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Purpose Individualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking. Methods This multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment. Results In total, 388 (MIPD n = 189; standard dosing n = 199) patients were analysed (median age 64 [IQR 55-71]). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96-1.41; p = 0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing; p = 0.24) or at day 3 (T3) (59.5% vs 60.4%; p = 0.84). There were no significant differences in other secondary outcomes. Conclusions We could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation., Author(s): Tim M. J. Ewoldt [sup.1] [sup.2] [sup.3], Alan Abdulla [sup.2] [sup.3], Wim J. R. Rietdijk [sup.2], Anouk E. Muller [sup.3] [sup.4] [sup.5], Brenda C. M. de Winter [sup.2] [sup.3], [...]

Model-informed precision dosing (MIPD) might be used to optimize antibiotic treatment. Procalcitonin (PCT) is a biomarker for severity of infection and response to antibiotic treatment. The aim of this study was to assess the impact of MIPD on the course of PCT and to investigate the association of PCT with pharmacodynamic target (PDT) attainment in critically ill patients. This is a secondary analysis of the DOLPHIN trial, a multicentre, open-label, randomised controlled trial. Patients with a PCT value available at day 1 (T1), day 3 (T3), or day 5 (T5) after randomisation were included. The primary outcome was the absolute difference in PCT concentration at T1, T3, and T5 between the MIPD and the standard dosing group. In total, 662 PCT concentrations from 351 critically ill patients were analysed. There was no statistically significant difference in PCT concentration between the trial arms at T1, T3, or T5. The median PCT concentration was highest in patients who exceeded 10× PDT at T1 [13.15 ng/mL (IQR 5.43–22.75)]. In 28-day non-survivors and in patients that exceeded PDT at T1, PCT decreased significantly between T1 and T3, but plateaued between T3 and T5. PCT concentrations were not significantly different between patients receiving antibiotic treatment with or without MIPD guidance. The potential of PCT to guide antibiotic dosing merits further investigation. [ABSTRACT FROM AUTHOR]

Background and Objective: Previous pharmacokinetic (PK) studies of ciprofloxacin in intensive care (ICU) patients have shown large differences in estimated PK parameters, suggesting that further investigation is needed for this population. Hence, we performed a pooled population PK analysis of ciprofloxacin after intravenous administration using individual patient data from three studies. Additionally, we studied the PK differences between these studies through a post-hoc analysis. Methods: Individual patient data from three studies (study 1, 2, and 3) were pooled. The pooled data set consisted of 1094 ciprofloxacin concentration–time data points from 140 ICU patients. Nonlinear mixed-effects modeling was used to develop a population PK model. Covariates were selected following a stepwise covariate modeling procedure. To analyze PK differences between the three original studies, random samples were drawn from the posterior distribution of individual PK parameters. These samples were used for a simulation study comparing PK exposure and the percentage of target attainment between patients of these studies. Results: A two-compartment model with first-order elimination best described the data. Inter-individual variability was added to the clearance, central volume, and peripheral volume. Inter-occasion variability was added to clearance only. Body weight was added to all parameters allometrically. Estimated glomerular filtration rate on ciprofloxacin clearance was identified as the only covariate relationship resulting in a drop in inter-individual variability of clearance from 58.7 to 47.2%. In the post-hoc analysis, clearance showed the highest deviation between the three studies with a coefficient of variation of 14.3% for posterior mean and 24.1% for posterior inter-individual variability. The simulation study showed that following the same dose regimen of 400 mg three times daily, the area under the concentration–time curve of study 3 was the highest with a mean area under the concentration–time curve at 24 h of 58 mg·h/L compared with that of 47.7 mg·h/L for study 1 and 47.6 mg·h/L for study 2. Similar differences were also observed in the percentage of target attainment, defined as the ratio of area under the concentration–time curve at 24 h and the minimum inhibitory concentration. At the epidemiological cut-off minimum inhibitory concentration of Pseudomonas aeruginosa of 0.5 mg/L, percentage of target attainment was only 21%, 18%, and 38% for study 1, 2, and 3, respectively. Conclusions: We developed a population PK model of ciprofloxacin in ICU patients using pooled data of individual patients from three studies. A simple ciprofloxacin dose recommendation for the entire ICU population remains challenging owing to the PK differences within ICU patients, hence dose individualization may be needed for the optimization of ciprofloxacin treatment. