Antibiotic resistance is a serious global health problem that poses a threat to the successful treatment of various bacterial infections, especially those caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). Conventional treatment of MRSA and VRE infections is challenging and often requires alternative or combination therapies that may have limited efficacy, higher costs, and/or more adverse effects. Therefore, there is an urgent need to find new strategies to combat antibiotic-resistant bacteria. Probiotics and antimicrobial peptides (AMPs) are two promising approaches that have shown potential benefits in various diseases. Probiotics are live microorganisms that confer health benefits to the host when administered in adequate amounts. AMPs, usually produced with probiotic bacteria, are short amino acid sequences that have broad-spectrum activity against bacteria, fungi, viruses, and parasites. Both probiotics and AMPs can modulate the host immune system, inhibit the growth and adhesion of pathogens, disrupt biofilms, and enhance intestinal barrier function. In this paper, we review the current knowledge on the role of probiotics and AMPs in targeting multi-drug-resistant bacteria, with a focus on MRSA and VRE. In addition, we discuss future directions for the clinical use of probiotics.

This retrospective study included pediatric intensive care unit patients receiving continuous veno-venous hemodiafiltration (CVVHDF) being treated with cefepime. The free drug concentration above one time the MIC ( fT >1×MIC) and four times a presumed MIC ( fT >4×MIC) of 8 μg/ml were calculated.

Extracorporeal life support (ECLS), including extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT), is a lifesaving therapy for critically ill children. Despite this, these modalities carry frustratingly high mortality rates. One driver of mortality may be altered drug disposition due to a combination of underlying illness, patient-circuit interactions, and drug-circuit interactions. Children receiving ECMO and/or CRRT routinely receive 20 or more drugs, and data supporting optimal dosing are lacking for most of these medications. The Pediatric Paracorporeal and Extracorporeal Therapies Summit (PPETS) gathered an international group of experts in the fields of ECMO, CRRT, and other ECLS modalities to discuss the current state of these therapies, disseminate innovative support strategies, share clinical experiences, and foster future collaborations. Here, we summarize the conclusions of PPETS and put forward a pathway to optimize pharmacokinetic (PK) research in this population. We must prioritize specific medications for in-depth study to improve drug use in ECLS and patient outcomes. Based on frequency of use, potential for adverse outcomes if dosed inappropriately, and lack of existing PK data, a list of high-priority drugs was compiled for future research. Researchers must additionally reconsider study designs, emphasizing pooling of resources through multicenter studies and the use of innovative PK modeling techniques. Finally, the integration of validated PK models into clinical practice must be streamlined to deliver optimal medication use at the bedside. Focusing on the proposed list of highlighted medications and key methodological considerations will maximize the impact of future research.

Aims: The aim of this study is to describe the disposition of tranexamic acid (TXA) in adult trauma patients and derive a dosing regimen that optimizes exposure based on a predefined exposure target. Methods: We performed a population pharmacokinetic (popPK) analysis of participants enrolled in the Tranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury (TAMPITI) trial (>= 18 years with traumatic injury, given >= 1 blood product and/or requiring immediate transfer to the operating room) who were randomized to a single dose of either 2 or 4 g of TXA <= 2 h from time of injury. PopPK analysis was conducted using nonlinear mixed-effects modelling (NONMEM). Simulations were then performed using the final model to generate estimated plasma TXA concentrations in 1000 simulated participants. Dosing schemes were evaluated to determine maintenance of TXA plasma concentrations >10 mg/L for >= 8 h after administration of the initial dose. Results: TXA PK was best described by a two-compartment model with proportional residual error and allometric scaling on all parameters. Platelet count, skeletal muscle oxygen saturation measured by near-infrared spectroscopy and interleukin-8 concentration were significant covariates on TXA clearance. Based on simulations, a 2 g IV bolus dose, repeated 3 h later, best achieved the target exposure. Conclusions: According to simulations from a popPK model of TXA, a 2 g IV bolus with a repeated dose 3 h later would be most likely to maintain concentrations >10 mg/L for 8 h in >95% of adult trauma patients and should be considered for patients with ongoing haemorrhage.

Background: Milrinone is commonly prescribed to critically ill patients who need extracorporeal life support such as extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). Currently, the effect of ECMO and CRRT on the disposition of milrinone is unknown. Methods: Ex vivo ECMO and CRRT circuits were primed with human blood and then dosed with milrinone to study drug extraction by the circuits. Milrinone percent recovery over time was calculated to determine circuit component interaction with milrinone. Results: Milrinone did not exhibit measurable interactions with the ECMO circuit, however, CRRT cleared 99% of milrinone from the experimental circuit within the first 2 hours. Conclusion: Milrinone dosing adjustments are likely required in patients who are supported with CRRT while dosing adjustments for ECMO based on these ex-vivo results are likely unnecessary. These results will help improve the safety and efficacy of milrinone in patients requiring ECMO and CRRT. Due to the limitations of ex-vivo experiments, future studies of milrinone exposure with ECLS should include patient circuit interactions as well as the physiology of critical illness.

OBJECTIVES: Primary objective: to quantify tocilizumab (TCZ) use in pediatric inpatients. Secondary objectives: to explore safety and clinical outcomes. METHODS: This retrospective cohort study took place in a free-standing, 564-bed children’s hospital. Pediatric inpatients who received intravenous TCZ from January 2016 to May 2021 were included. Data collected included demographics, indication, dose, number of administrations, safety events on days 0 to 7 after TCZ, use of extracorporeal support (ES), presence of concurrent infection, and survival to discharge. Exploratory analyses assessed characteristics associated with mortality. RESULTS: A total of 103 TCZ courses (n = 87 patients) were analyzed. Median age was 14 years. Tocilizumab indications included cytokine release syndrome (CRS; 56%), autoimmune disease (27%), graft-versus-host disease (GVHD; 5%), and COVID-19 (4%). The median TCZ dose was 8 mg/kg (IQR, 7.9–11.9), 18% of courses were administered during active infection, and ES was used in 15% of courses. New-onset alanine transaminase (ALT) or aspartate transaminase (AST) levels >3 times upper limit of normal (ULN) occurred in 53% and 60% of courses, respectively. Of 29 courses with evaluable hematologic data, 10% resulted in new-onset neutropenia and 3% in severe thrombocytopenia. Overall survival to discharge was 83%. In multivariable analyses, independent associations with mortality were found for the use of ES (OR, 8.68; 95% CI, 1.85–4.87), oncologic diagnosis (OR, 7.07; 95% CI, 1.14–89.29), and post-TCZ infection (OR, 11.17; 95% CI, 1.50–138.13). CONCLUSIONS: Tocilizumab is used for many pediatric inpatient indications, most commonly CRS. Newly identified transaminitis was common following TCZ administration. Risk factors for mortality are likely confounded by illness severity. Administration during active infection was not independently associated with increased mortality.