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Gregory Moeck - One of the best experts on this subject based on the ideXlab platform.
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In vitro stepwise selection of reduced susceptibility to lipoglycopeptides in enterococci.
Diagnostic microbiology and infectious disease, 2017Co-Authors: Francis F Arhin, Adam Belley, David Lalonde Seguin, Gregory MoeckAbstract:Abstract 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 20days. 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.
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Effects of Oritavancin on Coagulation Tests in the Clinical Laboratory.
Antimicrobial agents and chemotherapy, 2017Co-Authors: Adam Belley, Gregory Moeck, Richard Robson, John L. Francis, Dorothy M. Adcock, Stefan Tiefenbacher, Christopher M. Rubino, David Sylvester, Michael N. Dudley, Jeffery LoutitAbstract:Previous studies have shown that some lipoglycopeptide and lipopeptide antimicrobial agents may cause falsely elevated values for some phospholipid-dependent coagulation tests. The effect of Oritavancin, a lipoglycopeptide antibiotic, on coagulation test results was explored using pooled human plasma samples spiked with drug and in a clinical study after an infusion of a single 1,200-mg intravenous dose of Oritavancin in normal healthy volunteers. Pooled plasma with Oritavancin added ex vivo showed concentration-dependent prolongation of prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), and dilute Russell viper venom time (DRVVT) test results. In contrast, Oritavancin had no effect on the activated protein C resistance assay, chromogenic anti-factor Xa assay (anti-FXa), thrombin time, and an immunoassay for the laboratory diagnosis of heparin-induced thrombocytopenia. In participants that received a single dose of Oritavancin, elevations in PT/INR result, aPTT, DRVVT, activated clotting time, and silica clotting time occurred, with the maximum times to resolution of test interference determined to be 12, 120, 72, 24, and 18 h, respectively. The anti-FXa assay was unaffected, whereas transient elevations in D dimer levels were observed in 30% of participants, with a maximum time to resolution of 72 h. Although Oritavancin has no impact on the coagulation system in vivo, a single dose of Oritavancin can produce falsely elevated values of some coagulation tests used to monitor hemostasis. The interference of Oritavancin on affected tests is transient, and the test results revert to normal ranges within specified times after dosing.
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In vitro activity of Oritavancin against gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2015.
Diagnostic microbiology and infectious disease, 2017Co-Authors: James A. Karlowsky, Francis F Arhin, Gregory Moeck, Heather J. Adam, Andrew Walkty, Melanie R. Baxter, George G. ZhanelAbstract: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 MIC90, 0.12μg/mL; 99.9% Oritavancin-susceptible), methicillin-resistant S. aureus (n=728; Oritavancin MIC90, 0.12μg/mL; 99.7% Oritavancin-susceptible), Streptococcus pyogenes (n=218; Oritavancin MIC90, 0.25μg/mL; 100% Oritavancin-susceptible), Streptococcus agalactiae (n=269; Oritavancin MIC90, 0.12μg/mL; 100% Oritavancin-susceptible), and vancomycin-susceptible Enterococcus faecalis (n=508; Oritavancin MIC90, 0.06μg/mL; 100% Oritavancin-susceptible). Oritavancin, dalbavancin, and telavancin demonstrated equivalent in vitro activities (MIC90, 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.
