 24 h. Patients also received two 500 mg doses of oral clarithromycin every 12 h administered on day 1. Clinical cure, microbiological response, adverse events (AEs) and laboratory tests were assessed. FOCUS 1 registration number NCT00621504 (http://clinicaltrials.gov/ ct2/show/NCT00621504). Results: Of 613 enrolled patients, 298 received ceftaroline fosamil and 308 received ceftriaxone. Baseline characteristics between treatment groups were comparable. Clinical cure rates were as follows: CE population, 86.6% (194/224) for ceftaroline fosamil and 78.2% (183/234) for ceftriaxone [difference (95% CI), 8.4% (1.4, 15.4)]; and MITTE population, 83.8% (244/291) for ceftaroline fosamil and 77.7% (233/300) for ceftriaxone [difference (95% CI), 6.2% (20.2, 12.6)]. Clinical cure rates for CAP caused by S. pneumoniae in the microbiological MITTE population were 88.9% (24/27) and 66.7% (20/30) for ceftaroline fosamil and ceftriaxone, respectively. Both agents were well tolerated, with similar rates of AEs, serious AEs, deaths and discontinuations because of an AE. The most common AEs for ceftaroline fosamil-treated patients were diarrhoea, headache, insomnia and nausea, and the most common AEs for ceftriaxone-treated patients were hypokalaemia, hypertension, nausea and diarrhoea. Conclusions: Ceftaroline fosamil demonstrated high clinical cure and microbiological response rates in hospitalized patients with CAP of PORTrisk class III or IV. Ceftaroline fosamil was well tolerated, with a safety profile similar to that of ceftriaxone and consistent with the cephalosporin class. In this study, ceftaroline fosamil was an effective and well-tolerated treatment option for CAP

RESTORE-IMI 1: A Multicenter, Randomized, Doubleblind Trial Comparing Efficacy and Safety of Imipenem/Relebactam vs Colistin Plus Imipenem in Patients With Imipenem-nonsusceptible Bacterial Infections

Background. The β-lactamase inhibitor relebactam can restore imipenem activity against imipenem-nonsusceptible gram-negative pathogens. We evaluated imipenem/relebactam for treating imipenem-nonsusceptible infections. Methods. Randomized, controlled, double-blind, phase 3 trial. Hospitalized patients with hospital-acquired/ventilatorassociated pneumonia, complicated intraabdominal infection, or complicated urinary tract infection caused by imipenemnonsusceptible (but colistin- and imipenem/relebactam-susceptible) pathogens were randomized 2:1 to 5–21 days imipenem/ relebactam or colistin+imipenem. Primary endpoint: favorable overall response (defined by relevant endpoints for each infection type) in the modified microbiologic intent-to-treat (mMITT) population (qualifying baseline pathogen and ≥1 dose study treatment). Secondary endpoints: clinical response, all-cause mortality, and treatment-emergent nephrotoxicity. Safety analyses included patients with ≥1 dose study treatment. Results. Thirty-one patients received imipenem/relebactam and 16 colistin+imipenem. Among mITT patients (n = 21 imipenem/relebactam, n = 10 colistin+imipenem), 29% had Acute Physiology and Chronic Health Evaluation II scores >15, 23% had creatinine clearance <60 mL/min, and 35% were aged ≥65 years. Qualifying baseline pathogens: Pseudomonas aeruginosa (77%), Klebsiella spp. (16%), other Enterobacteriaceae (6%). Favorable overall response was observed in 71% imipenem/relebactam and 70% colistin+imipenem patients (90% confidence interval [CI] for difference, –27.5, 21.4), day 28 favorable clinical response in 71% and 40% (90% CI, 1.3, 51.5), and 28-day mortality in 10% and 30% (90% CI, –46.4, 6.7), respectively. Serious adverse events (AEs) occurred in 10% of imipenem/relebactam and 31% of colistin+imipenem patients, drug-related AEs in 16% and 31% (no drugrelated deaths), and treatment-emergent nephrotoxicity in 10% and 56% (P = .002), respectively. Conclusions. Imipenem/relebactam is an efficacious and well-tolerated treatment option for carbapenem-nonsusceptible infection

Effects of Alcohol on the Acquisition and Expression of Fear Potentiated Startle in Mouse Lines Selectively Bred for High and Low Alcohol Preference

