Identifying optimal dosing strategies for meropenem in the paediatric intensive care unit through modelling and simulation.

BACKGROUND: Meropenem, a ß-lactam antibiotic commonly prescribed for severe infections, poses dosing challenges in critically ill patients due to highly variable pharmacokinetics. OBJECTIVES: We sought to develop a population pharmacokinetic model of meropenem for critically ill paediatric and young adult patients. PATIENTS AND METHODS: Paediatric intensive care unit patients receiving meropenem 20-40 mg/kg every 8 h as a 30 min infusion were prospectively followed for clinical data collection and scavenged opportunistic plasma sampling. Nonlinear mixed effects modelling was conducted using Monolix®. Monte Carlo simulations were performed to provide dosing recommendations against susceptible pathogens (MIC ≤ 2 mg/L). RESULTS: Data from 48 patients, aged 1 month to 30 years, with 296 samples, were described using a two-compartment model with first-order elimination. Allometric body weight scaling accounted for body size differences. Creatinine clearance and percentage of fluid balance were identified as covariates on clearance and central volume of distribution, respectively. A maturation function for renal clearance was included. Monte Carlo simulations suggested that for a target of 40% fT > MIC, the most effective dosing regimen is 20 mg/kg every 8 h with a 3 h infusion. If higher PD targets are considered, only continuous infusion regimens ensure target attainment against susceptible pathogens, ranging from 60 mg/kg/day to 120 mg/kg/day. CONCLUSIONS: We successfully developed a population pharmacokinetic model of meropenem using real-world data from critically ill paediatric and young adult patients with an opportunistic sampling strategy and provided dosing recommendations based on the patients' renal function and fluid status.

Novel histone-derived antimicrobial peptides use different antimicrobial mechanisms.

The increase in multidrug resistant bacteria has sparked an interest in the development of novel antibiotics. Antimicrobial peptides that operate by crossing the cell membrane may also have the potential to deliver drugs to intracellular targets. Buforin 2 (BF2) is an antimicrobial peptide that shares sequence identity with a fragment of histone subunit H2A and whose bactericidal mechanism depends on membrane translocation and DNA binding. Previously, novel histone-derived antimicrobial peptides (HDAPs) were designed based on properties of BF2, and DesHDAP1 and DesHDAP3 showed significant antibacterial activity. In this study, their DNA binding, permeabilization, and translocation abilities were assessed independently and compared to antibacterial activity to determine whether they share a mechanism with BF2. To investigate the importance of proline in determining the peptides' mechanisms of action, proline to alanine mutants of the novel peptides were generated. DesHDAP1, which shows significant similarities to BF2 in terms of secondary structure, translocates effectively across lipid vesicle and bacterial membranes, while the DesHDAP1 proline mutant shows reduced translocation abilities and antimicrobial potency. In contrast, both DesHDAP3 and its proline mutant translocate poorly, though the DesHDAP3 proline mutant is more potent. Our findings suggest that a proline hinge can promote membrane translocation in some peptides, but that the extent of its effect on permeabilization depends on the peptide's amphipathic properties. Our results also highlight the different antimicrobial mechanisms exhibited by histone-derived peptides and suggest that histones may serve as a source of novel antimicrobial peptides with varied properties.