Omadacycline is a first‐in‐class aminomethylcycline antibiotic being evaluated in phase 3 studies as oral and intravenous monotherapy for bacterial infections. This was a phase 1, randomized, ...open‐label, 4‐period, crossover study that evaluated the effect of food consumption on the bioavailability of omadacycline. Healthy participant were randomized to 1 of 4 sequences, which included the following predose conditions in different orders (A) ≥6‐hour fast, (B) high‐fat, nondairy meal 4 hours before dosing, (C) high‐fat, nondairy meal 2 hours before dosing, and (D) high‐fat meal containing dairy 2 hours before dosing. Participants received a single 300‐mg oral dose of omadacycline during each treatment period; periods were separated by ≥5 days. Blood samples for pharmacokinetic (PK) analysis were collected over 24 hours after each dose, and safety assessments were performed during each treatment period. Least‐squares mean and 90% confidence intervals were compared for fed state vs fasted state. Thirty‐one participants were included in the PK analysis. Fasted AUC0‐∞, AUC0‐t, and AUC0‐24 were 10.2, 7.2, and 7.2 μg·h/mL, respectively, and Cmax was 0.6 μg/mL. Compared with a fasted dose, bioavailability was reduced by 15% to 17% by a nondairy meal 4 hours before dosing, 40% to 42% by a nondairy meal 2 hours before dosing, and 59% to 63% for a dairy meal 2 hours before dosing. Two participants experienced adverse events (mild nausea, mild somnolence). A 300‐mg oral dose of omadacycline administered within 2 to 4 hours after food had reduced bioavailability compared with the fasted state. Oral omadacycline should be administered in a fasted state.
This pooled analysis includes 2 phase 3, double-blind trials designed to evaluate the safety and efficacy of tigecycline, versus that of imipenem-cilastatin, in 1642 adults with complicated ...intra-abdominal infections. Patients were randomized to receive either tigecycline (initial dose of 100 mg, followed by 50 mg intravenously every 12 h) or imipenem-cilastatin (500/500 mg intravenously every 6 h) for 5–14 days. The primary end point was the clinical response at the test-of-cure visit (12–42 days after therapy) in the co-primary end point microbiologically evaluable and microbiological modified intent-to-treat populations. For the microbiologically evaluable group, clinical cure rates were 86.1% (441/512) for tigecycline, versus 86.2% (442/513) for imipenem-cilastatin (95% confidence interval for the difference, -4.5% to 4.4%; P < .0001 for noninferiority). Clinical cure rates in the microbiological modified intent-to-treat population were 80.2% (506/631) for tigecycline, versus 81.5% (514/631) for imipenem-cilastatin (95% confidence interval for the difference, -5.8% to 3.2%; P < .0001 for noninferiority). Nausea (24.4% tigecycline, 19.0% imipenem-cilastatin P = .01), vomiting (19.2% tigecycline, 14.3% imipenem-cilastatin P = .008), and diarrhea (13.8% tigecycline, 13.2% imipenem-cilastatin P = .719) were the most frequently reported adverse events. This pooled analysis demonstrates that tigecycline was efficacious and well tolerated in the treatment of patients with complicated intra-abdominal infections.
Cardiac resynchronization therapy (CRT) has recently emerged as an effective treatment for patients with moderate to severe systolic heart failure and ventricular dyssynchrony. The purpose of the ...present study was to determine whether improvements in left ventricular (LV) size and function were associated with CRT.
Doppler echocardiograms were obtained at baseline and at 3 and 6 months after therapy in 323 patients enrolled in the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial. Of these, 172 patients were randomized to CRT on and 151 patients to CRT off. Measurements were made of LV end-diastolic and end-systolic volumes, ejection fraction, LV mass, severity of mitral regurgitation (MR), peak transmitral velocities during early (E-wave) and late (A-wave) diastolic filling, and the myocardial performance index. At 6 months, CRT was associated with reduced end-diastolic and end-systolic volumes (both P<0.001), reduced LV mass (P<0.01), increased ejection fraction (P<0.001), reduced MR (P<0.001), and improved myocardial performance index (P<0.001) compared with control. beta-Blocker treatment status did not influence the effect of CRT. Improvements with CRT were greater in patients with a nonischemic versus ischemic cause of heart failure.
CRT in patients with moderate-to-severe heart failure who were treated with optimal medical therapy is associated with reverse LV remodeling, improved systolic and diastolic function, and decreased MR. LV remodeling likely contributes to the symptomatic benefits of CRT and may herald improved longer-term survival.
This prospective placebo-controlled trial was designed to determine whether intravenous immune globulin (IVIG) improves left ventricular ejection fraction (LVEF) in adults with recent onset of ...idiopathic dilated cardiomyopathy or myocarditis.
