Ticarcillin and piperacillin adsorption on to polyethersulfone haemodiafilter membranes in an ex-vivo circuit.

OBJECTIVES: To describe the adsorption of ticarcillin and piperacillin on to polyethersulfone (PES) membranes using the recirculation function on an ex-vivo renal replacement circuit. METHODS: Low (4-8 mg) or high (35-45 mg) doses of ticarcillin and low (4-8 mg) or high (70-80 mg) doses of piperacillin were added to 1 L of human blood-crystalloid mixture and circulated around an ex-vivo modified continuous renal replacement therapy machine at three different blood flow settings (150, 300 and 450 mL/min). Plasma samples were collected from the pre-filter port of the haemodiafilter circuit at consecutive timepoints for a total duration of 4 h. Plasma samples were measured using a validated ultra high performance liquid chromatography-tandem mass spectrometry method. RESULTS: Eighty-one samples including both drugs were collected from 18 experimental runs. Overall, the percentage of piperacillin adsorption for the low and high doses ranged from 21.3% to 27.1% and from 11.5% to 23%, and the percentage of ticarcillin adsorption for the low and high doses ranged from 4.2% to 14.3% and from 3.7% to 15.1%, respectively. The low dose of piperacillin consistently yielded more than 20% adsorption of dose for all blood flow rates. This decreased with high blood flow rates when the high dose of piperacillin was used. Ticarcillin generally displayed ≤5% adsorption, with the exceptions being the high dose at 150 mL/min and the low dose at 300 mL/min, which displayed ~15% adsorption. CONCLUSIONS: Adsorption of both drugs tended to be higher at the lowest blood flow rates and lowest doses. This is likely due to saturation of parts of the filter that have a chemical attraction to both piperacillin and ticarcillin. At low doses at all three blood flow rates, piperacillin demonstrated >20% adsorption, whereas ticarcillin tended to have low rates (up to ~≤15%) of adsorption on to PES membrane filters.

Population pharmacokinetics of ticarcillin in critically ill patients receiving extended daily diafiltration.

The aim of this study was to describe the population pharmacokinetics of ticarcillin during extended daily diafiltration (EDDf) in critically ill patients with acute kidney injury. Blood samples were collected from critically ill patients prescribed ticarcillin during one to two dosing intervals during which EDDf was performed. Plasma samples were measured using a validated ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method. Concentration-time data were analysed using a population pharmacokinetics approach with Pmetrics®. A total of 53 blood samples were collected from six critically ill patients (three male). The mean ± standard deviation patient age, weight and body mass index (BMI) was 43 ± 22 years, 88 ± 14 kg and 31 ± 5 kg/m2, respectively. A two-compartment linear model adequately described the data. Median population pharmacokinetic parameter estimates were as follows: clearance in the presence of EDDf (CLEDDf), 6.41 L/h; clearance of EDDf (CLnon-EDDf), 4.97 L/h; volume of distribution of the central compartment (Vc), 56.46 L; intercompartmental clearance from the central to peripheral compartment (kCP), 13.54 L/h; and intercompartmental clearance from the peripheral to central compartment (kPC), 21.93 L/h. This is the first population pharmacokinetic model of ticarcillin in patients receiving EDDf. Large pharmacokinetic variability was found, supporting further investigation of the pharmacokinetics of less-studied ß-lactam antibiotics in prolonged intermittent renal replacement therapy.

Population pharmacokinetics of vancomycin in critically ill patients receiving prolonged intermittent renal replacement therapy.

