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.

Background: Recently, several studies have assessed the effects of therapeutic drug monitoring of frequently prescribed beta-lactam antibiotics, for which they were quantified in human plasma samples. Beta-lactams are considered unstable, leading to extra challenges in quantification. Therefore, to ensure sample stability and minimize sample degradation before analysis, stability studies are crucial. This study investigated the stability of 10 frequently used beta-lactam antibiotics in human plasma at relevant storage conditions for clinical use. Methods: Amoxicillin, benzylpenicillin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, flucloxacillin, imipenem, meropenem, and piperacillin were analyzed using ultraperformance convergence chromatography tandem mass spectrometry and liquid chromatography tandem mass spectrometry. Their short-term and long-term stabilities were investigated by measuring quality control samples at low and high concentrations against freshly prepared calibration standards. Measured concentrations at each time point were compared with the concentrations at T = 0. Antibiotics were considered stable if recovery results were between 85% and 115%. Results: Short-term stability results indicated ceftriaxone, cefuroxime, and meropenem to be stable up to 24 hours at room temperature. All evaluated antibiotics, except imipenem, were stable on ice in a cool box for 24 hours. Amoxicillin, benzylpenicillin, and piperacillin were stable for 24 hours at 4–6°C. Cefotaxime, ceftazidime, cefuroxime, and meropenem were stable at 4–6°C up to 72 hours. Ceftriaxone and flucloxacillin were stable for 1 week at 4–6°C. Long-term stability results showed that all antibiotics were stable up to 1 year at −80°C, except imipenem and piperacillin, which were stable for 6 months at −80°C. Conclusions: Plasma samples for amoxicillin, benzylpenicillin, cefotaxime, ceftazidime, flucloxacillin, and piperacillin may be stored for a maximum of 24 hours in a cool box. Refrigeration is suitable for plasma samples of amoxicillin, benzylpenicillin, meropenem, and piperacillin for up to 24 hours and cefotaxime, ceftriaxone, ceftazidime and cefuroxime for 72 hours. Plasma samples for imipenem should be frozen directly at −80°C. For long-term storage, plasma samples can be stored at −80°C for a maximum of 6 months for imipenem and piperacillin and 12 months for all other evaluated antibiotics.

Background: Recent studies demonstrated that failure of achieving pharmacodynamic targets of commonly used antibiotics is common in critically ill patients. Therapeutic drug monitoring (TDM) can contribute to optimize the exposure of beta-lactams and ciprofloxacin. While evidence for TDM of these antibiotics is growing, translation into clinical implementation remains limited. Therefore, perceived barriers and facilitators are important for implementing TDM in this population. The primary aim of this study was to identify healthcare professionals’ barriers and facilitators for the implementation of TDM of beta-lactams and ciprofloxacin in Dutch intensive care units (ICU). Methods: We conducted a nationwide cross-sectional online survey among healthcare professionals (HCPs) involved in antibiotic treatment of ICU patients. An adapted version of the Measurement Instrument for Determinants of Innovations was sent out. Items were considered barriers when ≥ 20% of participants responded with a negative answer. If ≥ 80% of the participants responded with a positive answer, the item was considered a facilitator. Results: Sixty-four HCPs completed the survey, of which 14 were from academic hospitals, 25 from general hospitals, and 25 from teaching hospitals. Most participants were hospital pharmacists (59%) or medical specialists (23%). Eleven barriers and four facilitators for implementation of TDM of beta-lactams were identified; 17 barriers for TDM of ciprofloxacin and no facilitators. The most important barriers were a lack of conclusive evidence, organizational support, and low availability of assays. Additional barriers were a lack of consensus on which specific patients to apply TDM and which pharmacodynamic targets to use. Identified facilitators for beta-lactam TDM implementation are low complexity and high task perception, combined with the perception that TDM is important to prevent side effects and to adequately treat infections. Twenty-eight percent of participants reported that flucloxacillin could be analyzed in their hospital. Assay availability of other beta-lactams and ciprofloxacin was lower (3–17%). Conclusion: Several barriers were identified that could obstruct the implementation of TDM of beta-lactams and ciprofloxacin in the ICU. In particular, education, clear guidelines, and organizational support should be considered when creating tailored implementation strategies. Finally, evidence of beneficial clinical outcomes on TDM of beta-lactams and ciprofloxacin can enhance further implementation.

The number of pharmacokinetic (PK) models of meropenem is increasing. However, the daily role of these PK models in the clinic remains unclear, especially for critically ill patients. Therefore, we evaluated the published meropenem models on real-world ICU data to assess their suitability for use in clinical practice. All models were built in NONMEM and evaluated using prediction and simulation-based diagnostics for the ability to predict the subsequent meropenem concentrations without plasma concentrations (a priori), and with plasma concentrations (a posteriori), for use in therapeutic drug monitoring (TDM). Eighteen PopPK models were included for evaluation. The a priori fit of the models, without the use of plasma concentrations, was poor, with a prediction error (PE)% of the interquartile range (IQR) exceeding the ±30% threshold. The fit improved when one to three concentrations were used to improve model predictions for TDM purposes. Two models were in the acceptable range with an IQR PE% within ±30%, when two or three concentrations were used. The role of PK models to determine the starting dose of meropenem in this population seems limited. However, certain models might be suitable for TDM-based dose adjustment using two to three plasma concentrations.

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. 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). 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). 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.

Hepatic drug metabolism is important in improving drug dosing strategies in sepsis. Pharmacokinetics in the critically ill population are severely altered due to changes in absorption, distribution...