Optimise Dosing of Doripenem in critically ill patients receiving a form of dialysis called Continuous Veno-Venous Haemodialfiltration

Observational pharmacokinetic study - blood and dialysate sampling in critically ill patients. This project will run for 18 months. For each patient, drug dosing will be at the discretion of the clinician. Doses will be reconstituted in 10ml of diluent and given as intermittent infusion in 50ml over 60 minutes. Sample collection All patients will be sampled on 2 separate doses between DAY 1 and DAY 5 of treatment. 1. Plasma sample (3mls of blood for each sample) Samples will be collected pre and post filter at the following time points (0, 15, 30, 45, 60, 90, 120, 180 and 480 minutes). (Total blood removed during both days of sampling =54ml) 2. Filtrate/dialysate samples A new dialysate bag and filter will be placed at the start of dosing. If the filter is more than 12 hours old the filter will be changed by an ICU nurse using Aseptic technique. If the filter is less than 12 hours old it will be considered new and will not be changed. An aliquot (5ml) of the dialysis effluent will be taken from each bag of dialysis effluent collected throughout the study period to determine the amount of drug cleared by CVVHDF. The total volume of each bag of dialysis effluent sampled will be recorded. Small samples (5ml) of dialysis effluent will also be collected at the following time points 60, 120 and 180 minutes to enable the calculation of the sieving coefficient. Sieving coefficient = (Concentration of drug in effluent)/ (Concentration of drug in plasma) 3. Urine specimens Urine samples will be collected during the study period (if there is urine output) and will be used to calculate residual renal function (8 hour urinary creatinine clearance- to compare with other measures of renal function) All the collected blood samples will be centrifuged and stored at -80oC until assay. Other investigations Total Body Bioelectrical Impedance Total body bioelectrical impedance will be performed by experienced clinicians. This is a non-invasive process requiring connection of leads (similar to an echocardiogram) that measure resistance of electrical impulses throughout the body. The greater the resistance, the larger the volume of distribution and as such this method will be used for detecting altered fluid status. Data collection For each patient various de-identified clinical and demographic data will be collected: Patient demographics- Age, gender, weight, height Clinical details- Admission diagnosis, other concomitant drugs, allergies Physiological variables- temperature, mean arterial pressure, heart rate, respiratory rate Results of routine tests performed as standard ICU policy-biochemistry, microbiology studies, liver function tests, arterial blood gases, coagulation studies Disease Severity Scores – Sequential Organ Failure Assessment (SOFA) score & Acute Physiology and Chronic Health Evaluation II (APACHE II) score CVVHDF settings- blood flow rate, dialysate & filtrate flow rate, type of filter membrane & surface area of filter membrane, age of filter (times of all filter changes to be recorded), type of anticoagulation used