Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) support leads to complex pharmacokinetic alterations, whereas adequate drug dosing is paramount for efficacy and absence of toxicity in critically ill patients. Amikacin is a major antibiotic used in nosocomial sepsis, especially for these patients. We aimed to describe amikacin pharmacokinetics on V-A ECMO support and to determine relevant variables to improve its dosing. All critically ill patients requiring empirical antimicrobial therapy, including amikacin for nosocomial sepsis supported or not by V-A ECMO, were included in a prospective population pharmacokinetic study. This population pharmacokinetic analysis was built with a dedicated software, and Monte Carlo simulations were performed to identify doses achieving therapeutic plasma concentrations. Thirty-nine patients were included (control n = 15, V-A ECMO n = 24); 215 plasma assays were performed and used for the modeling process. Patients received 29 (24–33) and 32 (30–35) mg/kg of amikacin in control and ECMO groups, respectively. Data were best described by a two-compartment model with first-order elimination. Inter-individual variabilities were observed on clearance, central compartment volume (V₁)_, and peripherical compartment volume (V₂). Three significant covariates explained these variabilities: Kidney Disease Improving Global Outcomes (KDIGO) stage on amikacin clearance, total body weight on V_1, and ECMO support on V₂. Our simulations showed that the adequate dosage of amikacin was 40 mg/kg in KDIGO stage 0 patients, while 25 mg/kg in KDIGO stage 3 patients was relevant. V-A ECMO support had only a secondary impact on amikacin pharmacokinetics, as compared to acute kidney injury.

Introduction Caspofungin pharmacokinetics may be altered in critically ill patients. In vitro studies suggest significant drug adsorption with polyacrylonitrile (PAN) membranes during continuous renal replacement therapy (CRRT). Methods This study retrospectively analyzed 66 plasma caspofungin concentrations (pCAS_conc) from 35 ICU patients between 2021 and 2024, comparing those on PAN-CRRT (n = 19) versus those without (n = 47). Results Caspofungin is mainly prescribed for candidemia (40%) and invasive Candida infections (25.7%). Median pCAS_conc at 12 h was similar between groups, but at 18 and 24 h, it was significantly higher in the PAN-CRRT group [5.3 (4.1–6.9) vs. 3.3 (1.9–3.7) mg/L, p = 0.04 and 5.3 (3.9–5.8) vs. 3.1 (2.5–4.5) mg/L, p = 0.01, respectively]. ECMO use was more frequent in PAN-CRRT patients (75% vs. 21.7%, p = 0.01). Persistent candidemia occurred in three patients (one in PAN-CRRT, two in non-PAN-CRRT). Conclusion This study found no evidence of caspofungin depletion with PAN-CRRT, warranting further research on clinical outcomes.

Background: Adjusting drug therapy under veno-venous extracorporeal membrane oxygenation (VV ECMO) is challenging. Although impaired pharmacokinetics (PK) under VV ECMO have been reported for sedative drugs and antibiotics, data about amiodarone are lacking. We evaluated the pharmacokinetics of amiodarone under VV ECMO both in vitro and in vivo. Methods: In vitro: Amiodarone concentration decays were compared between closed-loop ECMO and control stirring containers over a 24 h period. In vivo: Potassium-induced cardiac arrest in 10 pigs with ARDS, assigned to either control or VV ECMO groups, was treated with 300 mg amiodarone injection under continuous cardiopulmonary resuscitation. Pharmacokinetic parameters C_max, T_max AUC and F were determined from both direct amiodarone plasma concentrations observation and non-linear mixed effects modeling estimation. Results: An in vitro study revealed a rapid and significant decrease in amiodarone concentrations in the closed-loop ECMO circuitry whereas it remained stable in control experiment. In vivo study revealed a 32% decrease in the AUC and a significant 42% drop of C_max in the VV ECMO group as compared to controls. No difference in T_max was observed. VV ECMO significantly modified both central distribution volume and amiodarone clearance. Monte Carlo simulations predicted that a 600 mg bolus of amiodarone under VV ECMO would achieve the amiodarone bioavailability observed in the control group. Conclusions: This is the first study to report decreased amiodarone bioavailability under VV ECMO. Higher doses of amiodarone should be considered for effective amiodarone exposure under VV ECMO.

The MONOD ANRS 12206 trial was designated to assess simplification of a successful lopinavir (LPV)-based antiretroviral treatment in HIV-infected children younger than 3 years of age using efavirenz (EFV; 25 mg/kg of body weight/day) to preserve the class of protease inhibitors for children in that age group. In this substudy, EFV concentrations were measured to check the consistency of an EFV dose of 25 mg/kg and to compare it with the 2016 FDA recommended dose. Fifty-two children underwent blood sampling for pharmacokinetic study at 6 months and 12 months after switching to EFV. We applied a Bayesian approach to derive EFV pharmacokinetic parameters using the nonlinear mixed-effect modeling (NONMEM) program. The proportion of midinterval concentrations 12 h after drug intake (C_{12 h}) corresponding to the EFV therapeutic pharmacokinetic thresholds (1 to 4 mg/liter) was assessed according to different dose regimens (25 mg/kg in the MONOD study versus the 2016 FDA recommended dose). With both the 25 mg/kg/day dose and the 2016 FDA recommended EFV dose, simulations showed that the majority ofC_{12 h}values were within the therapeutic range (62.6% versus 62.8%). However, there were more children underexposed with the 2016 FDA recommended dose (11.6% versus 1.2%). Conversely, there were more concentrations above the threshold of toxicity with the 25 mg/kg dose (36.2% versus 25.6%), withC_{12 h}values of up to 15 mg/liter. Only 1 of 52 children was switched back to LPV because of persistent sleeping disorders, but hisC_{12 h}value was within therapeutic ranges. A high EFV dose of 25 mg/kg per day in children under 3 years old achieved satisfactory therapeutic effective levels. However, the 2016 FDA recommended EFV dose appeared to provide more acceptable safe therapeutic profiles. (This study has been registered at ClinicalTrials.gov under identifier NCT01127204.)

Objective: This study aimed to analyze the outcomes and challenges associated with surgical redo procedures following aortic valve replacement for acute infective endocarditis. While transcatheter aortic valve implantation is growing in terms of its utilization for degenerative bioprostheses failure, valve-in-valve procedures are limited in acute aortic endocarditis. Surgical interventions for aortic prosthesis endocarditis carry a significant risk, with a higher mortality and morbidity, often requiring concomitant complex procedures. Methods: This was a retrospective, monocentric, observational study. We identified 352 patients with infective endocarditis from the institutional database. After applying the inclusion and exclusion criteria, 54 patients who underwent surgical re-operation between 2016 and 2023 were included. Endpoints included early and late mortality, complications, and major adverse cardiac and cerebrovascular events (MACCEs). Results: From the cohort, predominantly male and with an average age of 71.9 ± 12.1 years old (79.6%), the following notable findings were derived: isolated aortic valve replacement was feasible only in 34 patients (63%) while more complex procedures were demanded in the other cases; the overall 30-day mortality rate was 18.5%, post-operative ECMO occurred in 9.3% of cases, and post-operative new stroke in 2.7%; the 5-year overall survival rate was 58.3 ± 18.6%, while freedom from MACCEs was 41.7 ± 19.7%. Another re-intervention was required in three patients during follow-up, with one case attributed to re-endocarditis. Conclusions: Despite advancements in surgical and perioperative care, redo procedures for acute infective endocarditis pose significant risks, as evidenced by the high 30-day mortality rate. However, the 5-year survival suggests a relatively acceptable outcome, underscoring the complexities and challenges inherent in managing this condition surgically.