Patients undergoing hemodialysis (HD) are at greater risk of methicillin-resistant Staphylococcus aureus infections requiring intravenous vancomycin. Close vancomycin therapeutic drug monitoring is warranted in HD patients as renal clearance is the primary elimination pathway. Clinically, population pharmacokinetics (popPK) model‐informed dosing is commonly used. This study aimed to perform an external evaluation of published vancomycin popPK models developed for adults undergoing high-flux intermittent HD, and to create a dosing nomogram derived from the best performing model. A literature review was conducted through PubMed and EMBASE to identify relevant popPK models. External dataset was collected retrospectively from patients of two healthcare centers in Quebec, Canada. Selected models were implemented in NONMEM (v7.5; ICON Development Solutions). Predictive performance was assessed through prediction and simulation-based diagnostics. Results analyses and graphical representations were then performed with Microsoft Excel (v16.69.1; Microsoft Office), R (v4.3.1; Posit Software) and R Studio (v1.4; Posit Software). A total of 2386 vancomycin concentrations were collected from 274 patients and 476 antibiotic courses. Four vancomycin popPK models were selected for evaluation. None of the models demonstrated overall satisfactory and clinically acceptable predictive performance. Nonetheless, Bae et al.’s model was the best performing with a MDPE of 16.25% and MDAPE of 34.66%. Different predictive performance was also observed for vancomycin concentrations from samples collected during and between HD sessions. All evaluated models presented poor overall predictive performance. Further studies are required, through existing popPK model parameters re-estimation or new model development, to adequately describe vancomycin pharmacokinetics for our high-flux intermittent HD patients’ cohort.

Aim: Patients hospitalized in the intensive care units (ICU) with serious infections require rapid and optimal broad-spectrum antibiotic regimens to ensure favorable outcomes. The purpose of this study was to evaluate the exposure and pharmacokinetic/pharmacodynamic target attainment of meropenem in critically ill patients. Methods: We conducted a prospective observational study in two Canadian intensive care units (ICU) from January 2021 to December 2023. We included adult patients admitted in the ICU who received meropenem. On study day 1, 4 and 7 of antimicrobial therapy, three blood samples were collected: 1 h after meropenem dose administration, at the middle and at the end of the dosing interval. Samples were analyzed by ultra-high performance liquid chromatography with diode array detector. The pharmacokinetic profile of meropenem was evaluated, as well as the attainment of plasma concentrations above minimum inhibitory concentrations of 2, 4 and 8 mg/L at mid-point and at trough. Results: We enrolled twenty-eight patients and analyzed 167 meropenem concentrations. We observed large interindividual variability, with up to a 58-fold difference, but intra-patient variability was low. At mid-point, 52% of concentrations were below the target concentration of 8 mg/L, while this proportion increased to 73% for trough concentrations. Patients who failed to reach therapeutic concentrations all had normal to augmented renal clearance. Conclusion: The majority of ICU patients who received meropenem were underexposed for a target concentration of 8 mg/L, with significant interindividual variability. A more personalized approach such as TDM may help achieve optimal target concentration and potentially improve clinical outcomes.

A common approach to assess the efficacy of piperacillin is to firstly measure the total concentration, and to afterwards apply a theoretical unbound fraction of 70% to obtain the unbound concentration. However, hypoalbuminemia is a common phenomenon in critically ill patients, resulting in variations in unbound fraction. Therefore, we aimed to simulate the impact of piperacillin unbound fraction fluctuations on the predictive performance of a population pharmacokinetic model and on dosing recommendations of piperacillin. Unbound factors of 70, 75, 80 and 85% were applied to total concentrations of piperacillin administered by continuous infusion from an external dataset. A validated model was used for assessment of predictive performance and to estimate patient clearance. Dosing simulations were performed to evaluate target attainment. Variation in unbound fraction caused minimal impact on piperacillin clearance and target attainment but revealed to influence model evaluation.

Background Acute pulmonary exacerbation (APE) in cystic fibrosis patients is frequent and associated with a decline in pulmonary function, quality of life and survival. Tobramycin is often used in regimens requiring activity against Pseudomonas aeruginosa, however, an important number of centers do not use official dosing recommendation. The current dosing strategy may be suboptimal. Methods This retrospective cohort analysis was performed on all adult cystic fibrosis patients that were admitted at a tertiary care facility for treatment of APE and with tobramycin between January 2015 and December 2019. The primary objective was to evaluate the predictive performance of previously published pharmacokinetic (PK) models and, secondly, to evaluate potential factors that impact clinical outcomes. Clinical outcomes were only evaluated in a sub-group of patients with cultures positive for P. aeruginosa. Results A total of 202 APEs from 51 patients were included in the PK analysis. Two population PK models were assessed and failed to fit our data. In all, 109 APEs from 32 patients were included in the clinical analysis. Factors that significantly impacted clinical outcome were the number of prior APE and concomitant antibiotics. Clinical success rate for regimens containing at least one active agent against P. aeruginosa according to its susceptibility was 67%. Conclusion Population PK models evaluated in this study cannot be used to perform simulations. A new model must be developed for our population. In patients positive for P. aeruginosa, Ceftazidime in combination to tobramycin may be a superior regimen. APE history remains predictive for outcomes in adult CF patients treated for an APE.