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Steven L Barriere - One of the best experts on this subject based on the ideXlab platform.
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assessment of Telavancin minimal inhibitory concentrations by revised broth microdilution method in phase 3 complicated skin and skin structure infection clinical trial isolates
Diagnostic Microbiology and Infectious Disease, 2017Co-Authors: Jennifer I Smart, Martin E Stryjewski, Ralph G Corey, Whedy Wang, Steven L BarriereAbstract:The broth microdilution (BMD) MIC testing method for Telavancin was recently revised BMD (rBMD) to improve accuracy and reproducibility. Staphylococcus aureus isolates from Telavancin phase 3 complicated skin and skin-structure infection (cSSSI) studies were tested using the rBMD method. Retesting of 1132 isolates produced MICs ranging from ≤0.015 to 0.12μg/mL that were 8-fold lower than the original method. All isolates tested remained susceptible to Telavancin at the revised susceptibility breakpoint of 0.12μg/mL. The clinical cure and microbiological eradication rates were 90% (368/409) and 89% (366/409) for Telavancin-treated patients, and were similar for patients with methicillin-susceptible and -resistant S. aureus isolates and S. aureus isolates with elevated vancomycin MICs (≥1μg/mL). The data presented here are aimed to update the literature and better inform clinicians and clinical microbiologists about the revised Telavancin MICs, as well as the corresponding clinical and microbiological cure rates for cSSSI patients.
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Pharmacokinetics of intravenous Telavancin in healthy subjects with varying degrees of renal impairment
European journal of clinical pharmacology, 2015Co-Authors: Philip Worboys, Shekman L Wong, Steven L BarriereAbstract:Purpose We evaluated the effect of renal impairment (RI) on the pharmacokinetics of Telavancin and hydroxypropylbetadex (excipient in the Telavancin drug product).
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Variability in Telavancin Cross-Reactivity among Vancomycin Immunoassays
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Kevin W. Mcconeghy, Siyun Liao, Douglas Clark, Philip Worboys, Steven L Barriere, Keith A RodvoldAbstract:Telavancin is a semisynthetic lipoglycopeptide with a dual mechanism of action against Gram-positive pathogens. Two brief reports have suggested potential cross-reactivity of Telavancin with the vancomycin particle-enhanced turbidometric immunoassay (PETIA). The purpose of this study was to evaluate several commercially available vancomycin immunoassays (fluorescence polarization [FPIA], enzyme-multiplied immunoassays [EMIT], PETIA, and chemiluminescent immunoassay [CMIA]) for cross-reactivity with Telavancin. Seven sites were selected to analyze serum samples for vancomycin. Each site received a set of samples (n = 18) which combined drug-free serum with Telavancin, 7-OH Telavancin metabolite, or vancomycin. Immunoassays demonstrating potential cross-reactivity were further evaluated by sending a duplicate sample set to multiple laboratories. Cross-reactivity was defined as the percent theoretical concentration (reported concentration/theoretical concentration × 100). No cross-reactivity was seen with FPIA or EMIT. Within the theoretical concentration range of 5 to 120 μg/ml of Telavancin, the Synchron PETIA system reported vancomycin concentrations ranging from 4.7 to 54.2 μg/ml compared to vancomycin concentrations from 1.1 to 5.6 μg/ml for the Vista PETIA system. The Architect CMIA system reported vancomycin concentrations in the range of 0.27 to 0.97 μg/ml, whereas Advia Centaur XP CMIA reported vancomycin concentrations between 1.6 and 31.6 μg/ml. The Architect CMIA immunoassay had the lowest percent cross-reactivity (0.8 to 5.4%), while the Synchron PETIA immunoassay demonstrated the highest percent cross-reactivity (45.2 to 53.8%). Telavancin samples measured by liquid chromatography-mass spectroscopy were within 93.9 to 122% of theoretical concentrations. Vancomycin concentrations were not measured in any 7-OH Telavancin-spiked sample. Vancomycin concentrations measured by liquid chromatography-mass spectroscopy were within 57.2 to 113% of theoretical concentrations. PETIA and CMIA measured vancomycin concentrations in Telavancin-spiked samples. Significant variability in percent cross-reactivity was observed for each platform regardless of immunoassay method.
