Pharmacokinetic evaluation of linezolid administered intravenously in obese patients with pneumonia.

OBJECTIVES: Altered linezolid pharmacokinetics (PK) in obese individuals has been hypothesized in previous studies. However, specific dosing recommendations for this population are still lacking. The main goal of this study was to evaluate PK/pharmacodynamic (PKPD) target attainment when using a 600 mg intravenous q12h linezolid dose against MRSA in obese patients with pneumonia. METHODS: Fifteen obese pneumonia patients with a confirmed or suspected MRSA involvement treated with 600 mg of intravenous linezolid q12h were studied for 3 days. Population PK modelling was used to characterize the PK variability and to screen for influential patient characteristics. Monte Carlo simulations were carried out to investigate the PTA and time to target attainment for linezolid dosing against MRSA. RESULTS: A two-compartment model with linear elimination adequately described the data. Body weight and age both have a significant effect on linezolid clearance. Simulations demonstrate that the probability of attaining PKPD targets is low. Moreover, the PTA decreases with weight, and increases with age. Standard linezolid dosing in obese pneumonia patients with MRSA (MICs of 1-4 mg/L) leads to unacceptably low (near zero to 60%) PTA for patients <65 years old. CONCLUSIONS: Standard linezolid dosing is likely to provide insufficient target attainment against MRSA in obese patients. Body weight and especially age are important characteristics to be considered when administering linezolid to treat MRSA infections.

Ventricular arrhythmias and antioxidative medication: experimental study.

INTRODUCTION: Reperfusion arrhythmias could be due to free radicals, while contraction excitation feedback is the cause of arrhythmias generated by blood pressure elevation (BPE). The aim of this study was to test the antiarrhythmic effects of an antioxidant (vitamin C [vit C], 1.5 g), an iron-binding agent (deferoxamine [Def], 1 g), and their combination in an experimental model of arrhythmia based on these 2 mechanisms. METHODS: Thirty anaesthetised sheep were divided into 4 groups, depending on the infused agent: saline (8 sheep), combination of vit C and Def (8), Def (6), and vit C (8). Induction of ventricular arrhythmias was attempted in all animals using both ischaemia-reperfusion (phase I) and a combination of ischaemia and BPE (phase II). In all cases ischaemia was caused by ligating the left anterior descending coronary artery distally to the origin of the 1st diagonal artery, while reperfusion was achieved by releasing the ligation 45 min later. BPE was achieved by obstructing the ascending aorta or by administering intravenous metaraminol. All agents were infused intravenously for 15 min and their administration was started 30 min after the first ligation. Phases I and II lasted 50 and 20 min, respectively. RESULTS: Ventricular tachycardia/fibrillation (VT/VF) was induced in all animals in the control group (8/8) and in the Def group (6/6). VT/VF appeared in 6/8 of the animals in the vit C group (75%) and in only 3/8 of the animals in the combination therapy group (37.5%). The difference between the combination and control groups was statistically significant (p < 0.03). CONCLUSIONS: The intravenous administration of vit C and Def in combination protects against VT/VF induced by ischaemia-reperfusion and/or BPE. Administration of Def alone does not appear to help, while the action of vit C alone is not clear.