e This study describes the population pharmacokinetics of fosfomycin in critically ill patients. In this observational study, serial blood samples were taken over several dosing intervals of intravenous fosfomycin treatment. Blood samples were analyzed using a validated liquid chromatography-tandem mass spectrometry technique. A population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. Five hundred fifteen blood samples were collected over one to six dosing intervals from 12 patients. The mean (standard deviation) age was 62 (17) years, 67% of patients were male, and creatinine clearance (CL CR ) ranged from 30 to 300 ml/min. A two-compartment model with between-subject variability on clearance and volume of distribution of the central compartment (V c ) described the data adequately. Calculated CL CR was supported as a covariate on fosfomycin clearance. The mean parameter estimates for clearance on the first day were 2.06 liters/h, V c of 27.2 liters, intercompartmental clearance of 19.8 liters/h, and volume of the peripheral compartment of 22.3 liters. We found significant pharmacokinetic variability for fosfomycin in this heterogeneous patient sample, which may be explained somewhat by the observed variations in renal function.

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The combination product meropenem-vaborbactam, with activity against KPC-producing carbapenem-resistant Enterobacteriaceae, is likely to be used during renal replacement therapy. The aim of this work was to describe the extracorporeal removal (adsorption and clearance) of meropenem-vaborbactam during continuous venovenous hemofiltration (CVVH).

Evaluation of dosing regimens for critically ill patients requires pharmacokinetic data in this population. This prospective observational study aimed to describe the population pharmacokinetics of unbound ceftolozane and tazobactam in critically ill patients without renal impairment and to assess the adequacy of recommended dosing regimens for treatment of systemic infections. Patients received 1.5 or 3.0 g ceftolozane-tazobactam according to clinician recommendation. Unbound ceftolozane and tazobactam plasma concentrations were assayed, and data were analyzed with Pmetrics with subsequent Monte Carlo simulations. A two-compartment model adequately described the data from twelve patients. Urinary creatinine clearance (CLCR) and body weight described between-patient variability in clearance and central volume of distribution (V), respectively. Mean ± standard deviation (SD) parameter estimates for unbound ceftolozane and tazobactam, respectively, were CL of 7.2 ± 3.2 and 25.4 ± 9.4 liters/h, V of 20.4 ± 3.7 and 32.4 ± 10 liters, rate constant for distribution of unbound ceftolozane or tazobactam from central to peripheral compartment (Kcp) of 0.46 ± 0.74 and 2.96 ± 8.6 h−1, and rate constant for distribution of unbound ceftolozane or tazobactam from peripheral to central compartment (Kpc) of 0.39 ± 0.37 and 26.5 ± 8.4 h−1. With dosing at 1.5 g and 3.0 g every 8 h (q8h), the fractional target attainment (FTA) against Pseudomonas aeruginosa was ≥85% for directed therapy (MIC ≤ 4 mg/liter). However, for empirical coverage (MIC up to 64 mg/liter), the FTA was 84% with the 1.5-g q8h regimen when creatinine clearance is 180 ml/min/1.73 m2, whereas the 3.0-g q8h regimen consistently achieved an FTA of ≥85%. For a target of 40% of time the free drug concentration is above the MIC (40% fT>MIC), 3g q8h by intermittent infusion is suggested unless a highly susceptible pathogen is present, in which case 1.5-g dosing could be used. If a higher target of 100% fT>MIC is required, a 1.5-g loading dose plus a 4.5-g continuous infusion may be adequate.

20A high performance liquid chromatography -tandem mass spectrometry (LC-MS/MS) 21 method, using hydrophilic interaction liquid chromatography (HILIC) 22 chromatography for the analysis of fosfomycin in human plasma and urine, has been 23 developed and validated. The plasma method uses a simple protein precipitation 24 using a low volume sample (10 μL) and is suitable for the concentration range of 1 to 25 2000 μg/mL. The urine method involves a simple dilution of 10 μL of sample and is 26 suitable for a concentration range of 0.1 to 10 mg/mL. The plasma and urine results, 27 reported respectively, are for recovery (68, 72%), inter-assay precision (≤9.1%, 28 ≤8.1%) and accuracy (range -7.2 to 3.3%, -1.9 to 1.6%), LLOQ precision (4.7%, 3.1%) 29 and accuracy (1.7% and 1.2%), and includes investigations into the linearity, stability 30 and matrix effects. The method was used in a pilot pharmacokinetic study of a 31 critically ill patient receiving IV fosfomycin, which measured a maximum and 32 minimum plasma concentration of 222 μg/mL and 172 μg/mL, respectively, after the 33 initial dose, and a maximum and minimum plasma concentration of 868 μg/mL and 34 591 μg/mL, respectively, after the fifth dose. The urine concentration was 2.03 35 mg/mL after the initial dose and 0.29 mg/mL after the fifth dose.  This is the first method published that is suitable for the quantification of 47 fosfomycin in both plasma and urine. 48

The VAMS techniques provide acceptable validation data as assessed for lower limit of quantification, linearity, intra- and interday precision and accuracy, selectivity and matrix effects. Results from the recovery and stability studies suggest challenges remain for the analysis of fosfomycin in whole blood using VAMS.

Prescribing teams must be aware of the impact of critical illness on their patients and tailor antibiotic therapy appropriately to prevent the significant harms associated with suboptimal antibiotic administration.