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1 Assessment of Oritavancin Serum Protein Binding across Species 1 2 Running title: Oritavancin Serum Protein Binding 3 4
2016Co-Authors: Francis F Arhin, Ingrid Sarmiento, Adam Belley, Geoffrey Mckay, Sylvain Beaulieu, R. Parr, Gregory MoeckAbstract:2 Biophysical methods to study the binding of Oritavancin, a lipoglycopeptide, to serum 23 protein are confounded by nonspecific drug adsorption to labware surfaces. We assessed 24 Oritavancin binding to serum from mouse, rat, dog and human by a microbiological growth-25 based method under conditions that allow near-quantitative drug recovery. Protein binding was 26 similar across species, ranging from 81.9 % in human serum to 87.1 % in dog serum. These 27 estimates support translation of Oritavancin exposure from nonclinical studies to humans.28 3 Estimates of serum protein binding are essential to translate drug exposure from nonclinical 29 species to humans during assessments of toxicology, pharmacokinetics, and pharmacodynamics 30 since the free fraction dictates drug activity (3, 17, 18). Recent evidence supports the concept of 31 an “active fraction ” that offers insight into the pharmacodynamic behavior of highly protein-32 bound drugs such as daptomycin (20). 33 Oritavancin is a late-stage investigational lipoglycopeptide under study for treatment of 34 serious gram-positive infections (6). Nonspecific binding of Oritavancin to labware surfaces (1,2) 3
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In vitro activity of Oritavancin and comparator agents against staphylococci, streptococci and enterococci from clinical infections in Europe and North America, 2011–2014
International journal of antimicrobial agents, 2015Co-Authors: Douglas J. Biedenbach, Francis F Arhin, Gregory Moeck, Thomas F. Lynch, Daniel F. SahmAbstract:Oritavancin is a lipoglycopeptide that has been approved for the treatment of acute bacterial skin and skin-structure infections (ABSSSIs) caused by susceptible organisms. Oritavancin causes cell death by inhibiting cell wall synthesis as well as depolarising and permeabilising the cellular membrane of Gram-positive pathogens. The activities of Oritavancin in comparison with vancomycin, daptomycin and linezolid were determined against a collection of over 11000 recent clinical Gram-positive isolates from patient infections (2011-2014), including skin and skin-structure infections. A total of 7253 Staphylococcus aureus, 839 coagulase-negative staphylococci (CoNS), 1464 enterococci and 1637 β-haemolytic streptococci (βHS) were collected from the USA and Europe. Minimum inhibitory concentrations (MICs) were determined using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methods, and susceptibility was determined using CLSI and US Food and Drug Administration (FDA) (for Oritavancin) breakpoint criteria. Equivalent in vitro activity (MIC50/90, 0.015-0.03/0.06 μg/mL) was observed for Oritavancin against meticillin-resistant S. aureus (MRSA), meticillin-susceptible S. aureus (MSSA) and Enterococcus faecalis in both regions. Slightly higher Oritavancin MICs were obtained against CoNS, Streptococcus agalactiae, Enterococcus faecium (MIC90, 0.12 μg/mL) and against other βHS (MIC90, 0.25 μg/mL). Oritavancin demonstrated comparatively lower MICs than daptomycin and vancomycin when tested against multidrug-resistant S. aureus, vancomycin-resistant enterococci and erythromycin-resistant βHS. Oritavancin exhibited potent in vitro activity against the most common pathogens associated with ABSSSIs in the USA and Europe.
Francis F Arhin - One of the best experts on this subject based on the ideXlab platform.
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In vitro stepwise selection of reduced susceptibility to lipoglycopeptides in enterococci.
Diagnostic microbiology and infectious disease, 2017Co-Authors: Francis F Arhin, Adam Belley, David Lalonde Seguin, Gregory MoeckAbstract:Abstract 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 20days. 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.
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In vitro activity of Oritavancin against gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2015.
Diagnostic microbiology and infectious disease, 2017Co-Authors: James A. Karlowsky, Francis F Arhin, Gregory Moeck, Heather J. Adam, Andrew Walkty, Melanie R. Baxter, George G. ZhanelAbstract: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 MIC90, 0.12μg/mL; 99.9% Oritavancin-susceptible), methicillin-resistant S. aureus (n=728; Oritavancin MIC90, 0.12μg/mL; 99.7% Oritavancin-susceptible), Streptococcus pyogenes (n=218; Oritavancin MIC90, 0.25μg/mL; 100% Oritavancin-susceptible), Streptococcus agalactiae (n=269; Oritavancin MIC90, 0.12μg/mL; 100% Oritavancin-susceptible), and vancomycin-susceptible Enterococcus faecalis (n=508; Oritavancin MIC90, 0.06μg/mL; 100% Oritavancin-susceptible). Oritavancin, dalbavancin, and telavancin demonstrated equivalent in vitro activities (MIC90, 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.
