Omadacycline is the first intravenous and oral 9-aminomethylcycline in clinical development for use against multiple infectious diseases including acute bacterial skin and skin structure infections (ABSSSI), community-acquired bacterial pneumonia (CABP), and urinary tract infections (UTI). The comparative in vitro activity of omadacycline was determined against a broad panel of Gram-positive clinical isolates, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Lancefield groups A and B beta-hemolytic streptococci, penicillin-resistant Streptococcus pneumoniae (PRSP), and Haemophilus influenzae (H. influenzae). The omadacycline MIC 90 s for MRSA, VRE, and beta-hemolytic streptococci were 1.0 g/ml, 0.25 g/ml, and 0.5 g/ml, respectively, and the omadacycline MIC 90 s for PRSP and H. influenzae were 0.25 g/ml and 2.0 g/ml, respectively. Omadacycline was active against organisms demonstrating the two major mechanisms of resistance, ribosomal protection and active tetracycline efflux. In vivo efficacy of omadacycline was demonstrated using an intraperitoneal infection model in mice. A single intravenous dose of omadacycline exhibited efficacy against Streptococcus pneumoniae, Escherichia coli, and Staphylococcus aureus, including tet(M) and tet(K) efflux-containing strains and MRSA strains. The 50% effective doses (ED 50 s) for Streptococcus pneumoniae obtained ranged from 0.45 mg/kg to 3.39 mg/kg, the ED 50 s for Staphylococcus aureus obtained ranged from 0.30 mg/kg to 1.74 mg/kg, and the ED 50 for Escherichia coli was 2.02 mg/ kg. These results demonstrate potent in vivo efficacy including activity against strains containing common resistance determinants. Omadacycline demonstrated in vitro activity against a broad range of Gram-positive and select Gram-negative pathogens, including resistance determinant-containing strains, and this activity translated to potent efficacy in vivo.W idespread resistance to antibiotics, including resistance to the older tetracyclines (tetracycline, doxycycline, and minocycline), has limited their usefulness in recent years (1, 2). New tetracycline derivatives that inhibit resistant organisms have been approved or are in development, including the glycylcyclines and specifically tigecycline, and fluorocyclines, including eravacycline (TP-434), and both tigecycline and eravacycline have potent Grampositive and Gram-negative in vitro activity (3-6). The discovery of the 9-aminomethyl class of tetracyclines has led to the identification of omadacycline (PTK 0796) that is poised to begin phase 3 clinical trials in acute bacterial skin and skin structure infections (ABSSSI), community-acquired (CA) bacterial pneumonia (CABP), and urinary tract infections (UTI) with both an intravenous (i.v.) and oral tablet formulation. Omadacycline, (4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-9{[(2,2-dimethylpropyl)amino]methyl}-3, 10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, contains a four-ring carbocyclic skelet...
bOmadacycline is a novel first-in-class aminomethylcycline with potent activity against important skin and pneumonia pathogens, including community-acquired methicillin-resistant Staphylococcus aureus (MRSA), -hemolytic streptococci, penicillinresistant Streptococcus pneumoniae, Haemophilus influenzae, and Legionella. In this work, the mechanism of action for omadacycline was further elucidated using a variety of models. Functional assays demonstrated that omadacycline is active against strains expressing the two main forms of tetracycline resistance (efflux and ribosomal protection). Macromolecular synthesis experiments confirmed that the primary effect of omadacycline is on bacterial protein synthesis, inhibiting protein synthesis with a potency greater than that of tetracycline. Biophysical studies with isolated ribosomes confirmed that the binding site for omadacycline is similar to that for tetracycline. In addition, unlike tetracycline, omadacycline is active in vitro in the presence of the ribosomal protection protein Tet(O). Omadacycline is the first of the novel aminomethylcyclines, which are semisynthetic compounds related to the tetracyclines, to undergo clinical development (Fig. 1). The tetracycline family of antimicrobials has been in clinical use for over 60 years and includes tetracycline, doxycycline, and minocycline. As a class, they are well tolerated; have a broad spectrum of antimicrobial activity, including against Gram-positive bacteria, Gram-negative bacteria, anaerobes, and atypical bacteria; and