OBJECTIVES: The aim of this study was to describe the population pharmacokinetics of vancomycin during prolonged intermittent renal replacement therapy (PIRRT) in critically ill patients with acute kidney injury. METHODS: Critically ill patients prescribed vancomycin across two sites had blood samples collected during one to three dosing intervals during which PIRRT was performed. Plasma samples were assayed with a validated immunoassay method. Population pharmacokinetic analysis and Monte Carlo simulations were performed using Pmetrics®. The target vancomycin exposures were the area under the concentration-time curve within a 24-h period (AUC0-24)/minimum inhibitory concentration (MIC) ratio of 400 for efficacy and AUC0-24 700 for toxicity. RESULTS: Eleven critically ill patients (seven male) were enrolled and contributed 192 plasma samples. The patient's mean ± standard deviation (SD) age, weight and body mass index (BMI) were 57 ± 13 years, 98 ± 43 kg and 31 ± 9 kg/m2, respectively. A two-compartment linear model adequately described the data. The mean ± SD population pharmacokinetic parameter estimates were PIRRT clearance (CL) 3.47 ± 1.99 L/h, non-PIRRT CL 2.15 ± 2.07 L/h, volume of distribution of the central compartment (Vc) 41.85 ± 24.33 L, distribution rate constant from central to peripheral compartment 5.97 ± 7.93 per h and from peripheral to central compartment 5.29 ± 6.65 per h. Assuming a MIC of 1 mg/L, vancomycin doses of 25 mg/kg per day are suggested to be efficacious, whilst minimising toxic, exposures. CONCLUSIONS: This is the first population pharmacokinetic study of vancomycin in patients receiving PIRRT and we observed large pharmacokinetic variability. Empirically, weight-based doses that are appropriate for the duration of PIRRT, should be selected and supplemented with therapeutic drug monitoring.

Impact of ß-lactam antibiotic therapeutic drug monitoring on dose adjustments in critically ill patients undergoing continuous renal replacement therapy.

The objective of this study was to describe the effect of therapeutic drug monitoring (TDM) and dose adjustments of ß-lactam antibiotics administered to critically ill patients undergoing continuous renal replacement therapy (CRRT) in a 30-bed tertiary intensive care unit (ICU). ß-Lactam TDM data in our tertiary referral ICU were retrospectively reviewed. Clinical, demographic and dosing data were collected for patients administered ß-lactam antibiotics while undergoing CRRT. The target trough concentration range was 1-10× the minimum inhibitory concentration (MIC). A total of 111 TDM samples from 76 patients (46 male) with a mean ± standard deviation age of 56.6 ± 15.9 years and weight of 89.1 ± 25.8 kg were identified. The duration of antibiotic therapy was between 2 days and 42 days. TDM identified a need for dose modification of ß-lactam antibiotics in 39 (35%) instances; in 27 (24%) samples, TDM values resulted in decreasing the prescribed dose of ß-lactam antibiotic whereas an increase in the prescribed dose occurred in 12 (11%) cases. In patients treated for hospital-acquired pneumonia and primary or secondary bacteraemia, the dose was required to be decreased in 10/25 (40%) and 7/46 (15%) cases, respectively, to attain target concentrations. ß-Lactam TDM is a useful tool for guiding drug dosing in complex patients such as those receiving CRRT. Although over one-third of patients manifested concentrations outside the therapeutic range, most of these CRRT patients had excessive ß-lactam concentrations.

Improving antibiotic dosing in special situations in the ICU: burns, renal replacement therapy and extracorporeal membrane oxygenation.

PURPOSE OF REVIEW: Antibiotic dosing for critically ill patients that is derived from other patient groups is likely to be suboptimal because of significant antibiotic pharmacokinetic changes, particularly in terms of drug volume of distribution and clearance. Organ support techniques including renal replacement therapy (RRT) and extracorporeal membrane oxygenation (ECMO) increase the pharmacokinetic variability. This article reviews the recently published antibiotic pharmacokinetic data associated with burns patients, those receiving continuous RRT (CRRT), sustained low-efficiency dialysis (SLED) and ECMO. RECENT FINDINGS: These groups develop increases in volume of distribution that necessitate the use of higher initial doses to rapidly achieve therapeutic antibiotic concentrations. Burns patients have supranormal drug clearances requiring more frequent administration of antibiotics. Patients receiving CRRT or SLED have variable drug clearances related to different equipment and RRT settings at different institutions. ECMO presents a different challenge because there is such a dearth of data with higher than standard doses potentially required, even in the presence of end-organ failure. SUMMARY: In the context of such variable pharmacokinetics, a guideline approach to dosing remains elusive because of insufficient available data and, therefore, use of therapeutic drug monitoring should be considered advantageous where possible.