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pooled analysis of single dose Oritavancin in the treatment of acute bacterial skin and skin structure infections caused by gram positive pathogens including a large patient subset with methicillin resistant staphylococcus aureus
International Journal of Antimicrobial Agents, 2016Co-Authors: Ralph G Corey, Francis F Arhin, Daniel F. Sahm, Matthew Wikler, Barry N Kreiswirth, Jose R Mediavilla, Samantha Good, Claude Fiset, Hai Jiang, Greg MoeckAbstract:Oritavancin is a lipoglycopeptide antibiotic with bactericidal activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The phase 3 studies SOLO I and SOLO II demonstrated comparable efficacy and safety of a single dose of Oritavancin compared with 7-10 days of twice-daily vancomycin in adults with acute bacterial skin and skin-structure infections (ABSSSIs). The present analysis assessed clinical responses by pathogen at 48-72 h and at study days 14-24 in SOLO patients within the pooled data set. Of the 1959 patients in the pooled SOLO studies, 1067 had at least one baseline Gram-positive pathogen and 405 had MRSA. Clinical response rates were similar for Oritavancin- and vancomycin-treated patients by pathogen, including Staphylococcus aureus with or without the Panton-Valentine leukocidin (pvl) gene and from different clonal complexes, and were similar for pathogens within each treatment group. Oritavancin exhibited potent in vitro activity against all baseline pathogens, with MIC90 values (minimum inhibitory concentration required to inhibit 90% of the isolates) of 0.12 µg/mL for Staphylococcus aureus, 0.25 µg/mL for Streptococcus pyogenes and 0.06 µg/mL for Enterococcus faecalis. Whereas both Oritavancin and vancomycin achieved similarly high rates of clinical response by pathogen, including methicillin-susceptible and -resistant Staphylococcus aureus, Oritavancin provides a single-dose alternative to 7-10 days of twice-daily vancomycin to treat ABSSSIs.
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1 Assessment of Oritavancin Serum Protein Binding across Species 1 2 Running title: Oritavancin Serum Protein Binding 3 4
2016Co-Authors: Francis F Arhin, Ingrid Sarmiento, Adam Belley, Geoffrey Mckay, Sylvain Beaulieu, R. Parr, Gregory MoeckAbstract:2 Biophysical methods to study the binding of Oritavancin, a lipoglycopeptide, to serum 23 protein are confounded by nonspecific drug adsorption to labware surfaces. We assessed 24 Oritavancin binding to serum from mouse, rat, dog and human by a microbiological growth-25 based method under conditions that allow near-quantitative drug recovery. Protein binding was 26 similar across species, ranging from 81.9 % in human serum to 87.1 % in dog serum. These 27 estimates support translation of Oritavancin exposure from nonclinical studies to humans.28 3 Estimates of serum protein binding are essential to translate drug exposure from nonclinical 29 species to humans during assessments of toxicology, pharmacokinetics, and pharmacodynamics 30 since the free fraction dictates drug activity (3, 17, 18). Recent evidence supports the concept of 31 an “active fraction ” that offers insight into the pharmacodynamic behavior of highly protein-32 bound drugs such as daptomycin (20). 33 Oritavancin is a late-stage investigational lipoglycopeptide under study for treatment of 34 serious gram-positive infections (6). Nonspecific binding of Oritavancin to labware surfaces (1,2) 3
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Results from Oritavancin Resistance Surveillance Programs (2011 to 2014): Clarification for Using Vancomycin as a Surrogate To Infer Oritavancin Susceptibility.
