TR-701 is the orally active prodrug of TR-700, a novel oxazolidinone that demonstrates four-to eightfoldgreater activity than linezolid (LZD) against Staphylococcus and Enterococcus spp. In this study evaluating the in vitro sensitivity of LZD-resistant isolates, TR-700 demonstrated 8-to 16-fold-greater potency than LZD against all strains tested, including methicillin-resistant Staphylococcus aureus (MRSA), strains of MRSA carrying the mobile cfr methyltransferase gene, and vancomycin-resistant enterococci. The MIC 90 for TR-700 against LZD-resistant S. aureus was 2 g/ml, demonstrating the utility of TR-700 against LZD-resistant strains. A model of TR-700 binding to 23S rRNA suggests that the increased potency of TR-700 is due to additional target site interactions and that TR-700 binding is less reliant on target residues associated with resistance to LZD.Oxazolidinone antibiotics are one of the newest classes of antibiotics developed within the past 30 years, with linezolid (LZD) representing the only marketed member of this class. In 2000, LZD (Zyvox) was granted approval for the treatment of infections associated with vancomycin-resistant Enterococcus faecium, nosocomial pneumonia, community-acquired pneumonia due to Streptococcus pneumoniae and methicillin-sensitive Staphylococcus aureus (MSSA), and complicated skin and skin structure infections, including cases due to methicillinresistant Staphylococcus aureus (MRSA) (1). Later approvals included pediatric use, pneumonia due to multidrugresistant S. pneumoniae, and treatment of diabetic foot infections, without osteomyelitis, caused by gram-positive bacteria. These approvals represent important milestones for the novel oxazolidinone class in the treatment of serious infections.Oxazolidinones have been shown to bind to the 50S ribosomal subunit and inhibit protein translation (31). A model of the binding of LZD to the 23S rRNA peptidyl transferase region has been previously published, based upon in vivo crosslinking experiments (18). This model predicts that LZD would specifically interfere with the binding of the amino acid portion of the aminoacyl tRNA to the ribosomal A site. The recent crystal structure of LZD bound to the 50S ribosomal subunit confirms these findings and suggests that the mechanism of inhibition involves competition with the incoming A site substrates (13). Mutations in the 23S rRNA central loop of domain V, the peptidyl transferase center (PTC), are associated with the development of LZD resistance.
Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. However, growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highly conserved ATP-binding subunits of DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD), we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models.
Many virulent strains of Enterococcus faecalis produce a two-subunit toxin, termed cytolysin. Cytolysin expression is regulated by one of the subunits (CylL(S)'') through a quorum-sensing autoinduction mechanism. We found that when target cells are absent, the other subunit (CylL(L)'') forms a complex with CylL(S)'', blocking it from autoinducing the operon. When target cells are present, however, CylL(L)'' binds preferentially to the target, allowing free CylL(S)'' to accumulate above the induction threshold. Thus, enterococci use CylL(L)'' to actively probe the environment for target cells, and when target cells are detected, allows the organism to express high levels of cytolysin in response.
IMPORTANCE The Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) study is the only ongoing nationwide antibiotic resistance surveillance program specific to ocular pathogens. OBJECTIVE To report resistance rates and trends among common ocular isolates collected during the first 5 years of the ARMOR study. DESIGN, SETTING, AND PARTICIPANTS This antibiotic resistance surveillance study was performed at an independent central laboratory. Clinical centers across the United States were invited to submit ocular isolates of Staphylococcus aureus, coagulase-negative staphylococci (CoNS), Streptococcus pneumoniae, Haemophilus influenzae, and
The antibacterial spectrum of besifloxacin, a novel fluoroquinolone recently approved for treatment of ocular infections, was studied using 2,690 clinical isolates representing 40 species. Overall, besifloxacin was the most potent agent tested against gram-positive pathogens and anaerobes and was generally equivalent to comparator fluoroquinolones in activity against most gram-negative pathogens. Besifloxacin demonstrated potent, broad-spectrum activity, which was particularly notable against gram-positive and gram-negative isolates that were resistant to other fluoroquinolones and classes of antibacterial agents.Bacterial conjunctivitis is an inflammation of the transparent mucous membrane covering the globe of the eye. This common ocular surface infection is caused by a broad variety of bacteria and is usually treated with broad-spectrum topical ophthalmic antibacterials (1,13,19,20). The increasing prevalence of drug-resistant ocular isolates highlights the need for the development of new agents for the treatment of bacterial infections (8). Besifloxacin ( Fig. 1) is a novel 8-chloro-fluoroquinolone agent with potent, bactericidal activity against prevalent