Comparative Population Pharmacokinetics of Darunavir in SARS-CoV-2 Patients vs. HIV Patients: The Role of Interleukin-6

Background: Darunavir is an anti-HIV protease inhibitor repurposed for SARS-CoV-2 treatment. Objective: The aim of this study was to assess the population pharmacokinetics of darunavir in SARS-CoV-2 patients compared with HIV patients. Methods: Two separate models were created by means of a nonlinear mixed-effect approach. The influence of clinical covariates on each basic model was tested and the association of significant covariates with darunavir parameters was assessed at multivariate regression and classification and regression tree (CART) analyses. Monte Carlo simulation assessed the influence of covariates on the darunavir concentration versus time profile. Results: A one-compartment model well-described darunavir concentrations in both groups. In SARS-CoV-2 patients (n = 30), interleukin (IL)-6 and body surface area were covariates associated with darunavir oral clearance (CL/F) and volume of distribution (Vd), respectively; no covariates were identified in HIV patients (n = 25). Darunavir CL/F was significantly lower in SARS-CoV-2 patients compared with HIV patients (4.1 vs. 10.3\ua0L/h; p < 0.001). CART analysis found that an IL-6 level of 18\ua0pg/mL may split the SARS-CoV-2 population in patients with low versus high darunavir CL/F (mean \ub1 standard deviation 3.47 \ub1 1.90 vs. 8.03 \ub1 3.24\ua0L/h; proportion of reduction in error = 0.46). Median (interquartile range) darunavir CL/F was significantly lower in SARS-CoV-2 patients with IL-6 levels 65 18\ua0pg/mL than in SARS-CoV-2 patients with IL-6 levels < 18\ua0pg/mL or HIV patients (2.78 [2.16\u20134.47] vs. 7.24 [5.88\u201310.38] vs. 9.75 [8.45\u201313.79]\ua0L/h, respectively; p < 0.0001). Increasing IL-6 levels affected darunavir concentration versus time simulated profiles. We hypothesized that increases in IL-6 levels associated with severe SARS-CoV-2 disease may downregulate the cytochrome P450 (CYP)\ua03A4-mediated metabolism of darunavir. Conclusions: This is a proof-of-concept of SARS-CoV-2 disease\u2013drug interactions, and may support the need for optimal dose selection of sensitive CYP3A4 substrates in severe SARS-CoV-2 patients

Modelling the radiation action for the estimation of biological effects in humans

It is well known that ionizing radiation can induce biological effects at different levels, from DNA, chromosomes and cells up to tissues, organs and entire organisms. Theoretical models and Monte Carlo codes, especially those based on radiation track structure, can be of great help to elucidate the underlying mechanisms and to perform reliable predictions where data are lacking. In this work we will present and discuss a mechanistic ab initio model and a Monte Carlo code able to simulate the induction of chromosome aberrations (CAs) in human cells. This endpoint is particularly relevant, since some aberration types can lead to cell death, while others can lead to cell conversion to malignancy. The model is based on the hypothesis that only clustered lesions (CLs) of the DNA double-helix can evolve into aberrations. Simulated dose-response curves for CAs induced by different radiation types (including heavy ions) will be shown, together with applications to cancer risk estimation and biodosimetry. In this framework, we will also discuss examples of medical applications - including astronauts' exposure to space radiation - obtained with the FLUKA code, also taking into account the role of nuclear interactions

Effect of Lactoferrin on Clinical Outcomes of Hospitalized Patients with COVID-19: The LAC Randomized Clinical Trial

As lactoferrin is a nutritional supplement with proven antiviral and immunomodulatory abilities, it may be used to improve the clinical course of COVID-19. The clinical efficacy and safety of bovine lactoferrin were evaluated in the LAC randomized double-blind placebo-controlled trial. A total of 218 hospitalized adult patients with moderate-to-severe COVID-19 were randomized to receive 800 mg/die oral bovine lactoferrin (n = 113) or placebo (n = 105), both given in combination with standard COVID-19 therapy. No differences in lactoferrin vs. placebo were observed in the primary outcomes: the proportion of death or intensive care unit admission (risk ratio of 1.06 (95% CI 0.63–1.79)) or proportion of discharge or National Early Warning Score 2 (NEWS2) ≤ 2 within 14 days from enrollment (RR of 0.85 (95% CI 0.70–1.04)). Lactoferrin showed an excellent safety and tolerability profile. Even though bovine lactoferrin is safe and tolerable, our results do not support its use in hospitalized patients with moderate-to-severe COVID-19

Il nulla e la libert\ue0. Intervista a Sergio Givone

Intervista a Sergio Givone sul rapporto tra nulla e libert\ue0

Estetica

Organo dell'A.I.S.E. (Associazione Italiana degli Studiosi di Estetica). Comitato scientifico internazionale che vaglia gli articoli proposti, composto da: C. Angelino, O. Breidbach, M. Cacciari, M. Donà, F. Duque, G. Figal, M. Frank, A. Giannatiempo Quinzio, D. Harth, G. Marchianò, R. Milani, J.-L. Nancy, A, Pagnini, M. Pezzella, F. Rella, M. Saison, G. Vattimo, F. Volpi, M. Vozza, S. Zecchi

Should High-dose Daptomycin be an Alternative Treatment Regimen for Enterococcal Endocarditis?