Antimicrobial agents and chemotherapy, 2016Co-Authors: Ronald N Jones, Francis F Arhin, Michael N. Dudley, Greg Moeck, Paul R. Rhomberg, Rodrigo E MendesAbstract:Measurement of vancomycin susceptibility has been shown to be highly predictive as a surrogate measure of Oritavancin susceptibility among clinically indicated Gram-positive species. Results of studying over 30,000 pathogens (from 2011 to 2014) by cross-susceptibility analysis and determining the poor reproducibility of Oritavancin-nonsusceptible results showed nearly perfect surrogate testing accuracy (99.86 to 99.94%). Any isolate of an indicated organism species with locally reproducible Oritavancin-nonsusceptible results (extremely rare) should be referred to a reference laboratory for confirmation of the results and determination of the resistance mechanism.
Thomas R Parr - One of the best experts on this subject based on the ideXlab platform.
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Oritavancin Pharmacokinetics and Bone Penetration in Rabbits
Antimicrobial agents and chemotherapy, 2015Co-Authors: Dario Lehoux, Adel Rafai Far, Valerie Ostiguy, Cordelia Cadieux, Mireille Malouin, Odette Belanger, Thomas R ParrAbstract:The pharmacokinetics and bone concentrations of Oritavancin were investigated after a single intravenous dose was administered to rabbits. The pharmacokinetic profile of Oritavancin in rabbits showed that it is rapidly distributed to bone tissues, with concentrations remaining stable for up to 168 h, the last measured time point. Based on these findings, further evaluation of Oritavancin for the treatment of infections in bone tissues is warranted.
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Activity of Oritavancin and comparators in vitro against standard and high inocula of Staphylococcus aureus.
International journal of antimicrobial agents, 2011Co-Authors: Francis F Arhin, Ingrid Sarmiento, Thomas R Parr, Gregory MoeckAbstract:In this study, the impact of inoculum density on the growth inhibitory and killing activities of Oritavancin and comparators (vancomycin, daptomycin and linezolid) in vitro against four Staphylococcus aureus strains at clinically relevant drug concentrations was studied. Broth microdilution and time-kill assays were performed using a standard inoculum [ca. 10(5)colony-forming units (CFU)/mL as per Clinical and Laboratory Standards Institute (CLSI) guidelines] and a high inoculum (ca. 10(7)CFU/mL). Whereas minimal inhibitory concentrations (MICs) of comparators were 2-8-fold higher when tested at high inoculum, Oritavancin MICs were 16-fold higher for all strains at the high inoculum relative to the standard inoculum. However, in time-kill assays, when tested at its fC(min) [trough concentration of free (non-protein-bound) drug] and fC(max) (peak concentration of non-protein-bound drug), Oritavancin retained its bactericidal activity against a vancomycin-susceptible, meticillin-susceptible S. aureus (VS-MSSA) strain and a vancomycin-susceptible, meticillin-resistant S. aureus (VS-MRSA) strain both at standard and high inocula. At its fC(max), Oritavancin was bactericidal at standard inoculum but not at high inoculum against two vancomycin-intermediate S. aureus (VISA) strains. Against both VISA strains at standard inoculum, Oritavancin at its fC(min) reduced cell density by between 2 and 3 log (bacteriostatic), predicting that it will retain activity against certain VISA infections. However, Oritavancin had no substantial growth inhibitory effect against either VISA strain at high inoculum, suggesting that in rare VISA infections with an anticipated high bacterial burden such as endocarditis, alternative Oritavancin dosing strategies, including combinations with other agents, may be explored.
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In vitro characterization of Oritavancin clearance from human blood by low-flux, high-flux, and continuous renal replacement therapy dialyzers.
