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Objectives To describe the population pharmacokinetics of cefazolin in infected hospitalized patients requiring intermittent haemodialysis (IHD). Methods This prospective population pharmacokinetic study was conducted in IHD patients prescribed cefazolin 2 g three times weekly. Plasma samples were collected at prespecified timepoints and assayed for total and unbound concentrations using validated LC. Pharmacokinetic modelling and dosing simulations were performed using Pmetrics®. PTA in plasma suitable for MSSA (unbound trough concentrations of ≥2 mg/L for the final 24 h of a 72 h interval) were simulated for different dosing regimens. A PTA of ≥95% was deemed acceptable. Results A total of 260 cefazolin concentrations (130 total, 130 unbound) were collected from 16 patients (14 female) with a median age of 51 years. The median (IQR) pre-dialysis unbound cefazolin concentration for a 3 day dose interval trough was 17.7 (13.5–31.4) mg/L. The median (IQR) unbound fraction was 0.38 (0.32–0.46). The lowest pre-dialysis unbound concentration was 9.1 mg/L. A two-compartment model with a complex protein-binding component adequately described the data. The mean unbound cefazolin CL during IHD was 16.4 ± 4.26 L/h, compared with 0.40 ± 0.19 L/h when dialysis was off. Duration of time on haemodialysis (TOH) was the only covariate supported in the final model. The 2 g three-times-weekly regimen was associated with a PTA of 99.7% on dosing simulations to maintain unbound concentrations of ≥2 mg/L with TOH of 6 months. The 1 g three-times-weekly post-dialysis was associated with a PTA of 95.4%. Conclusions A 2 g three-times-weekly post-dialysis cefazolin regimen is supported for MSSA infections. [ABSTRACT FROM AUTHOR]

Fosfomycin has been used to treat carbapenem‐resistant Acinetobacter baumannii (CRAB) infections. However, there is insufficient information on dosage adjustment among critically ill patients with renal impairment. This study aims to evaluate the attainment of PK/PD targets for different dosage regimens of CRAB treatment in critically ill patients based on their renal function. Monte Carlo simulations were conducted to assess the probability of achieving time above the minimum inhibitory concentration (T > MIC) of 80% and 100% and to determine the cumulative fraction response (CFR) against institutional MICs. Our results demonstrated that administering fosfomycin 20–24 g/day to individuals with normal renal function (CrCl ≥60 mL/min) achieved the target at a MIC of ≤64 and ≤32 μg/mL during the first 24 h of treatment and at steady state, respectively. Notably, those with renal impairment achieved higher MIC values at a steady state despite dosage reduction. None of the regimens reached the target CFR. Our study suggested that administering fosfomycin at least 20 g/day to those with normal renal function provides sufficient exposure throughout the treatment course when the MIC value is ≤32 μg/mL. Less aggressive dosing regimens are advisable for patients with renal impairment. Additional clinical studies are necessary to verify our suggestions. [ABSTRACT FROM AUTHOR]

Background Cerebral ventriculitis might be caused by Gram-negative bacteria, including ESBL producers. Temocillin may be a useful treatment option in this scenario; however, no consistent data are available regarding its penetration into the CSF. Objectives To describe the population pharmacokinetics of temocillin in plasma and CSF and to determine the probability for different simulated dosing regimens to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets in the CSF. Methods Ten post-neurosurgical critically ill adult patients requiring continuous drainage of CSF were included in this monocentric, prospective, open-label, non-randomized study. They received 2 g loading dose temocillin over 30 min IV infusion, followed by a 6 g continuous infusion over 24 h. Total and unbound concentrations were measured in plasma (n = 88 and 86) and CSF (n = 88 and 88) samples and used to build a population PK model. Monte Carlo simulations were performed to estimate the PTA at 100% C ss>MIC (steady state concentration above the MIC) in CSF. Results All patients were infected with Enterobacterales with temocillin MICs ≤8 mg/L. The median (min-max) temocillin penetration in CSF was 12.1% (4.3-25.5) at steady state. Temocillin unbound plasma pharmacokinetics were best described by a one-compartment model. PTA for the applied dosing regimen was >90% for bacteria with MIC ≤ 4 mg/L. Conclusions The currently approved dose of 6 g by continuous infusion may be adequate for the treatment of ventriculitis by Enterobacterales with MIC ≤ 4 mg/L if considering 100% C ss>MIC as the PK/PD target to reach. Higher maintenance doses could help covering higher MICs, but their safety would need to be assessed. [ABSTRACT FROM AUTHOR]