and drug-resistant pathogens (6). Clinical development of the agent for use as a topical ophthalmic agent has been completed, and the agent has demonstrated consistent safety and efficacy in three bacterial conjunctivitis clinical trials (14,16,21). Pharmacokinetic studies demonstrated that after a single topical dose of 0.6% besifloxacin ophthalmic suspension, mean besifloxacin levels in human tears ranged from 610 g/ml at 10 min postadministration to 1.6 g/ml at 24 h postadministration (12). Here, the in vitro activity of besifloxacin against a broad range of aerobic and anaerobic bacterial species, including problematic drug-resistant strains, was evaluated.Totals of 2,535 aerobic and 155 anaerobic bacterial clinical isolates from Eurofins Medinet (Chantilly, VA) were selected for the study. The majority of isolates were from 2005 to 2008, and wherever possible, isolates were from ocular and respiratory specimens of U.S. origin. Susceptibility testing was conducted per Clinical and Laboratory Standards Institute reference methods (9-11).Activity of besifloxacin against gram-positive aerobes. Against Enterococcus faecalis and E. faecium, including vancomycin-resistant enterococci, besifloxacin was more potent than the comparator fluoroquinolones, as well as azithromycin, vancomycin, and tobramycin (Table 1). Besifloxacin further demonstrated excellent activity against Listeria monocytogenes, similar to that of tobramycin and penicillin and better than that observed with comparator fluoroquinolones.For Staphylococcus aureus and S. epidermidis, previously reported MIC 50 s/MIC 90 s were consistent with current besifloxacin values for quinolone-susceptible and quinolone-resistant subsets (3,5,14). Besifloxacin was especially potent against ciprofloxacin-resistant isolates; for example, the MIC 90 s for non-ciprofloxacin-susceptible S. aureus were 4 g/ml for...
Telavancin is an investigational, rapidly bactericidal lipoglycopeptide antibiotic that is being developed to treat serious infections caused by gram-positive bacteria. A baseline prospective surveillance study was conducted to assess telavancin activity, in comparison with other agents, against contemporary clinical isolates collected from 2004 to 2005 from across the United States. Nearly 4,000 isolates were collected, including staphylococci, enterococci, and streptococci (pneumococci, beta-hemolytic, and viridans). Telavancin had potent activity against Staphylococcus aureus and coagulase-negative staphylococci (MIC range, 0.03 to 1.0 g/ml), independent of resistance to methicillin or to multiple agents. Telavancin activity was particularly potent against all streptococcal groups (MIC 90 s, 0.03 to 0.12 g/ml). Telavancin had excellent activity against vancomycin-susceptible enterococci (MIC 90 , 1 g/ml) and was active against VanB strains of vancomycinresistant enterococci (MIC 90 , 2 g/ml) but less active against VanA strains (MIC 90 , 8 to 16 g/ml). Telavancin also demonstrated activity against vancomycin-intermediate S. aureus and vancomycin-resistant S. aureus strains (MICs, 0.5 g/ml to 1.0 g/ml and 1.0 g/ml to 4.0 g/ml, respectively). These data may support the efficacy of telavancin for treatment of serious infections with a wide range of gram-positive organisms.Antibiotic resistance in gram-positive bacteria is a continuing health care problem, both in hospitals and in the community. Telavancin is a novel, once-daily, intravenously administered lipoglycopeptide that is being developed to treat serious infections caused by gram-positive bacteria. It has shown promising results in patients with complicated skin and skin structure infections (SSSIs) (i.e., cellulitis, major abscess, infected wound/ulcer, or burn complicated by a requirement for surgical intervention and/or involvement of deeper tissues), including those infected with methicillin-resistant Staphylococcus aureus (MRSA) (19,20,21). A U.S. Food and Drug Administration New Drug Application has been filed for telavancin based on two completed phase 3 clinical trials for the treatment of complicated SSSIs (20), and two phase 3 trials for the treatment of hospital-acquired pneumonia have finished patient enrollment.Like vancomycin and teicoplanin, telavancin inhibits the polymerization of cell wall peptidoglycan precursors by binding to their D-alanyl-D-alanine termini, but telavancin has greater activity than vancomycin in this interaction (50% inhibitory concentration, 0.14 M versus 2.0 M) (8). Additionally, the interaction of telavancin with peptidoglycan precursors facilitates the perturbation of bacterial plasma membrane function, which leads to concentration-dependent membrane depolarization and increases in membrane permeability (8). The second mode of action is likely responsible for the more rapid and extensive bactericidal activity of telavancin than vancomycin and teicoplanin.Telavancin exhibits potent in vitro antibacterial activity ...
Doripenem and meropenem were more active than imipenem against Enterobacteriaceae and P. aeruginosa from the USA. Carbapenem resistance mechanisms included serine carbapenemases, elevated AmpC activity, efflux and porin deficiencies occurring mostly in P. aeruginosa. Metallo-β-lactamases were found in <0.1% of isolates.
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