The International journal of artificial organs, 2011Co-Authors: Atul Kumar, Thomas R Parr, Henry J. Mann, Mani Keshtgarpour, Michael A. Flynn, Hong Deng, Adel Rafai Far, Susan R. MoriartyAbstract:Background: Oritavancin is an investigational lipoglycopeptide antibiotic under clinical development for the treatment of gram-positive bacterial infections. The impact of hemodialysis on plasma concentrations of Oritavancin is unknown and may be important in making dosage adjustments in such patients. The present study sought to determine the clearance of Oritavancin from human blood by various commercially available dialyzers in an in vitro hemodialysis model. Methods: Three types each of low-flux (Dicea 130, F6, and Polyflux 14L) and high-flux (Revaclear, Exeltra 150, and Optiflux F160NR) dialyzers and one type of continuous renal replacement therapy (CRRT) dialyzer (Prismaflex M100) were studied. Heparinized human blood containing Oritavancin (200 mg/L) was circulated from a reservoir to the dialyzers and back to the reservoir. Fresh dialysate was pumped through the dialyzers in a countercurrent manner. Blood samples from each side of the dialyzers and contaminated dialysate samples were collected at periodic intervals. Oritavancin levels were analyzed by a liquid chromatography/mass spectrometry method with a limit of quantification of 12.5 ng/mL and plasma clearances of Oritavancin were calculated. Results: The mean dialytic clearance of Oritavancin was insignificant for each of the low-flux, high-flux and CRRT dialyzers. Clinically significant amounts of Oritavancin were not detected in dialysate during any of the experimental dialysis sessions. Conclusions: The clearance of Oritavancin from human blood by the dialyzers used in this study is insignificant. Further clinical studies would be required before making changes in dosage of Oritavancin in hemodialysis patients.
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Assessment of Oritavancin Serum Protein Binding across Species
Antimicrobial agents and chemotherapy, 2010Co-Authors: Francis F Arhin, Ingrid Sarmiento, Adam Belley, Thomas R Parr, Geoffrey A Mckay, Sylvain Beaulieu, Gregory MoeckAbstract:Biophysical methods to study the binding of Oritavancin, a lipoglycopeptide, to serum protein are confounded by nonspecific drug adsorption to labware surfaces. We assessed Oritavancin binding to serum from mouse, rat, dog, and human by a microbiological growth-based method under conditions that allow near-quantitative drug recovery. Protein binding was similar across species, ranging from 81.9% in human serum to 87.1% in dog serum. These estimates support the translation of Oritavancin exposure from nonclinical studies to humans.
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Time–kill kinetics of Oritavancin and comparator agents against Streptococcus pyogenes☆
International journal of antimicrobial agents, 2009Co-Authors: Francis F Arhin, Ingrid Sarmiento, Thomas R Parr, Geoffrey A Mckay, Sylvain Beaulieu, Gregory MoeckAbstract:The activity of Oritavancin in vitro against recent clinical isolates of Streptococcus pyogenes, including antibiotic-resistant strains, was characterised by determination of broth microdilution minimal inhibitory concentrations as well as time–kill assays. Ten clinical isolates of S. pyogenes, three of which were resistant to erythromycin, as well as one reference S. pyogenes strain were tested. In the time–kill assays, Oritavancin and the comparators vancomycin, teicoplanin, linezolid, penicillin, erythromycin and daptomycin were tested at static concentrations approximating their free peak (fCmax) and free trough (fCmin) concentrations in plasma when administered at approved doses for skin and skin-structure infections. At its fCmax predicted from a 200 mg dose in humans, Oritavancin exerted bactericidal activity (≥3 log kill relative to the starting inoculum) within 15 min to 3 h against all tested strains. Daptomycin exhibited bactericidal activity at its fCmax for all but one strain; time to cidality was between 15 min and 6 h. At fCmin, only Oritavancin was bactericidal against all the tested strains. Oritavancin displayed concentration-dependent killing of all isolates in vitro. Oritavancin was more rapidly bactericidal than the comparators at physiologically relevant concentrations against all strains tested. These data support the potential utility of Oritavancin in infections with contemporary isolates of S. pyogenes, including drug-resistant strains.
Rodrigo E Mendes - One of the best experts on this subject based on the ideXlab platform.