Rationale: Anxiety disorders and alcohol-use disorders frequently co-occur in humans perhaps because alcohol relieves anxiety. Studies in humans and rats indicate that alcohol may have greater anxiolytic effects in organisms with increased genetic propensity for high alcohol consumption. Objectives and Methods: The purpose of this study was to investigate the effects of moderate doses of alcohol (0.5, 1.0, 1.5 g/kg) on the acquisition and expression of anxiety-related behavior using a fear-potentiated startle (FPS) procedure. Experiments were conducted in two replicate pairs of mouse lines selectively bred for high- (HAP1 and HAP2) and low- (LAP1 and LAP2) alcohol preference; these lines have previously shown a genetic correlation between alcohol preference and FPS (HAP\u3eLAP; Barrenha and Chester 2007). In a control experiment, the effect of diazepam (4.0 mg/kg) on the expression of FPS was tested in HAP2 and LAP2 mice. Results: The 1.5 g/kg alcohol dose moderately decreased the expression of FPS in both HAP lines but not LAP lines. Alcohol had no effect on the acquisition of FPS in any line. Diazepam reduced FPS to a similar extent in both HAP2 and LAP2 mice. Conclusions: HAP mice may be more sensitive to the anxiolytic effects of alcohol than LAP mice when alcohol is given prior to the expression of FPS. These data collected in two pairs of HAP/LAP mouse lines suggest that the anxiolytic response to alcohol in HAP mice may be genetically correlated with their propensity toward high alcohol preference and robust FPS

Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances. These guidelines are intended for use by healthcare professionals who care for patients at risk for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), including specialists in infectious diseases, pulmonary diseases, critical care, and surgeons, anesthesiologists, hospitalists, and any clinicians and healthcare providers caring for hospitalized patients with nosocomial pneumonia. The panel's recommendations for the diagnosis and treatment of HAP and VAP are based upon evidence derived from topic-specific systematic literature reviews

Ciprofloxacin-loaded calcium alginate wafers prepared by freeze-drying technique for potential healing of chronic diabetic foot ulcers

Calcium alginate (CA) wafer dressings were prepared by lyophilization of hydrogels to deliver ciprofloxacin (CIP) directly to the wound site of infected diabetic foot ulcers (DFUs). The dressings were physically characterized by scanning electron microscopy (SEM), texture analysis (for mechanical and in vitro adhesion properties), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). Further, functional properties essential for wound healing, i.e., porosity, in vitro swelling index, water absorption (Aw), equilibrium water content (EWC), water vapor transmission rate (WVTR), evaporative water loss (EWL), moisture content, in vitro drug release and kinetics, antimicrobial activity, and cell viability (MTT assay) were investigated. The wafers were soft, of uniform texture and thickness, and pliable in nature. Wafers showed ideal wound dressing characteristics in terms of fluid handling properties due to high porosity (SEM). XRD confirmed crystalline nature of the dressings and FTIR showed hydrogen bond formation between CA and CIP. The dressings showed initial fast release followed by sustained drug release which can inhibit and prevent re-infection caused by both Gram-positive and Gram-negative bacteria. The dressings also showed biocompatibility (> 85% cell viability over 72 h) with human adult keratinocytes. Therefore, it will be a potential medicated dressing for patients with DFUs infected with drug-resistant bacteria

Safety and efficacy of omadacycline for treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections in patients with mild-to-moderate renal impairment

Background: Many antibiotics require dosage adjustments in patients with renal impairment. In Phase III studies, omadacycline was non-inferior to moxifloxacin and linezolid in adults with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI), respectively. This analysis evaluated efficacy and safety measures from three omadacycline studies by patient renal function. Methods: Patients were stratified as having normal renal function (creatinine clearance 89 mL/min), mild renal impairment (creatinine clearance 60-89 mL/min) or moderate renal impairment (creatinine clearance < 60 mL/min); creatine clearance <= 30 mL/min (severe renal impairment) was an exclusion criterion. Efficacy endpoints were clinical success at the early clinical response (ECR) and post-treatment evaluation (PTE) time-points. Safety was evaluated as treatment-emergent adverse events (TEAEs) and laboratory measures. Results: This subgroup analysis included 773 patients with CABP and 1339 patients with ABSSSI in intent to-treat (ITT) and modified ITT populations, respectively. Clinical success rates were high at ECR and PTE across the studies (CABP 75-90%; ABSSSI 74-95%), and broadly similar between treatments, irrespective of renal function. Rates of TEAEs in patients with ABSSSI ranged from 33% to 52%, and were similar across renal function groups. In patients with CABP, higher rates were observed in patients with moderate renal impairment (56-61%) compared with patients with normal renal function or mild renal impairment (35- 49%). The most common TEAEs were nausea and vomiting. Conclusions: Clinical success was similar across renal function groups, indicating no notable difference in the efficacy of omadacycline in patients with mild or moderate renal impairment. Omadacycline and comparators displayed similar safety profiles. (C) 2020 The Authors. Published by Elsevier Ltd