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Analysis of Phase 3 Telavancin nosocomial pneumonia data excluding patients with severe renal impairment and acute renal failure
The Journal of antimicrobial chemotherapy, 2014Co-Authors: Antoni Torres, Martin E Stryjewski, Ethan Rubinstein, G. R. Corey, Steven L BarriereAbstract:Objectives: Telavancin is approved in Europe for the treatment of nosocomial pneumonia caused by methicillinresistant Staphylococcus aureus when other alternatives are not suitable. The approved European prescribing information contraindicates the use of Telavancin in patients with severe renal impairment (creatinine clearance ,30 mL/min, including patients on haemodialysis) and pre-existing acute renal failure owing to the higher observed mortality in these patients. Data from the ATTAIN studies were reanalysed, excluding patients with these contraindicating conditions at baseline. (At the time of submission of this article, the European marketing authorization of Telavancin for the treatment of nosocomial pneumonia was suspended pending evidence of a new European Medicines Agency-approved supplier. Clinigen Healthcare Ltd, Theravance’s commercialization partner for Telavancin in Europe, is in the process of seeking approval of a new manufacturing source.) Methods: A post hoc analysis of data from two Phase 3 ATTAIN trials of Telavancin for the treatment of Grampositive nosocomial pneumonia assessing clinical outcomes and safety. Results: The all-treated population for this analysis represented 84.2% (1266/1503) of the ATTAIN all-treated population. The cure rates in the clinically evaluable population were similar in the Telavancin (82.5%, 231/280) and vancomycin (81.3%, 243/299) groups [treatment difference (95% CI): 1.3% (25.0% to 7.6%)], and were consistent with the overall ATTAIN study results. The cure rate was higher in the Telavancin than the vancomycin treatment group in microbiologically evaluable patients with only Gram-positive pathogens isolated at baseline [85.0% (130/153) versus 75.2% (109/145), respectively; treatment difference (95% CI): 9.7% (0.6%–18.8%)]. The incidences of adverse events were similar between treatment groups and consistent with the overall findings of the ATTAIN study. Conclusions: This analysis demonstrated that in the subset of patients without severe renal impairment or pre-existing acute renal failure, clinical and safety outcomes were similar in the Telavancin and vancomycin treatment groups.
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Impact of Telavancin on prothrombin time and activated partial thromboplastin time as determined using point-of-care coagulometers.
Journal of thrombosis and thrombolysis, 2013Co-Authors: Mike Ero, James W. Janc, Nathaniel R. Harvey, Jack L. Harbert, Kay H. Chin, Steven L BarriereAbstract:Telavancin is approved in the United States, Canada, and Europe (At the time of submission, the Telavancin European marketing authorization for nosocomial pneumonia was suspended until Theravance provides evidence of a new European Medicines Agency approved supplier) as an antibiotic to treat certain Gram-positive bacterial skin infections. Telavancin has been shown to prolong plasmatic prothrombin (PT) and activated partial thromboplastin (aPTT) clotting times in clinical diagnostic lab-based assays. In this study, we evaluated the potential for Telavancin to prolong whole blood PT/International Normalized Ratio (INR) and aPTT tests on point-of-care (POC) instruments. Whole blood collected from 8 healthy subjects was supplemented with Telavancin to final concentrations of 0, 10, 20, and 100 μg/ml. Final concentrations were selected to match trough, twice trough, and peak plasma levels following the approved 10 mg/kg dose. Four widely employed POC coagulation instruments were chosen to be representative of the POC platforms currently in use.. These systems were the Roche Coaguchek XS, the Abbott iSTAT, the ITC Hemochron SIG+, and the Alere INRatio2 POC devices. The PT/INR measured by the Coaguchek XS showed the greatest sensitivity to the presence of Telavancin. The PT/INR measured by the Hemochron SIG+ and iSTAT were sensitive to Telavancin but to a lesser extent. The INRatio2 was the least sensitive to the presence of Telavancin when testing the whole blood PT/INR. Only the Hemochron SIG+ device was capable of measuring aPTT and showed a concentration-dependent increase in aPTT. This study supports the current recommendation that PT and aPTT monitoring be conducted immediately to the next dose of Telavancin when coagulation parameters are tested using POC instrumentation.
Michael J Rybak - One of the best experts on this subject based on the ideXlab platform.