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antimicrobial activity of Oritavancin and comparator agents when tested against gram positive bacterial isolates causing infections in cancer patients 2014 16
Journal of Antimicrobial Chemotherapy, 2018Co-Authors: M A Pfaller, Robert K. Flamm, Helio S Sader, M Castanheira, Rodrigo E MendesAbstract:Objectives The in vitro activity of Oritavancin was assessed against clinically relevant Gram-positive pathogens causing infections in cancer patients in European and US hospitals. Methods A total of 1357 Gram-positive cocci (GPC) were included. Isolates were predominantly from bloodstream infections (54.6%). The most frequently isolated GPC were Staphylococcus aureus (43.6%), CoNS (14.4%) and Enterococcus spp. (22.0%). Results Oritavancin (99.8% susceptible) showed modal MIC, MIC50 and MIC90 results of 0.015, 0.015-0.03 and 0.06 mg/L, respectively, when tested against S. aureus, regardless of methicillin susceptibility or geographical region. CoNS isolates from the USA demonstrated an MIC90 of Oritavancin (MIC90, 0.12 mg/L) that was slightly higher than that for isolates from European countries (MIC90 0.06 mg/L). Oritavancin inhibited all Enterococcus faecalis and Enterococcus faecium, including VRE, at ≤ 0.25 mg/L. Oritavancin exhibited MIC50 results of 0.03 and 0.008-0.015 mg/L when tested against isolates of β-haemolytic streptococci and viridans group streptococci, respectively, regardless of geographical region. Conclusions Oritavancin had potent activity in vitro against this contemporary collection of European and US GPC isolates from cancer patients.
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Oritavancin in vitro activity against gram positive organisms from european and united states medical centers results from the sentry antimicrobial surveillance program for 2010 2014
Diagnostic Microbiology and Infectious Disease, 2018Co-Authors: M A Pfaller, Robert K. Flamm, Helio S Sader, M Castanheira, Rodrigo E MendesAbstract:Abstract The in vitro activity of Oritavancin was assessed against 44,715 gram-positive pathogens causing infections in European and United States (US) hospitals (2010-2014). There were no substantive differences (>±2-fold dilution) in Oritavancin MIC 50 or MIC 90 values for different species/organism groups over time or by region. Oritavancin (99.9% susceptible) showed modal MIC, MIC 50 and MIC 90 results of 0.03, 0.03 and 0.06-0.12 mg/L when tested against Staphylococcus aureus , regardless of methicillin susceptibility, year, or region. Coagulase-negative staphylococci from the US and Europe demonstrated equal MIC 50 values for Oritavancin (MIC 50 , 0.03 mg/L). Oritavancin inhibited 99.9% of E. faecalis and all E. faecium at ≤0.5 mg/L, including vancomycin-resistant isolates. Oritavancin exhibited MIC 50 results of 0.03 and ≤0.008 mg/L when tested against BHS and VGS isolates, respectively, regardless of geographical region. Oritavancin maintained potent activity in vitro against this contemporary collection of European and US gram-positive isolates over 5 years (2010-2014).
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Oritavancin in vitro activity against contemporary staphylococcus aureus isolates responsible for invasive community and healthcare associated infections among patients in the united states 2013 2014
Diagnostic Microbiology and Infectious Disease, 2016Co-Authors: Leonard R Duncan, Ronald N Jones, Helio S Sader, Robert K. Flamm, Rodrigo E MendesAbstract:Abstract Oritavancin has been approved in the United States and European Union for the treatment of acute bacterial skin and skin structure infections caused by several Gram-positive pathogens including Staphylococcus aureus . In this study, the in vitro activity of Oritavancin and comparator agents was assessed against 1008 isolates of contemporary invasive community- or healthcare-associated S. aureus (790 and 218 isolates, respectively). All sampled contemporary (2013–2014) S. aureus isolates were susceptible at ≤0.12μg/mL to Oritavancin (MIC 50/90 values, 0.03/0.06μg/mL), regardless of origin or susceptibility phenotype.
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Oritavancin Activity Tested against Molecularly Characterized Staphylococci and Enterococci Displaying Elevated Linezolid MIC Results.
