Publications by authors named "Anouk E Muller"
Aims: The beta-lactam antibiotic temocillin is increasingly used to treat extended-spectrum beta-lactamase (ESBL-producing) strains; however, its protein binding is complex. This study aims to predict unbound temocillin concentrations in various participant groups to determine its impact on the probability of target attainment (PTA) and to improve dosing recommendations.
Methods: The plasma pharmacokinetics were analysed using non-linear mixed-effects modelling.
Background: NOSO-5O2 is the first clinical candidate of a new antimicrobial class-the odilorhabdins. The pharmacodynamics of NOSO-502 were studied in vitro and in vivo to establish the pharmacodynamic index (PDI) driver.
Methods: A dilutional pharmacokinetic system was used for in vitro experiments.
Objectives: To expand a translational pharmacokinetic-pharmacodynamic (PKPD) modelling approach for assessing the combined effect of polymyxin B and minocycline against Klebsiella pneumoniae.
Methods: A PKPD model developed based on in vitro static time-kill experiments of one strain (ARU613) was first translated to characterize that of a more susceptible strain (ARU705), and thereafter to dynamic time-kill experiments (both strains) and to a murine thigh infection model (ARU705 only). The PKPD model was updated stepwise using accumulated data.
Article Synopsis
- - Achieving successful antimicrobial therapy requires personalized drug dosing due to differences in how patients metabolize drugs and their pathogens' susceptibility, which is reflected in minimum inhibitory concentration (MIC) values.
- - Therapeutic drug monitoring (TDM) and population pharmacokinetic (popPK) models help tailor dosing regimens by analyzing drug behavior across various patients, while machine learning (ML) techniques can enhance dose individualization by identifying patterns in large datasets.
- - The challenge is to balance model complexity with practical clinical application, ensuring regulatory compliance, accurate outcome measurement, and the incorporation of new technologies like real-time biosensors for better monitoring and adjustments in treatment.
A Pooled Population Pharmacokinetic Study of Oral and Intravenous Administration of Clavulanic Acid in Neonates and Infants: Targeting Effective Beta-Lactamase Inhibition.
Stef Schouwenburg Fleur M Keij Gerdien A Tramper-Stranders René F Kornelisse Irwin K M Reiss Anouk E Muller
Clin Pharmacol Ther
January 2025
Article Synopsis
- The study investigates the pharmacokinetics of oral clavulanic acid in neonates and infants, as existing data on this topic is limited.
- It analyzes combined data from four datasets using a one-compartment model to determine dosing regimens and exposure levels based on age and body weight.
- Findings indicate that an amoxicillin/clavulanic acid ratio of 4:1 is optimal, with significant differences in exposure levels based on varying threshold concentrations, laying groundwork for future research.
Article Synopsis
- WCK 4282 combines cefepime and tazobactam to treat infections resistant to piperacillin/tazobactam and cefepime, aiming to optimize dosing for effective treatment against ESBL-producing pathogens.
- The study involved creating pharmacokinetic models to determine optimal dosing based on patients' renal function, identifying specific dosage adjustments for varying levels of kidney function and those undergoing haemodialysis.
- The proposed dosing regimens ensure sufficient exposure of these antibiotics to effectively target infections with a cefepime/tazobactam MIC of up to 16 mg/L.
Article Synopsis
- - Drain-associated intracerebral infections are serious medical emergencies that are hard to treat because antibiotics struggle to reach the infection site, especially with the rise of multidrug-resistant bacteria, leading to potential use of off-label intrathecal (IT) antibiotics.
- - The study reviewed existing literature on IT dosing regimens and summarized clinical experiences with various antibiotics, showing how factors like the size of the ventricular system and CSF drainage volume influence treatment effectiveness.
- - While many side effects were noted for benzylpenicillin in earlier years, other antibiotics had mostly minor and reversible side effects when used properly, providing insight for choosing IT dosing strategies in cases of antibiotic resistance.
Article Synopsis
- In an ICU study comparing model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin to standard dosing, no overall significant clinical outcome differences were found among all patients.
- Subgroup analysis revealed lower 28-day mortality for patients with a SOFA score below 8 receiving MIPD, but higher mortality for those with a higher SOFA score.