Sixty-two patients (37 men, 25 women; mean age +/-SD 43.0+/-12.3 years) with recent onset (</=6 months of symptoms) of dilated cardiomyopathy and LVEF </=0.40 were randomized to 2 g/kg IVIG or placebo. All underwent an endomyocardial biopsy before randomization, which revealed cellular inflammation in 16%. The primary outcome was change in LVEF at 6 and 12 months after randomiz. Overall, LVEF improved from 0.25+/-0.08 to 0.41+/-0.17 at 6 months (P<0.001) and 0.42+/-0.14 (P<0.001 versus baseline) at 12 months. The increase was virtually identical in patients receiving IVIG and those given placebo (6 months: IVIG 0.14+/-0.12, placebo 0.14+/-0.14; 12 months: IVIG 0.16+/-0.12, placebo 0.15+/-0.16). Overall, 31 (56%) of 55 patients at 1 year had an increase in LVEF >/=0.10 from study entry, and 20 (36%) of 56 normalized their ejection fraction (>/=0.50). The transplant-free survival rate was 92% at 1 year and 88% at 2 years.
These results suggest that for patients with recent-onset dilated cardiomyopathy, IVIG does not augment the improvement in LVEF. However, in this overall cohort, LVEF improved significantly during follow-up, and the short-term prognosis remains favorable.
Background: Worsening renal function in patients hospitalized for heart failure portends a poor prognosis. However, criteria used to define worsening renal function are arbitrary, and the ...implications of different definitions remain unclear. We therefore compared the prognostic importance of various definitions of worsening renal function in 1,002 patients hospitalized for congestive heart failure (CHF). Methods and Results: The patient population was 49% female, aged 67 ± 15 years. Twenty-three percent had a prior history of renal failure, 73% had known depressed ejection fraction, and 63% had known CHF. On admission to the hospital, 47% were receiving ACE inhibitors, 22% β-blockers, 70% diuretics and 6% NAID's. 72% developed increased serum creatinine during the hospitalization, with 20% developing an increase of ≥ 0.5 mg/dL. Worsening renal function predicted both in-hospital mortality and length of stay > 10 days. Even an increased creatinine of 0.1 mg/dL was associated with worse outcome. Sensitivity for death decreased from 92% to 65% as the threshold for increased creatinine was raised from 0.1 to 0.5 mg/dL, with specificity increasing from 28% to 81%. At a threshold of a 0.3 mg/dL increase, sensitivity was 81% and specificity was 62% for death and 64% and 65% for length of stay >10 days. Adding a requirement of final creatinine of ≥ 1.5 mg/dL improved specificity. Conclusions: This analysis demonstrates that any detectable decrease in renal function is associated with increased mortality and prolonged hospital stay. This suggests that therapeutic interventions which improve renal function might be beneficial.
Omadacycline is a first-in-class aminomethylcycline antibiotic that circumvents common tetracycline resistance mechanisms. In vitro omadacycline has potent activity against Gram-positive aerobic ...bacteria including methicillin-resistant Staphylococcus aureus, penicillin-resistant and multidrug-resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus spp. It is also active against common Gram-negative aerobes, some anaerobes and atypical bacteria including Legionella spp. and Chlamydia spp. Ongoing Phase III clinical trials with omadacycline are investigating once daily doses of 100 mg intravenously followed by once-daily doses of 300 mg orally for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. This paper provides an overview of the microbiology, nonclinical evaluations, clinical pharmacology and initial clinical experience with omadacycline.
Current estimates of the incidence of stroke among patients with coronary artery disease are as low as 3.4 percent per 1000 patient-years of follow-up.
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Stroke is also a known but infrequent early ...complication of myocardial infarction. In the two-week period after myocardial infarction, the reported incidence of stroke ranges between 0.7 percent and 4.7 percent.
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After myocardial infarction, focal areas of akinesia or dyskinesia (or both) in the left ventricle appear to increase the risk of mural thrombi.
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Moreover, a greater extent of myocardial damage and greater left ventricular dysfunction after anterior myocardial infarction, as well as the . . .
Omadacycline for Community-Acquired Bacterial Pneumonia Stets, Roman; Popescu, Monica; Gonong, Joven R ...
New England journal of medicine/The New England journal of medicine,
02/2019, Letnik:
380, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Omadacycline is a new antimicrobial that is related to tetracyclines and is active against a broad range of pathogens. In this randomized, controlled trial involving 774 adults, omadacycline was ...found to be noninferior to moxifloxacin in the treatment of community-acquired bacterial pneumonia.
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