Objectives: The aim of this study is to describe the in vitro adsorption of anti-infective drugs onto an extracorporeal cytokine adsorber. Methods: Various anti-infective drugs (β-lactams, quinolones, aminoglycosides, glycopeptides, azole antimycotics) were prepared in normal saline 0.9% and human albumin 5%, and pumped through a cytokine cartridge (CytoSorb^®; CytoSorbents Corporation, Monmouth Junction, NJ, USA) at a flow rate of 1.2 L/h for 1.5 h. In addition, meropenem and ciprofloxacin were dissolved in reconstituted blood and run through a CytoSorb cartridge, which was integrated into a continuous renal replacement therapy circuit with a flow rate of 2 L/h for 18 h. Samples from the solution, pre- and post-filter, were quantified by high-performance liquid chromatography with ultraviolet detection and fluorescence polarisation immunoassay. Results: Observed mean clearance of the drugs in normal saline was 1.22 ± 0.07 L/h. In human albumin, clearance was 1.29 ± 0.08 L/h. In reconstituted blood, clearance of meropenem decreased from 5.4 to 1.4 L/h and for ciprofloxacin from 6.3 to 4.3 L/h within the first 1.5 h because of early drug adsorption. Continuous renal replacement therapy clearance measured without CytoSorb was stable at 2 and 1.7 L/h, respectively. Approximately 400 mg of meropenem and 300 mg of ciprofloxacin had been adsorbed by CytoSorb, suggesting that these amounts are the maximum adsorptive capacity for these drugs. Conclusion: In these settings, all tested drugs were adsorbed by the cartridge in relevant amounts. The identified maximum adsorptive capacity and the rapid decline in concentration during the first 1.5 h of CytoSorb use suggest that the administration of an additional dose within the first hours of CytoSorb treatment may be reasonable. In addition, early therapeutic drug monitoring should be considered.

Cefiderocol is a new siderophore-cephalosporin for the treatment of multi-drug resistant Gram-negative pathogens. As a reserve agent, it will and should be used primarily in critically ill patients in the upcoming years. Due to the novelty of the substance little data on the pharmacokinetics in critically ill patients with septic shock and renal failure (including continuous renal replacement therapy and cytokine adsorber therapy) is available. We performed therapeutic drug monitoring in a cohort of five patients treated with cefiderocol, to improve the knowledge on pharmacokinetics in this vulnerable patient population. As expected for a cephalosporin with predominantly renal elimination the maintenance dose could be reduced in patients with renal impairment or on continuous renal replacement therapy. The manufacturer’s dosing instructions were sufficient to achieve a drug level well above the MIC. However, the addition of a cytokine adsorber might reduce serum levels substantially, so that in this context therapeutic drug monitoring and dose adjustment are recommended.

Objectives: To describe the population PKs of ceftazidime in critically ill patients receiving sustained low-efficiency dialysis (SLED). Patients and methods: This study was performed in ICUs of a university hospital. We collected blood samples during three consecutive days of SLED sessions in patients receiving ceftazidime. Concentration versus time curves were analysed using a population PKs approach with Pmetrics^®. Monte Carlo simulation for the first 24 h including a 6 h SLED session was performed with the final model. The fractional target attainment against the MIC of Pseudomonas aeruginosa was executed using targets of 50 and 100% fT _> MIC. Results: In total, 211 blood samples of 16 critically ill patients under SLED were collected. SLED treatments were 299.3 (68.4) min in duration. A two-compartment linear population PK model was most appropriate. The mean (SD) CL of ceftazidime on SLED, and off SLED were 5.32 (3.2), 1.06 (1.0) L/h respectively. The PTA for 50% fT _> MIC for a dose of 1 g intravenously every 8 h was 98%. Assuming a target of 100% fT _> MIC a dose of 2 g every 12 h covers isolates with MIC ≤8 mg/L with a PTA of 96%. Conclusion: In critically ill patients receiving SLED, ceftazidime 1 g every 8 h and ceftazidime 2 g every 12 h appear to be sufficient for achieving traditional (50% fT _> MIC) and aggressive PD targets (100% fT _> MIC) for susceptible isolates (MIC ≤8 mg/L), respectively.

Cefiderocol is a new siderophore cephalosporin approved for the treatment of multidrug resistant bacteria including activity against carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa. As cephalosporins are known for their high pharmacokinetic variability in critically ill patients, cefiderocol therapeutic drug monitoring might become a valuable tool. Therefore, we aimed to develop and validate a simple, rapid, cost-effective high performance liquid chromatography (HPLC) method for the quantification of cefiderocol in serum. Samples were treated for protein precipitation followed by chromatographic separation on a reverse phase column (HPLC C-18) with gradient elution of the mobile phase. Cefiderocol was detected via UV absorption and quantification was performed with the internal standard (metronidazole) method. The calibration range showed linearity from 4 to 160 mg/L. The intra and interday precision was less than 10% with a recovery rate of 81%. The method was successfully used for the analysis of subsequent serum samples of critically ill patients and showed good performance in monitoring serum levels and optimizing antibiotic therapy.