Introduction Previous series on the use of daptomycin in enterococcal infective endocarditis (EIE) have shown various outcomes, including higher mortality rates. We analyzed the effectiveness of high-dose daptomycin for the treatment of EIE. Methods We performed a prospective study from 2010 to 2018 in a referral center in patients with native (NVE) and prosthetic valve endocarditis (PVE) due to Enterococcus spp. The standard high-dose daptomycin at our institution is 10-12 mg/kg/day (CLCr > 30 ml/min). We compared the efficacy of a daptomycin-based regimen (DBR) versus daptomycin-sparing regimen (DSR) and daptomycin monotherapy versus combination therapy. Primary endpoints of the study were evaluation of risk factors associated with 30-day mortality and failure at end of therapy. Results We collected 43 EIE cases; 29 were NVE (67.4%). Overall, 16 (37.2%) were treated with DBR, mainly with combination regimens (11, 68.7%), in the majority of cases in association with ss-lactam (7, 43.7%). The mean administered dose of daptomycin was 10.125 mg/kg/day (range 8-12 mg/kg/day). Overall, patients treated with DBR compared with patients treated with DSR had no higher mortality rates and/or failure at end of therapy (6.2% vs. 22. 2%; P 0.41 and MICs 0.25-2 mg/l, 6.2% vs. 3.7%; P 1.0). In the sub-group of patients with NVE and PVE treated with DBR and DSR, no difference was found regarding the primary endpoints on the single or combined use of daptomycin. Conclusion Our findings suggest that high-dose daptomycin might be used as an alternative treatment regimen in EIE

Daptomycin-containing regimens for treatment of Gram-positive endocarditis

Purpose: Infective endocarditis (IE) is a severe infection, and a leading cause of mortality and morbidity. Due to its favourable microbiological and pharmacological characteristics, daptomycin is routinely used in clinical practice for treating IE. Methods: A prospective study was conducted at a large tertiary-care hospital in Italy over an 8-year period (January 2010-January 2018) on all patients with native-valve endocarditis (NVE) or prosthetic-valve endocarditis (PVE) caused by Gram-positive bacteria. Patients with NVE and PVE treated with regimens that included daptomycin at different dosages (daptomycin-containing regimens, DCR) were compared with those treated with non-DCR. Primary endpoints of the study were 30-day mortality and clinical treatment failure. Results: During the study period, 327 patients with Gram-positive NVE (n = 224, 68.8%) or PVE (n = 103, 31.2%) were analysed. Eighty-four (37.5%) NVE patients were treated with daptomycin, alone (59.9%) or with other antimicrobials. Most PVE patients (n = 61, 58%) were treated with a DCR, which always consisted of daptomycin plus other drugs. Among PVE patients, treatment with a DCR was associated with lower 30-day mortality than treatment with a non-DCR (6.5% vs. 38%, P < 0.001). Among NVE patients treated with DCRs, risk factors for 30-day mortality were streptococcal infections, persistent bacteraemia, and standard-dose (4-6 mg/kg) rather than high-dose daptomycin therapy. Overall, surgical treatment of IE and DCR were associated with clinical success and 30-day survival. Conclusions: Compared with non-DCRs, using single-drug or multiple-drug DCRs is associated with lower 30-day mortality in PVE, but with higher 30-day mortality in NVE at approved doses and in a subgroup of streptococcal IE. (C) 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved

Multidrug-resistant Pseudomonas aeruginosa skin and soft-tissue infection successfully treated with ceftolozane/tazobactam

Ceftolozane/tazobactam (C/T) is a novel beta-lactam/beta-lactamase inhibitor combination antibiotic approved by the US Food and Drug Administration for the treatment of complicated intra-abdominal and urinary tract infections due to Gram-negative bacteria, particularly extended-spectrum beta-lactamase-producing Enterobacteriaceae and multidrug-resistant (MDR) Pseudomonas aeruginosa strains. Here we report a case of MDR P. aeruginosa skin and soft-tissue infection successfully treated with C/T. (C) 2017 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved

Authors\u2019 Reply to Cattaneo et al.: \u201cComment on: Comparative Population Pharmacokinetics of Darunavir in SARS-CoV-2 Patients vs. HIV Patients: The Role of Interleukin6\u201d

n