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. Here, we explained the mechanism behind the failure of molnupiravir in hospitalized patients and identified alternative dosing strategies that would improve therapeutic outcomes in all patients with COVID-19. We showed that delaying therapy initiation markedly decreased the antiviral effect of molnupiravir, and these results were directly related to intracellular drug triphosphate pools and intracellular viral burden at the start of therapy. The adverse influence of therapeutic delay could be overcome by increasing drug exposure, which increased intracellular molnupiravir triphosphate concentrations that inhibited viral replication. These findings illustrated that molnupiravir must be administered as early as possible following COVID-19 symptom onset to maximize therapeutic efficacy. Higher doses may be effective in patients hospitalized with severe disease, but the safety of high-dose molnupiravir regimens is unknown. Our findings could be extended to design effective regimens with nucleoside analogs for other RNA viruses, especially those with pandemic potential. IMPORTANCE In this study, we showed that early intervention with molnupiravir resulted in a greater antiviral effect, and we explained the mechanism behind this phenomenon. Our results predicted and explained the failure of molnupiravir in hospitalized patients and highlighted the utility of preclinical pharmacodynamic studies to design optimal antiviral regimens for the treatment of viral diseases. This contrasts with the procedure that was implemented early in the pandemic in which clinical studies were conducted in the absence of preclinical experimentation. These findings are significant and demonstrated the importance of experimental approaches in antiviral development for treatments against COVID-19 as well as other viral diseases.

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). Based on DeLong's tests, the PBE-mCSRS approach showed significantly better overall agreement with experts' opinion compared to the other approaches. Comparison of CSRS with mCSRS (both without PBE) suggested that the more discriminatory characteristics of the mCSRS method is based on the integration of variance scaling into the mCSRS method. Contrary to the ABE approach, the application of PBE-mCSRS approach for assessing APSD profiles of three dry powder inhaler (DPI) formulations supported the pharmacokinetic bioequivalence assessment of these formulations.

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. Given this situation, polymyxin combination therapy, which is increasingly being used clinically, has been suggested as a possible means of increasing antimicrobial activity and reducing the development of resistance. Although considerable in vitro data support this view, investigations of polymyxin combination therapy in patients have only recently commenced. The currently available clinical data for polymyxin combinations are generally limited to retrospective analyses and small, low-powered, prospective studies using traditional dosage regimens that achieve low plasma concentrations. Considering the potential for rapid development of resistance to polymyxins, well-designed clinical trials that include higher-dose polymyxin regimens are urgently required to provide a more definitive answer regarding the role of polymyxin combination therapy compared with monotherapy. In this article, we provide an overview of key in vitro and clinical investigations examining CMS/colistin and polymyxin B combination therapy.

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. Serial blood samples were taken on 2 days of treatment and used for population pharmacokinetic analysis with S-ADAPT. RESULTS: The median (IQR) age was 62 (53-71) years, the median (IQR) weight was 77 (67-96) kg and the median (IQR) APACHE II score was 29 (19-32). The median blood, dialysate and replacement fluid rates were 200, 1000 and 1000 mL/h, respectively. A two-compartment linear model with doripenem clearance described by CVVHDF, renal or non-renal mechanisms was most appropriate. The mean value for total doripenem clearance was 4.46 L/h and volume of distribution was 38.0 L. Doripenem clearance by CVVHDF was significantly correlated with the replacement fluid flow rate and accounted for ∼30%-37% of total clearance. A dose of 500 mg intravenously every 8 h achieved favourable pharmacokinetic/pharmacodynamics for all patients up to an MIC of 4 mg/L. CONCLUSIONS: This is the first paper describing the pharmacokinetics/pharmacodynamics of doripenem in critically ill patients with AKI receiving CVVHDF. A dose of 500 mg intravenously every 8 h was appropriate for our CVVHDF settings for infections caused by susceptible bacteria.

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 ß-lactamases. We examined the activity of cefepime against P. aeruginosa wild-type strain PAO1 and its isogenic AmpC stably derepressed mutant in our hollow-fiber infection model. Dose-ranging studies demonstrated complete failure with resistance emergence (both isolates). Inoculum range studies demonstrated ultimate failure for all inocula. Lower inocula failed last (10 days to 2 weeks). Addition of a ß-lactamase inhibitor suppressed resistance even with the stably derepressed isolate. Tobramycin combination studies demonstrated resistance suppression in both the wild-type and the stably derepressed isolates. Quantitating the RNA message by quantitative PCR demonstrated that tobramycin decreased the message relative to that in cefepime-alone experiments. Western blotting with AmpC-specific antibody for P. aeruginosa demonstrated decreased expression. We concluded that suppression of ß-lactamase expression by tobramycin (a protein synthesis inhibitor) was at least part of the mechanism behind resistance suppression. Monte Carlo simulation demonstrated that a regimen of 2 g of cefepime every 8 h plus 7 mg/kg of body weight of tobramycin daily would provide robust resistance suppression for Pseudomonas isolates with cefepime MIC values up to 8 mg/liter and tobramycin MIC values up to 1 mg/liter. For P. aeruginosa resistance suppression, combination therapy is critical.

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). For ertapenem the maximum concentration of the drug in plasma (C(max)) was 256 mg/liter, the half-life was 20.7 h, and the area under the plasma concentration-time curve (AUC) was 830 mg. h/liter. The concentrations in fecal samples were (mean value) 37.2 and 32.7 mg/kg on day 4 and day 8, respectively. Ceftriaxone exhibited a mean C(max) of 315 mg/liter, a half-life of 7.6 h, and an AUC of 1,556 mg. h/liter. The mean concentrations in fecal samples were 153 and 258 mg/kg on day 4 and day 8, respectively. No accumulation of ertapenem or ceftriaxone was detected at steady state. A slightly but significantly decreased AUC for ertapenem was detected for the female volunteers. No serious adverse event was observed. Both antibiotics induced a marked decrease in the anaerobic microflora (4-log-unit decreases in lactobacilli, bifidobacteria, clostridia, and bacteroides) and Escherichia coli, whereas the number of enterococci increased (4 log units). A slight overgrowth of yeasts was observed with both regimens. In all cases the microflora returned to normal levels on days 21 to 35.