Antimicrobial agents and chemotherapy
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Antimicrob. Agents Chemother. · Jul 2017
Randomized Controlled TrialEffects on the QT Interval of a Gatifloxacin-Containing Regimen versus Standard Treatment of Pulmonary Tuberculosis.
The effects on ventricular repolarization-recorded on the electrocardiogram (ECG) as lengthening of the QT interval-of acute tuberculosis and those of standard and alternative antituberculosis regimens are underdocumented. A correction factor (QTc) is introduced to make the QT independent of the heart rate, translating into the slope of the regression line between QT and heart rate being close to zero. ECGs were performed predosing and 1 to 5 h postdosing (month 1, month 2, and end of treatment) around drugs' peak concentration time in tuberculosis patients treated with either the standard 6-month treatment (rifampin and isoniazid for 6 months and pyrazinamide and ethambutol for 2 months; "control") or a test regimen with gatifloxacin, rifampin, and isoniazid given for 4 months (pyrazinamide for the first 2 months) as part of the OFLOTUB study, a randomized controlled trial conducted in five African countries. ⋯ No evidence was found of an association between Cmax of the antituberculosis drugs 1 month into treatment and the length of QTcF. Neither a standard 6-month nor a 4-month gatifloxacin-based regimen appears to carry a sizable risk of QT prolongation in patients with newly diagnosed pulmonary tuberculosis. This is to date the largest data set studying the effects of antituberculosis regimens on the QT, both for the standard regimen and for a fluoroquinolone-containing regimen. (This study has been registered at ClinicalTrials.gov under identifier NCT00216385.).
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Antimicrob. Agents Chemother. · Mar 2017
Randomized Controlled TrialSafety, Tolerability, and Pharmacokinetics of MEDI8897, the Respiratory Syncytial Virus Prefusion F-Targeting Monoclonal Antibody with an Extended Half-Life, in Healthy Adults.
Prevention of respiratory syncytial virus (RSV) illness in infants is a major public health priority, but there is no approved vaccine. Palivizumab is a monoclonal antibody that provides RSV prophylaxis but requires 5 monthly injections and is approved only for infants who experience the greatest morbidity and mortality from RSV. Thus, there remains a significant unmet medical need for prevention of RSV disease in healthy infants. ⋯ Antidrug antibody (ADA) responses were detected in a similar proportion of placebo (15.2%) and MEDI8897 (13.7%) recipients. The safety profile of MEDI8897 was similar to that of the placebo. These results support clinical studies of the i.m. administration of a single dose of MEDI8897 in the target population of infants to provide protection for the duration of the RSV season. (This study has been registered at ClinicalTrials.gov under identifier NCT02114268.).
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Antimicrob. Agents Chemother. · Aug 2016
Randomized Controlled Trial Observational StudyInfluence of Renal Replacement Modalities on Amikacin Population Pharmacokinetics in Critically Ill Patients on Continuous Renal Replacement Therapy.
The objective of this study was to describe amikacin pharmacokinetics (PK) in critically ill patients receiving equal doses (30 ml/kg of body weight/h) of continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHDF). Patients receiving amikacin and undergoing CVVH or CVVHDF were eligible. Population pharmacokinetic analysis and Monte Carlo simulation were undertaken using the Pmetrics software package for R. ⋯ Dosing simulations for amikacin supported the use of high dosing regimens (≥25 mg/kg) and extended intervals (36 to 48 h) for most patients when considering PK/pharmacodynamic (PD) targets of a maximum concentration in plasma (Cmax)/MIC ratio of ≥8 and a minimal concentration of ≤2.5 mg/liter at the end of the dosing interval. The mean clearance of amikacin was 1.8 ± 1.3 liters/h by CVVHDF and 1.3 ± 1 liters/h by CVVH. On the basis of simulations, a strategy of an extended-interval high loading dose of amikacin (25 mg/kg every 48 h) associated with therapeutic drug monitoring (TDM) should be the preferred approach for aminoglycoside treatment in critically ill patients receiving continuous renal replacement therapy (CRRT). (This study is a substudy of a trial registered at ClinicalTrials.gov under number NCT01403220.).
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Antimicrob. Agents Chemother. · Feb 2015
Randomized Controlled TrialAssessment of time to clinical response, a proxy for discharge readiness, among hospitalized patients with community-acquired pneumonia who received either ceftaroline fosamil or ceftriaxone in two phase III FOCUS trials.
The primary driver of health care costs for patients with community-acquired pneumonia (CAP) is the hospital length of stay (LOS). Unfortunately, hospital LOS comparisons are difficult to make from phase III CAP trials because of their structured designs and prespecified treatment durations. However, an opportunity still exists to draw inferences about potential LOS differences between treatments through the use of surrogates for hospital discharge. ⋯ In the Cox regression, ceftaroline was associated with a shorter time to a clinical response (HR, 1.16, P=0.02). The methodology employed here provides a framework to draw comparative effectiveness inferences from phase III CAP efficacy trials. (The FOCUS trials whose data were analyzed in this study have been registered at ClinicalTrials.gov under registration no. NCT00621504 and NCT00509106.).
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Antimicrob. Agents Chemother. · Feb 2015
Randomized Controlled TrialAnalysis of the phase 3 ESTABLISH trials of tedizolid versus linezolid in acute bacterial skin and skin structure infections.
Tedizolid, a novel oxazolidinone with activity against a wide range of Gram-positive pathogens, was evaluated in two noninferiority phase 3 acute bacterial skin and skin structure infection trials. The data from individual trials showed its noninferior efficacy compared to that of linezolid and a favorable tolerability profile. To evaluate potential differences, the pooled data were analyzed. ⋯ Fewer tedizolid than linezolid patients had platelet counts of <150,000 cells/mm3 at the EOT (tedizolid, 4.9%; linezolid, 10.8%; P=0.0003) and during the postbaseline period through the last day of active drug visit (tedizolid, 6.4%; linezolid, 12.6%; P=0.0016). Efficacy was achieved with a 6-day once-daily course of therapy with the option of an intravenous/oral regimen, and fewer low platelet counts and gastrointestinal side effects were reported with tedizolid than with linezolid, all of which aligns well with antimicrobial stewardship principles. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01170221 and NCT01421511.).