Antimicrobial agents and chemotherapy, 2016Co-Authors: Rodrigo E Mendes, David J Farrell, Helio S Sader, Robert K. Flamm, Ronald N JonesAbstract:Oritavancin (MIC50/90, 0.03/0.06 to 0.12 μg/ml) had potent activity against linezolid-resistant staphylococci, as well as Enterococcus faecalis and Enterococcus faecium (Oritavancin MIC50/90, 0.015/0.12 μg/ml against both species). All linezolid-resistant isolates were inhibited by Oritavancin at ≤0.12 μg/ml. These results confirmed the absence of cross-resistance between linezolid and Oritavancin in staphylococci and enterococci.
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Results from Oritavancin Resistance Surveillance Programs (2011 to 2014): Clarification for Using Vancomycin as a Surrogate To Infer Oritavancin Susceptibility.
Antimicrobial agents and chemotherapy, 2016Co-Authors: Ronald N Jones, Francis F Arhin, Michael N. Dudley, Greg Moeck, Paul R. Rhomberg, Rodrigo E MendesAbstract:Measurement of vancomycin susceptibility has been shown to be highly predictive as a surrogate measure of Oritavancin susceptibility among clinically indicated Gram-positive species. Results of studying over 30,000 pathogens (from 2011 to 2014) by cross-susceptibility analysis and determining the poor reproducibility of Oritavancin-nonsusceptible results showed nearly perfect surrogate testing accuracy (99.86 to 99.94%). Any isolate of an indicated organism species with locally reproducible Oritavancin-nonsusceptible results (extremely rare) should be referred to a reference laboratory for confirmation of the results and determination of the resistance mechanism.
Adam Belley - One of the best experts on this subject based on the ideXlab platform.
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In vitro stepwise selection of reduced susceptibility to lipoglycopeptides in enterococci.
Diagnostic microbiology and infectious disease, 2017Co-Authors: Francis F Arhin, Adam Belley, David Lalonde Seguin, Gregory MoeckAbstract:Abstract 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 20days. 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.
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Effects of Oritavancin on Coagulation Tests in the Clinical Laboratory.
Antimicrobial agents and chemotherapy, 2017Co-Authors: Adam Belley, Gregory Moeck, Richard Robson, John L. Francis, Dorothy M. Adcock, Stefan Tiefenbacher, Christopher M. Rubino, David Sylvester, Michael N. Dudley, Jeffery LoutitAbstract:Previous studies have shown that some lipoglycopeptide and lipopeptide antimicrobial agents may cause falsely elevated values for some phospholipid-dependent coagulation tests. The effect of Oritavancin, a lipoglycopeptide antibiotic, on coagulation test results was explored using pooled human plasma samples spiked with drug and in a clinical study after an infusion of a single 1,200-mg intravenous dose of Oritavancin in normal healthy volunteers. Pooled plasma with Oritavancin added ex vivo showed concentration-dependent prolongation of prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), and dilute Russell viper venom time (DRVVT) test results. In contrast, Oritavancin had no effect on the activated protein C resistance assay, chromogenic anti-factor Xa assay (anti-FXa), thrombin time, and an immunoassay for the laboratory diagnosis of heparin-induced thrombocytopenia. In participants that received a single dose of Oritavancin, elevations in PT/INR result, aPTT, DRVVT, activated clotting time, and silica clotting time occurred, with the maximum times to resolution of test interference determined to be 12, 120, 72, 24, and 18 h, respectively. The anti-FXa assay was unaffected, whereas transient elevations in D dimer levels were observed in 30% of participants, with a maximum time to resolution of 72 h. Although Oritavancin has no impact on the coagulation system in vivo, a single dose of Oritavancin can produce falsely elevated values of some coagulation tests used to monitor hemostasis. The interference of Oritavancin on affected tests is transient, and the test results revert to normal ranges within specified times after dosing.