- Patients with a SOFA below 8 showed increased ICU length of stay with MIPD, suggesting faster dosage recommendations might be crucial for improving outcomes in ICU settings.
Article Synopsis
- A population pharmacokinetic model was created to analyze how different dosing regimens of fosfomycin affect its effectiveness against Escherichia coli, following intravenous administration in healthy volunteers.
- The study involved eight men who received fosfomycin through two methods: intermittent doses of 8 g every 8 hours and a continuous infusion of 1 g/h, with a focus on achieving specific pharmacokinetic/pharmacodynamic targets in both plasma and urine.
- Results indicated that while the standard dose of 4 g every 8 hours achieved targeted effectiveness for MICs up to 16 mg/L, higher doses or continuous infusions may be necessary to effectively treat infections at the clinical breakpoint of 32 mg/L.
Article Synopsis
- Standard antibiotic dosing isn't effective for critically ill patients due to their unique pharmacokinetics, making it essential to understand protein binding for optimal antibiotic effectiveness.
- The study utilized data from the DOLPHIN trial to evaluate ceftriaxone concentrations, developing a non-linear binding model to predict unbound drug levels, which are crucial for pharmacological activity.
- Results revealed that unbound ceftriaxone levels differ significantly between peak and trough samples, with existing prediction models showing strong sensitivity for high concentrations but lacking specificity for predicting subtherapeutic levels.
Article Synopsis
- * An evaluation of 18 published models showed poor predictive accuracy without plasma concentrations, but improved results when using 2 to 3 concentrations for therapeutic drug monitoring (TDM).
- * Overall, while PK models are not very effective for determining initial meropenem doses, some may be useful for adjusting doses based on TDM when certain plasma concentration data is available.
Article Synopsis
- Polymyxin B has been used since the 1950s, but research on its pharmacokinetics (PK) and pharmacodynamics (PD) has been limited, particularly regarding its effectiveness against certain bacterial strains.
- In a study involving neutropenic infected mice, researchers found that the pharmacokinetic profile of polymyxin B was non-linear, with the fAUC/MIC index being the most indicative of efficacy against Klebsiella pneumoniae, while E. coli showed better correlation with fCmax/MIC.
- The study concluded that polymyxin B's standard dosing regimen may not effectively treat serious infections due to low kill rates against most clinical isolates, suggesting it might not be reliable as a standalone treatment.
Pharmacodynamics of Temocillin in Neutropenic Murine Infection Models.
Antimicrob Agents Chemother
February 2023
Article Synopsis
- Temocillin's effectiveness in treating infections was studied in neutropenic mice, focusing on its pharmacokinetics (PK) and pharmacodynamics (PD) against E. coli and K. pneumoniae.
- The study revealed that a lower percentage of time the drug concentration exceeds the minimum inhibitory concentration (%T>MIC) is needed for a bacteriostatic effect in lung infections compared to thigh infections.
- The findings suggest that temocillin can be a valuable treatment option for patients with pneumonia, as it achieved significant bacterial reduction in the lung infection model.
Article Synopsis
- * The multicenter randomized clinical trial involved 388 ICU patients and evaluated outcomes like ICU length of stay, mortality rates, and drug level attainment, revealing no significant differences between MIPD and standard dosing.
- * The results suggest that MIPD did not provide any advantages in improving ICU stay or other health outcomes, indicating that alternative methods for optimizing antibiotic dosing should be explored.
Article Synopsis
- Limited studies have been done on the pharmacodynamic targets of cefepime, a fourth-generation cephalosporin, leading to reliance on conventional targets for analysis.!* -
- The study used both a murine lung infection model and an in vitro pharmacokinetic model to determine cefepime's target for effective bacterial killing, focusing on the percentage of time unbound drug concentrations exceed the minimum inhibitory concentration (MIC).!* -
- Results showed that cefepime's pharmacodynamic targets (30% for in vivo and 34.2% for in vitro) are lower than typical for cephalosporins, suggesting its unique properties may contribute to this reduced requirement for effectiveness.!*
Article Synopsis
- - Temocillin, an antibiotic, shows about 85% plasma protein binding in healthy individuals, but its binding in patients experiencing infections or other complications was previously unexplored.
