To better understand the molecular events involved in the origin of new pathogenic bacteria, we studied the evolution of a highly virulent clone of serotype M1 group A Streptococcus (GAS). Genomic, DNA-DNA microarray, and single-nucleotide polymorphism analyses indicated that this clone evolved through a series of horizontal gene transfer events that involved (1) the acquisition of prophages encoding streptococcal pyrogenic exotoxin A and extracellular DNases and (2) the reciprocal recombination of a 36-kb chromosomal region encoding the extracellular toxins NAD+-glycohydrolase (NADase) and streptolysin O (SLO). These gene transfer events were associated with significantly increased production of SLO and NADase. Virtual identity in the 36-kb region present in contemporary serotype M1 and M12 isolates suggests that a serotype M12 strain served as the donor of this region. Multiple horizontal gene transfer events were a crucial factor in the evolutionary origin and emergence of a very abundant contemporary clone of serotype M1 GAS.

The activities of telavancin and vancomycin were compared in vitro and in the rabbit model of aortic valve endocarditis against a methicillin-resistant Staphylococcus aureus strain, COL, and a vancomycin-intermediate S. aureus (VISA) strain, HIP 5836. Telavancin was bactericidal in time-kill studies at a concentration of 5 g/ml against both COL and HIP5836. Vancomycin was bacteriostatic at 5 g/ml and bactericidal at 10 g/ml against COL and was bacteriostatic at 10 g/ml against VISA strain HIP 5836. Compared to untreated controls, a twice-daily regimen of 30 mg/kg of telavancin reduced mean aortic valve vegetation titers of the COL strain by 4.7 log 10 CFU/g after 4 days of therapy and sterilized 6/11 vegetations compared to 3.4 log 10 CFU/g with 3/10 vegetations sterilized for a regimen of twice-daily vancomycin, 30 mg/kg; these differences were not statistically significant. Telavancin was significantly more effective than vancomycin in the VISA model, producing a 5.5 log 10 CFU/g reduction versus no reduction in CFU with vancomycin. In experiments comparing 2-day regimens of telavancin at 30 mg/kg and 50 mg/kg twice daily, organisms were rapidly eliminated from vegetations, but the effect was not different between the two doses. These results suggest that telavancin may be an effective treatment for endocarditis and other serious staphylococcal infections accompanied by bacteremia, including infections caused by staphylococci not susceptible to vancomycin.Telavancin (formerly known as TD-6424) is an investigational lipoglycopeptide derivative of vancomycin (4, 5). It is more rapidly bactericidal than vancomycin in vitro, exhibits concentration-dependent killing, and is active against strains with reduced susceptibility to vancomycin (6, 7). This in vitro activity is likely due to the novel, multiple mechanisms of action of telavancin, including effects on membrane permeability as well as inhibition of peptidoglycan synthesis (4). In animal models of soft-tissue infection, telavancin is efficacious and more potent than vancomycin or linezolid (3). Telavancin is in phase 3 clinical trials as a once daily agent for treatment of serious infections caused by gram-positive pathogens. The purpose of the present study was to compare the efficacy of telavancin to vancomycin against antibiotic-resistant Staphylococcus aureus in a rabbit model of aortic valve endocarditis.(This work was presented in part at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois, 14 to 17 September 2003.) MATERIALS AND METHODSBacterial strains. In separate experiments, endocarditis was established with either of two S. aureus isolates: the homogeneous, highly methicillin-resistant S. aureus (MRSA) strain COL or a vancomycin-intermediate S. aureus (VISA) strain, HIP 5836, which is a methicillin-resistant (nafcillin MIC, 16 g/ml), ␤-lactamase-producing clinical isolate from a patient in New Jersey (originally designated strain 992) (2, 9).Susceptibility studies. MICs were determined by the standard micr...