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1 Assessment of Oritavancin Serum Protein Binding across Species 1 2 Running title: Oritavancin Serum Protein Binding 3 4
2016Co-Authors: Francis F Arhin, Ingrid Sarmiento, Adam Belley, Geoffrey Mckay, Sylvain Beaulieu, R. Parr, Gregory MoeckAbstract:2 Biophysical methods to study the binding of Oritavancin, a lipoglycopeptide, to serum 23 protein are confounded by nonspecific drug adsorption to labware surfaces. We assessed 24 Oritavancin binding to serum from mouse, rat, dog and human by a microbiological growth-25 based method under conditions that allow near-quantitative drug recovery. Protein binding was 26 similar across species, ranging from 81.9 % in human serum to 87.1 % in dog serum. These 27 estimates support translation of Oritavancin exposure from nonclinical studies to humans.28 3 Estimates of serum protein binding are essential to translate drug exposure from nonclinical 29 species to humans during assessments of toxicology, pharmacokinetics, and pharmacodynamics 30 since the free fraction dictates drug activity (3, 17, 18). Recent evidence supports the concept of 31 an “active fraction ” that offers insight into the pharmacodynamic behavior of highly protein-32 bound drugs such as daptomycin (20). 33 Oritavancin is a late-stage investigational lipoglycopeptide under study for treatment of 34 serious gram-positive infections (6). Nonspecific binding of Oritavancin to labware surfaces (1,2) 3
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pharmacodynamics of a simulated single 1 200 milligram dose of Oritavancin in an in vitro pharmacokinetic pharmacodynamic model of methicillin resistant staphylococcus aureus infection
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Adam Belley, Francis F Arhin, Ingrid Sarmiento, Hong Deng, Warren E. Rose, Greg MoeckAbstract:The safety and efficacy of a single 1,200-mg dose of the lipoglycopeptide Oritavancin are currently being investigated in two global phase 3 studies of acute bacterial skin and skin structure infections. In this study, an in vitro pharmacokinetic/pharmacodynamic model was established to compare the free-drug pharmacodynamics associated with a single 1,200-mg dose of Oritavancin to once-daily dosing with daptomycin at 6 mg/kg of body weight and twice-daily dosing with vancomycin at 1,000 mg against three methicillin-resistant Staphylococcus aureus (MRSA) strains over 72 h. The area under the bacterial-kill curve (AUBKC) was used to assess the antibacterial effect of each dosing regimen at 24 h (AUBKC0-24), 48 h (AUBKC0-48), and 72 h (AUBKC0-72). The rapid bactericidal activities of Oritavancin and daptomycin contributed to lower AUBKC0-24s for the three MRSA strains than with vancomycin (P < 0.05, as determined by analysis of variance [ANOVA]). Oritavancin exposure also resulted in a lower AUBKC0-48 and AUBKC0-72 against one MRSA strain and a lower AUBKC0-48 for another strain than did vancomycin exposure (P < 0.05). Furthermore, daptomycin exposure resulted in a lower AUBKC0-48 and AUBKC0-72 for one of the MRSA isolates than did vancomycin exposure (P < 0.05). Lower AUBKC0-24s for two of the MRSA strains (P < 0.05) were obtained with Oritavancin exposure than with daptomycin. Thus, the antibacterial effect from the single-dose regimen of Oritavancin is as effective as that from either once-daily dosing with daptomycin or twice-daily dosing with vancomycin against the MRSA isolates tested in an in vitro pharmacokinetic/pharmacodynamic model over 72 h. These results provide further justification to assess the single 1,200-mg dose of Oritavancin for treatment of acute bacterial skin and skin structure infections.
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Assessment of Oritavancin Serum Protein Binding across Species
Antimicrobial agents and chemotherapy, 2010Co-Authors: Francis F Arhin, Ingrid Sarmiento, Adam Belley, Thomas R Parr, Geoffrey A Mckay, Sylvain Beaulieu, Gregory MoeckAbstract:Biophysical methods to study the binding of Oritavancin, a lipoglycopeptide, to serum protein are confounded by nonspecific drug adsorption to labware surfaces. We assessed Oritavancin binding to serum from mouse, rat, dog, and human by a microbiological growth-based method under conditions that allow near-quantitative drug recovery. Protein binding was similar across species, ranging from 81.9% in human serum to 87.1% in dog serum. These estimates support the translation of Oritavancin exposure from nonclinical studies to humans.