- - A study was conducted involving different patient groups (non-ICU with UTI, ICU with ventriculitis, or sepsis) that found temocillin's plasma protein binding decreased significantly in patients, especially those with severe infections, and was influenced by albumin levels and inflammation markers.
- - Results indicated that while temocillin binding did occur in patients, it was 2-4 times lower than in healthy individuals, and drug interactions, particularly with fluconazole, could further alter its effectiveness by increasing the unbound fraction of the
Article Synopsis
- Flucloxacillin has been a long-standing treatment for methicillin-susceptible Staphylococcus aureus (MSSA), yet its pharmacodynamics are not fully understood.
- The study measured minimum inhibitory concentrations (MICs) of 305 MSSA isolates to establish wild-type distribution and tested the drug's effectiveness using a neutropenic mouse infection model.
- The findings revealed that maintaining flucloxacillin concentrations above certain thresholds (specifically, a percentage of time the unbound concentration remains above MIC) correlates with treatment efficacy, suggesting ways to optimize human dosing regimens.
Article Synopsis
- Antibiotic treatment for bone and joint infections (BJI) often follows standard dosing, but it's unclear if this provides sufficient concentration at the infection site to effectively kill bacteria.
- A literature review assessed the concentration of antibiotics in bone and synovial tissues of humans, noting details like patient numbers, dosing, and sampling methods, while comparing findings to epidemiological cutoff values for targeted bacteria.
- While some antibiotics like ciprofloxacin and vancomycin showed adequate exposure with standard dosing, the overall research is limited and varied, indicating the need for more thorough studies on pharmacokinetics and pharmacodynamics in BJI.
Article Synopsis
- The study aimed to analyze how cefotaxime is processed in critically ill adult patients and identify optimal dosages for effective treatment against specific bacteria, namely Enterobacterales and Staphylococcus aureus.!* -
- By sampling 92 patients during drug intervals and using a 2-compartment model for pharmacokinetics, the research found that factors like kidney function and albumin levels significantly affect drug clearance.!* -
- The study concluded that dosing regimens of cefotaxime, specifically 1 g every 8 hours for Enterobacterales and continuous infusion of 6 g per 24 hours for S. aureus, are most effective based on patients’ kidney and albumin levels.!*
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.
View Article and Find Full Text PDFArticle Synopsis
- Clavulanic acid is a β-lactam inhibitor widely used in pediatrics, but its mechanism of action and specific dosing guidelines remain unclear, especially given potential adverse effects.
- A systematic review identified 18 studies on the pharmacokinetics of clavulanic acid in children, revealing significant variability in drug exposure influenced by factors like age and disease state.
- The study highlights major knowledge gaps about this variability and calls for more research on pharmacokinetics and pharmacodynamics in pediatric patients to improve dosing strategies.
Article Synopsis
- This study compares parametric and nonparametric population pharmacokinetic modeling of the antibiotic imipenem in critically ill patients to enhance dosing effectiveness.* -
- While both modeling approaches showed adequate predictive performance for patients with eGFRs (estimated Glomerular Filtration Rate) ≥ 78 mL/min, they were less reliable for patients with lower eGFRs.* -
- Simulations revealed that while 50% of the Probability of Target Attainment (PTA) results were similar between models, differences arose due to higher variability in the nonparametric model, highlighting the need for further investigation on clinical implications.*
Background: With increasing knowledge of beta-lactam pharmacodynamics and interpatient and intrapatient variability in pharmacokinetics, the usefulness of therapeutic drug monitoring (TDM) is becoming increasingly clear. However, little research has been conducted to identify potential barriers and facilitators in the clinical implementation of beta-lactam TDM. This study provides an overview of the current practices of beta-lactam TDM and barriers and facilitators in its implementation.
View Article and Find Full Text PDFArticle Synopsis
- Early antibiotic initiation and appropriate dosing are crucial for effectively treating infections in critically ill patients, as their altered physiology affects drug metabolism and susceptibility of bacteria.
- Therapeutic Drug Monitoring (TDM) is increasingly recommended for optimizing antibiotic dosing, particularly for glycopeptides and aminoglycosides, to enhance clinical outcomes.
- Future improvements in TDM could involve model-informed precision dosing and advanced monitoring techniques, like real-time biosensors, to better tailor antibiotic therapy and reduce toxicity.