Why Molnupiravir Fails in Hospitalized Patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has radically altered daily life. Effective antiviral therapies to combat COVID-19, especially severe disease, remain scarce. Molnupiravir is an antiviral that has shown clinical efficacy against mild-to-moderate COVID-19 but failed to provide benefit to hospitalized patients with severe disease.

Cascade Impactor Equivalence Testing: Comparison of the Performance of the Modified Chi-Square Ratio Statistic (mCSRS) with the Original CSRS and EMA's Average Bioequivalence Approach.

The performances of three statistical approaches for assessing in vitro equivalence was evaluated with a set of 55 scenarios of realistic test (T) and reference (R) cascade impactor (CI) profiles (originally employed by the Product Quality Research Institute to evaluate the chi-square ratio statistic: CSRS) by comparing the outcomes against experts' opinion (surrogate for the truth). The three methods were (A) a stepwise aerodynamic particle size distribution (APSD) equivalence test integrating population bioequivalence (PBE) testing of impactor-sized mass (ISM) with the CSRS (PBE-CSRS approach), previously suggested by the USFDA; (B) the combination of PBE testing of single actuation content and ISM with the newly suggested modified CSRS (PBE-mCSRS approach), a method employing reference variance scaling; and (C) EMA's average bioequivalence (ABE approach). Based on Monte-Carlo simulations, both PBE-CSRS and ABE approaches resulted in high misclassification rates, the former with highest false-pass rate and the latter with highest false-fail rate at both ≥ 50% and ≥ 80% classification threshold values (the % of simulations or experts necessary to judge a given scenario as equivalent).

Polymyxin combinations: pharmacokinetics and pharmacodynamics for rationale use.

Since their reintroduction into the clinic in the 1980s, the polymyxin antibiotics colistin-administered intravenously as an inactive prodrug, colistin methanesulfonate (CMS)-and polymyxin B have assumed an important role as salvage therapy for otherwise untreatable gram-negative infections. However, the emerging pharmacodynamic and pharmacokinetic data on CMS/colistin and polymyxin B indicate that polymyxin monotherapy is unlikely to generate plasma concentrations that are reliably efficacious. Additionally, regrowth and the emergence of resistance with monotherapy are commonly reported even when concentrations exceed those achieved clinically.

Doripenem population pharmacokinetics and dosing requirements for critically ill patients receiving continuous venovenous haemodiafiltration.

Objectives: Doripenem is a newer carbapenem with little data available to guide effective dosing during renal replacement therapy in critically ill patients. The objective of this study was to determine the population pharmacokinetics of doripenem in critically ill patients undergoing continuous venovenous haemodiafiltration (CVVHDF) for acute kidney injury (AKI).

Methods: This was an observational pharmacokinetic study in 12 infected critically ill adult patients with AKI undergoing CVVHDF and receiving 500 mg of doripenem intravenously every 8 h as a 60 min infusion.

Resistance emergence mechanism and mechanism of resistance suppression by tobramycin for cefepime for Pseudomonas aeruginosa.

The panoply of resistance mechanisms in Pseudomonas aeruginosa makes resistance suppression difficult. Defining optimal regimens is critical. Cefepime is a cephalosporin whose 3' side chain provides some stability against AmpC β-lactamases.

Ertapenem pharmacokinetics and impact on intestinal microflora, in comparison to those of ceftriaxone, after multiple dosing in male and female volunteers.

The pharmacokinetics of ertapenem and ceftriaxone were investigated in an open, randomized, two-period crossover study after single- and multiple-dose administration in 10 healthy volunteers (five women and five men). Both antibiotics were administered intravenously once daily for 7 days at dosages of 1 g (ertapenem) and 2 g (ceftriaxone). The concentrations of the antibiotics in serum and urine were quantified by the agar well diffusion method bioassay and, in addition, for ertapenem only, by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS).