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The propensity of oritavancin to select for stably elevated oritavancin minimum inhibitory concentrations (MICs) was studied by serial passaging of strains in broth containing oritavancin for 20 days. Seven clinical strains of Enterococcus faecalis and E. faecium were studied; they included vancomycin-susceptible and both VanA and VanB vancomycin-resistant isolates. Stepwise oritavancin selection yielded stably elevated oritavancin MICs in six of the seven strains, with MIC increases ranging from 4–32-fold. By comparison, stepwise selection with comparator agents dalbavancin (4- to >128-fold MIC increases), telavancin (4–8-fold MIC increases) and daptomycin (4–32-fold MIC increases) also yielded selectants with elevated MICs of the respective agents. Oritavancin selectants retained parental MICs of vancomycin, daptomycin, linezolid and rifampicin. Some, but not all of the oritavancin selectants also showed MIC increases to the lipoglycopeptides telavancin, dalbavancin and teicoplanin, suggesting that within the lipoglycopeptide class, different mechanisms of action may be elucidated. [ABSTRACT FROM AUTHOR]

Abstract: Human serum albumin (HSA) did not affect oritavancin MICs against non–vancomycin-intermediate Staphylococcus aureus (non-VISA) strains. In time–kill assays, oritavancin bactericidal activity in the presence of HSA was significantly more rapid than comparators against non-VISA strains. HSA increased oritavancin MICs by 4-fold for VISA strains, reflective of reduced oritavancin activity in time–kill assays with HSA. [Copyright &y& Elsevier]

Abstract: A 9-laboratory M23-A2 quality control (QC) study was performed to evaluate reproducibility of oritavancin MICs against reference strains of Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumoniae using broth microdilution assays in the presence of polysorbate 80. Polysorbate 80 has previously been shown to be required for accurate measurement of oritavancin broth microdilution MICs. Greater than 95% of replicate results (n = 270/organism) fell within the following QC ranges (in micrograms per milliliter): S. aureus ATCC 29213, 0.015 to 0.12; E. faecalis ATCC 29212, 0.008 to 0.03; and S. pneumoniae ATCC 49619, 0.001 to 0.004. Oritavancin MIC QC ranges were, thus, narrow and reproducible. Parameters affecting testing results in the presence of polysorbate 80 were also evaluated. Oritavancin MICs were equivalent to or within 1 doubling dilution of those obtained under standard Clinical and Laboratory Standards Institute testing conditions, regardless of incubation time (18, 24, or 48 h), Ca2+ concentration, pH, or frozen panel storage time (up to 6 months). [Copyright &y& Elsevier]

Abstract: The RNA polymerase holoenzyme is a proven target for antibacterial agents. A high-throughput screening program based on this enzyme from Staphylococcus aureus had previously identified a 2-ureidothiophene-3-carboxylate as a low micromolar inhibitor. An investigation of the relationships between the structures of this class of compounds and their inhibitory- and antibacterial activities is described here, leading to a set of potent RNA polymerase inhibitors with antibacterial activity. Characterization of this bioactivity, including studies of the mechanism of action, is provided, highlighting the power of the reverse chemical genetics approach in providing tools to inhibit the bacterial RNA polymerase. [Copyright &y& Elsevier]

Abstract This study proposes a supplier sustainability performance evaluation framework for evaluating and selecting suppliers based on their sustainability performance. An integrated model which uses fuzzy-Shannon Entropy to determine the sustainability criteria weights and fuzzy-Inference system to prioritize suppliers from the individual sustainability dimensions perspective is proposed to aid in the evaluation and selection. A Pakistan manufacturing company is used to exemplify the applicability and usefulness of the proposed suppliers' sustainability performance evaluation decision framework. The results show that amongst the economic, environmental and social sustainability dimensions, three criteria, namely: 'Quality' (10.87%), 'Cleaner Technology Implementation' (11.51%) and 'Information Disclosure' (13.75%), respectively, are the topmost ranked criteria. Across the triple-sustainability dimensions, suppliers 3 was ranked the topmost suppliers overall. This means that, to improve the sustainability of the company's supply chain, supplier 3 is most appropriate and recommended amongst the four suppliers for partnership. Managerial implications, limitations and further research directions are discussed. [ABSTRACT FROM AUTHOR]

Methicillin-resistant Staphylococcus aureus (MRSA) infections constitute a threat to the public health due to their prevalence and associated mortality and morbidity. Several agents have been recently approved to treat MRSA skin infections including lipoglycopeptides (dalbavancin, oritavancin, and telavancin), ceftaroline, and tedizolid. This study compared the MIC, minimum bactericidal concentration (MBC), and time-kill of these agents alongside daptomycin, linezolid, and vancomycin against MRSA (n = 15); meropenem, cefazolin, and nafcillin were also included against methicillin-susceptible S. aureus (MSSA [n = 12]). MIC and MBC testing was conducted in accordance with Clinical and Laboratory Standards Institute guidelines, and time-kills were evaluated at multiples of the MIC and the free-drug maximum plasma concentration ( f C max ) at both standard and high inoculum densities for a subset of MRSA (n = 2) and MSSA (n = 2). MRSA and MSSA were highly susceptible to all agents, with the lipoglycopeptides having the most potent activity by MIC 50/90 . All agents excluding tedizolid and linezolid were bactericidal by MBC for MRSA and MSSA, though dalbavancin and telavancin exhibited strain-specific bactericidal activity for MRSA. All agents excluding tedizolid and linezolid were bactericidal by time-kill at their respective f C max against MRSA and MSSA at standard inoculum density, though oritavancin exhibited the most rapid bactericidal activity. Oritavancin and daptomycin at their respective f C max maintained similar kill curves at high inoculum density. In contrast, the killing observed with other agents was typically reduced or slowed at high inoculum density. These data demonstrate the rapid bactericidal activity of oritavancin and daptomycin against S. aureus relative to other MRSA agents regardless of bacterial burden. [ABSTRACT FROM AUTHOR]

Abstract: Screening of a chemical library in a DNA helicase assay involving the Pseudomonas aeruginosa DnaB helicase provided a triaminotriazine inhibitor with good antibacterial activity but associated cytotoxicity toward mammalian cells. Synthesis of analogs provided a few inhibitors that retained antibacterial activity and demonstrated a significant reduction in cytotoxicity. The impact of serum and initial investigations toward a mode of action highlight several features of this class of compounds as antibacterials. [Copyright &y& Elsevier]

Gram-positive bacterial pathogens isolated from patient specimens submitted to 15 Canadian hospital laboratories from 2011 to 2015 were tested in the coordinating laboratory for susceptibility to oritavancin and comparative antimicrobial agents using the Clinical and Laboratory Standards Institute M07-A10 (2015) broth microdilution method. Oritavancin's in vitro activity was equivalent to, or more potent than, vancomycin, daptomycin, linezolid, and tigecycline against methicillin-susceptible Staphylococcus aureus ( n = 2680; oritavancin MIC 90 , 0.12 μg/mL; 99.9% oritavancin-susceptible), methicillin-resistant S. aureus ( n = 728; oritavancin MIC 90 , 0.12 μg/mL; 99.7% oritavancin-susceptible), Streptococcus pyogenes ( n = 218; oritavancin MIC 90 , 0.25 μg/mL; 100% oritavancin-susceptible), Streptococcus agalactiae ( n = 269; oritavancin MIC 90 , 0.12 μg/mL; 100% oritavancin-susceptible), and vancomycin-susceptible Enterococcus faecalis ( n = 508; oritavancin MIC 90 , 0.06 μg/mL; 100% oritavancin-susceptible). Oritavancin, dalbavancin, and telavancin demonstrated equivalent in vitro activities (MIC 90 , μg/mL) against 602 isolates of MSSA (0.06, 0.06, 0.06, respectively) and 144 isolates of MRSA (0.12, 0.06, 0.06, respectively) collected in 2015. [ABSTRACT FROM AUTHOR]

Abstract: As therapeutic agents of choice in the treatment of complicated infections, glycopeptide antibiotics are often preferentially used in cases of osteomyelitis, an infection located in bone and notoriously difficult to successfully manage. Yet frequent and heavy doses of these systemically administered antibiotics are conventionally prescribed to obtain higher antibiotic levels in the bone and reduce the high recurrence rates. Targeting antibiotics to the bone after systemic administration would present at least three potential advantages: (i) greater efficacy, by concentrating the therapeutic agent in bone; (ii) greater convenience, through a reduction in the frequency of administration; and (iii) greater safety, by reducing the levels of systemic drug exposure. We present here the design, synthesis and in vitro evaluation of eight prodrugs of the glycopeptide antibacterial agents vancomycin and oritavancin taking advantage of the affinity of the bisphosphonate group for bone for delivery to osseous tissues. [Copyright &y& Elsevier]

Abstract: Osteomyelitis is a difficult to treat bacterial infection of the bone. Delivering antibacterial agents to the bone may overcome the difficulties in treating this illness by effectively concentrating the antibiotic at the site of infection and by limiting the toxicity that may result from systemic exposure to the large doses conventionally used. Using bisphosphonates as osteophilic functional groups, different forms of fluoroquinolone esters were synthesized and evaluated for their ability to bind bone and to release the parent antibacterial agent. Bisphosphonated glycolamide fluoroquinolone esters were found to present a profile consistent with effective and rapid bone binding and efficient release of the active drug moiety. They were assessed for their ability to prevent bone infection in vivo and were found to be effective when the free fluoroquinolones were not. [Copyright &y& Elsevier]