No abstract

A prospective study was undertaken to determine whether feeding farm animals antibiotics in feed caused changes in the intestinal bacterial flora of farm dwellers and their neighbors. Chickens were fed tetracycline-supplemented feed (tet-feed), and, as expected, within one week their intestinal flora contained almost entirely tetracycline-resistant organisms. Increased numbers of resistant intestinal bacteria also appeared, but more slowly, in farm members, but not their neighbors. Within five and six months, 31.3 per cent of weekly fecal samples from farm dwellers contained greater than 80 per cent tetracycline-resistant bacteria as compared to 6.8 per cent of the samples from the neighbors (P less than 0.001). Seven of the 11 farm members, but only three of the 24 neighbors, had two or more fecal samples containing greater than 80 per cent tetracycline-resistant coliforms (P less than 0.01). These resistant bacteria contained transferable plasmids conferring multiple antibiotic resistances. Selective pressure by tet-feed for antibiotic-resistant bacteria in chickens extends to human beings in contact with chickens and the feed.

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...