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to assess pharmacodynamic target attainment in critically ill patients and identify factors influencing target attainment and mortality outcomes., Methods: We analysed data from the DOLPHIN trial. Beta-lactam and ciprofloxacin peak and trough concentration were measured within the first 36 h (T1) after initiation of treatment. The study outcome included the rate of pharmacodynamic target attainment of 100 % ƒT >1xEpidemiological cut-off value (ECOFF) for beta-lactams, and of fAUC 0-24h /ECOFF>125 for ciprofloxacin at T1., Results: The target attainment rates were 78.1 % (n = 228/292) for beta-lactams, and 41.5 % (n = 39/94) for ciprofloxacin, respectively. Lower estimated glomerular filtration rate and higher SOFA score were associated with target attainment. In patients receiving beta-lactams, 28-day mortality was significantly higher in patients who attained 100 % ƒT >1xECOFF (28.9 % vs. 12.5 %; p = 0.01). In the multivariate analysis, attainment of 100 % ƒT >4xECOFF , but not 100 % ƒT >1xECOFF , was associated with a higher 28-day mortality (OR 2.70, 95 % CI 1.36-5.48 vs. OR 1.28, 95 % CI 0.53-3.34)., Conclusions: A high rate of target attainment (100 % ƒT >1xECOFF ) for beta-lactams and a lower rate for ciprofloxacin was observed. Achieving exposures of 100 % ƒT >4xECOFF was associated with 28-day mortality. The impact of antibiotic target attainment on clinical outcome needs to be a focus of future research., Competing Interests: Declaration of competing interest BCPK reports grants or contracts unrelated to this work from IMI, European Union, and Prinses Beatrix Foundation; Foundation Coolsingel; a role as unpaid Board member for IATDMCT, ESCMID EPASG, SWAB. All other authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: Antibiotic dosing is not optimal in the ICU. Our recent trial investigated the effect of model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin and showed no significant differences in clinical outcomes in all patients. This study aimed to identify subgroups of patients in which the MIPD of these antibiotics could be beneficial for clinical outcomes., Methods: We analysed data from the DOLPHIN randomized controlled trial, which compared MIPD to standard dosing of beta-lactam antibiotics and ciprofloxacin in 388 ICU patients. We divided patients into subgroups based on baseline characteristics and assessed the effect of MIPD on 28-day mortality, 6-month mortality, change in sequential organ failure assessment (delta-SOFA), and ICU length of stay (LOS)., Results: We found a lower 28-day mortality in patients with a SOFA below 8 randomized to MIPD (OR 0.40; 95% CI 0.17-0.88). However, patients with a higher SOFA show an increased 28-day mortality (OR 1.94; 95% CI 1.07-3.59) in the MIPD group. ICU LOS was increased in patients receiving MIPD with a SOFA below 8 (IRR 1.36; 95% CI 1.01-1.83) and those receiving MIPD for ceftriaxone (IRR 1.76; 95% CI 1.24-2.51). Patients receiving a dose recommendation within 24 hours show a trend towards decreased ICU LOS (IRR 0.77; 95% CI 0.52-1.16) and higher delta-SOFA (estimate -1.19; 95% CI -2.98-0.60)., Conclusions: ICU patients with a SOFA below 8 using MIPD had an increased ICU LOS but a lower 28-day mortality. Fast dose recommendations using MIPD of beta-lactam antibiotics and ciprofloxacin needs to be investigated in ICU patients., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Quantification of beta-lactam antibiotics can be performed by using liquid chromatography in combination with tandem mass spectrometry (MS/MS) or ultraviolet (UV) detection. Since beta-lactam antibiotics are known as highly polar analytes, using standard reversed phase chromatography will result in very early elution, which is often not desirable. Some retention is preferred to reduce matrix effects, because a high amount of non-retained molecular matrix species elute early from the column. For highly polar analytes, ultra-performance convergence chromatography (UPC 2 ) may be a suitable alternative. This method is based on supercritical fluid chromatography. To our knowledge, we developed the first UPC 2 -MS/MS method for the determination of amoxicillin, benzylpenicillin, flucloxacillin, piperacillin, cefotaxime, cefuroxime, ceftazidime, imipenem, meropenem, and the free fraction of cefuroxime and flucloxacillin in human plasma. The method was validated according to the Food and Drug Administration guidelines. The method was found linear (r 2 >0.990) for all analytes. The inaccuracies and imprecisions were < 15% for all analytes. The matrix effect and recovery were nearly all consistent with coefficient of variation of less than 15% and no significant carryover effect was observed. Furthermore, this method was found to be suitable for daily routine analysis in hospital settings, requiring only 50 µL of plasma. This novel, sensitive, and specific UPC 2 -MS/MS method demonstrated its value in the analysis of a more than 800 human plasma samples in a clinical trial using simple and fast sample preparation and short analysis run time of only 5 min., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: : Emerging studies suggest that antibiotic pharmacokinetics (PK) are difficult to predict in critically ill patients. The high intra- and inter-patient PK variability makes it challenging to accurately predict the appropriate dosage required for a given patient. Identifying patients at risk could help clinicians to consider more individualized dosing regimens and perform therapeutic drug monitoring. We provide an overview of relevant predictors associated with target (non-)attainment of β-lactam antibiotics in critically ill patients., Areas Covered: : This narrative review summarizes patient and clinical characteristics that can help to predict the attainment of target serum concentrations and to provide guidance on antimicrobial dose optimization. Literature was searched using Embase and Medline database, focusing on β-lactam antibiotics in critically ill patients., Expert Opinion: : Adequate concentration attainment can be anticipated in critically ill patients prior to initiating empiric β-lactam antibiotic therapy based on readily available demographic and clinical factors. Male gender, younger age, and augmented renal clearance were the most significant predictors for target non-attainment and should be considered in further investigations to develop dosing algorithms for optimal β-lactam therapy.