have proven effective in the treatment of a variety of bacterial infections involving respiratory tract, skin and skin structure, urinary tract, and intra-abdominal sites (1, 2).When first released in the 1950s to 1960s, the tetracyclines were an important component of the antibiotic armamentarium. Their clinical use declined in subsequent years, primarily due to the increasing prevalence of tetracycline resistance and the availability of effective alternative therapies. There are two major mechanisms of tetracycline resistance: efflux and ribosome protection. The two mechanisms have been described in Gram-positive and Gram-negative bacteria either separately or together, with ribosome protection generally more common in Gram-positive bacteria and efflux in Gram-negative bacteria (3). The most common genotypes of ribosome protection are tet(M) and tet(O). Efflux is determined by a family of related genotypes, in particular, tet(K) and tet(B) (2).Omadacycline has potent activity against important skin and lung pathogens, including community-acquired methicillin-resistant Staphylococcus aureus (MRSA), -hemolytic streptococci, penicillin-resistant Streptococcus pneumoniae, Haemophilus influenzae, and Legionella. The compound specifically overcomes tetracycline resistance mechanisms and is not affected by mechanisms of resistance to other classes of antibiotics. Omadacycline is entering phase 3 development for treatment of acute bacterial skin and skin structure infections (ABSSSI), community-acqu...
The steady-state concentrations of omadacycline and tigecycline in the plasma, epithelial lining fluid (ELF), and alveolar cells (AC) of 58 healthy adult subjects were obtained. Subjects were administered either omadacycline at 100 mg intravenously (i.v.) every 12 h for two doses followed by 100 mg i.v. every 24 h for three doses or tigecycline at an initial dose of 100 mg i.v. followed by 50 mg i.v. every 12 h for six doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject following the start of the fifth dose of omadacycline at 0.5, 1, 2, 4, 8, 12, or 24 h and after the start of the seventh dose of tigecycline at 2, 4, 6, or 12 h. The value of the area under the concentration-time curve (AUC) from time zero to 24 h postdosing (AUC0–24) (based on mean concentrations) in ELF and the ratio of the ELF to total plasma omadacycline concentration based on AUC0–24 values were 17.23 mg · h/liter and 1.47, respectively. The AUC0–24 value in AC was 302.46 mg · h/liter, and the ratio of the AC to total plasma omadacycline concentration was 25.8. In comparison, the values of the AUC from time zero to 12 h postdosing (AUC0–12) based on the mean concentrations of tigecycline in ELF and AC were 3.16 and 38.50 mg · h/liter, respectively. The ratio of the ELF and AC to total plasma concentrations of tigecycline based on AUC0–12 values were 1.71 and 20.8, respectively. The pharmacokinetic advantages of higher and sustained concentrations of omadacycline compared to those of tigecycline in plasma, ELF, and AC suggest that omadacycline is a promising antibacterial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens.
Coronavirus disease 2019 (COVID-19) pandemic is affecting millions of patients worldwide. The consequences of initial exposure to SARS-CoV-2 go beyond pulmonary damage, with a particular impact on lipid metabolism. Decreased levels in HDL-C were reported in COVID-19 patients. Since HDL particles display antioxidant, anti-inflammatory and potential anti-infectious properties, we aimed at characterizing HDL proteome and functionality during COVID-19 relative to healthy subjects. HDLs were isolated from plasma of 8 severe COVID-19 patients sampled at admission to intensive care unit (Day 1, D1) at D3 and D7, and from 16 sex- and age-matched healthy subjects. Proteomic analysis was performed by LC-MS/MS. The relative amounts of proteins identified in HDLs were compared between COVID-19 and controls. apolipoprotein A-I and paraoxonase 1 were confirmed by Western-blot analysis to be less abundant in COVID-19 versus controls, whereas serum amyloid A and alpha-1 antitrypsin were higher. HDLs from patients were less protective in endothelial cells stiumalted by TNFα (permeability, VE-cadherin disorganization and apoptosis). In these conditions, HDL inhibition of apoptosis was blunted in COVID-19 relative to controls. In conclusion, we show major changes in HDL proteome and decreased functionality in severe COVID-19 patients.
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