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2009. Activity of Telavancin against staphylococcus aureus strains with various vancomycin susceptibilities in an in vitro pharmacokinetic/pharmacodynamic model with simulated endocardial vegetations. Antimicrob. Agents Chemother
2016Co-Authors: Steven N. Leonard, Michael J RybakAbstract:We investigated the activity of Telavancin, a novel lipoglycopeptide, alone and combined with gentamicin or rifampin (rifampicin) against strains of Staphylococcus aureus with various vancomycin susceptibilities. Strains tested included methicillin (meticillin)-resistant S. aureus (MRSA) 494, methicillin-sensitive S. aureus (MSSA) 1199, heteroresistant glycopeptide-intermediate S. aureus (hGISA) 1629, which was confirmed by a population analysis profile, and glycopeptide-intermediate S. aureus (GISA) NJ 992. Regimens of 10 mg/kg Telavancin daily and 1 g vancomycin every 12 h were investigated alone and combined with 5 mg/kg gentamicin daily or 300 mg rifampin every 8 h in an in vitro model with simulated endocardial vegetations over 96 h. Telavancin demonstrated significantly greater killing than did vancomycin (P < 0.01) for all isolates except MRSA 494 (P 0.07). Telavancin absolute reductions, in log10 CFU/g, at 96 h were 2.8 0.5 for MRSA 494, 2.8 0.3 for MSSA 1199, 4.2 0.2 for hGISA 1629, and 4.1 0.3 for GISA NJ 992. Combinations of Telavancin with gentamicin significantly enhanced killing compared to Telavancin alone against all isolates (P < 0.001) except MRSA 494 (P 0.176). This enhancement was most evident against hGISA 1629, where killing to the level of detection (2 log10 CFU/g) was achieved at 48 h (P < 0.001). The addition of rifampin to Telavancin resulted in significant (P < 0.001) enhancement of killing against only MSSA 1199. No changes in Telavancin suscepti-bilities were observed. These results suggest that Telavancin may have therapeutic potential, especially agains
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activity of Telavancin against staphylococcus aureus strains with various vancomycin susceptibilities in an in vitro pharmacokinetic pharmacodynamic model with simulated endocardial vegetations
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Michael J Rybak, Steven N. Leonard, Celine VidaillacAbstract:We investigated the activity of Telavancin, a novel lipoglycopeptide, alone and combined with gentamicin or rifampin (rifampicin) against strains of Staphylococcus aureus with various vancomycin susceptibilities. Strains tested included methicillin (meticillin)-resistant S. aureus (MRSA) 494, methicillin-sensitive S. aureus (MSSA) 1199, heteroresistant glycopeptide-intermediate S. aureus (hGISA) 1629, which was confirmed by a population analysis profile, and glycopeptide-intermediate S. aureus (GISA) NJ 992. Regimens of 10 mg/kg Telavancin daily and 1 g vancomycin every 12 h were investigated alone and combined with 5 mg/kg gentamicin daily or 300 mg rifampin every 8 h in an in vitro model with simulated endocardial vegetations over 96 h. Telavancin demonstrated significantly greater killing than did vancomycin (P < 0.01) for all isolates except MRSA 494 (P = 0.07). Telavancin absolute reductions, in log10 CFU/g, at 96 h were 2.8 ± 0.5 for MRSA 494, 2.8 ± 0.3 for MSSA 1199, 4.2 ± 0.2 for hGISA 1629, and 4.1 ± 0.3 for GISA NJ 992. Combinations of Telavancin with gentamicin significantly enhanced killing compared to Telavancin alone against all isolates (P < 0.001) except MRSA 494 (P = 0.176). This enhancement was most evident against hGISA 1629, where killing to the level of detection (2 log10 CFU/g) was achieved at 48 h (P < 0.001). The addition of rifampin to Telavancin resulted in significant (P < 0.001) enhancement of killing against only MSSA 1199. No changes in Telavancin susceptibilities were observed. These results suggest that Telavancin may have therapeutic potential, especially against strains with reduced susceptibility to vancomycin. Combination therapy, particularly with gentamicin, may improve bacterial killing against certain strains.
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comparative activity of the new lipoglycopeptide Telavancin in the presence and absence of serum against 50 glycopeptide non susceptible staphylococci and three vancomycin resistant staphylococcus aureus
Journal of Antimicrobial Chemotherapy, 2006Co-Authors: Kimberly D Leuthner, Michael J Rybak, Chrissy M CheungAbstract:Background: Telavancin, a new multifunctional lipoglycopeptide antibiotic, exhibits broad-spectrum Gram-positive activity against a variety of pathogens. We examined the effects of human serum and antimicrobial concentrations on the activity of Telavancin against glycopeptide-intermediate staphylococcal species (GISS), heteroresistant GISS (hGISS) and three vancomycin-resistant Staphylococcus aureus (VRSA) compared with vancomycin, quinupristin/dalfopristin, linezolid and daptomycin. Methods:MICandMBCswereperformedagainstallantimicrobials.Time–killexperimentswereperformed usingtwostrainsofGISS(Mu50;NJ992)andVRSA(VRSAMI;VRSAPA)at1,2,4,8,16and32·MIC.Telavancin and daptomycin were evaluated in the presence and absence of serum. Results: All GISS and hGISS were susceptible to the tested agents with Telavancin and quinupristin/ dalfopristin demonstrating the lowest MIC, followed by daptomycin, linezolid and vancomycin. Against VRSA, daptomycin and quinupristin/dalfopristin had the lowest MIC, followed by linezolid, Telavancin and vancomycin. In the presence of serum, Telavancin and daptomycin MICs increased 1- to 4-fold. Concentration-dependent activity was demonstrated by Telavancin and daptomycin, in the presence and absence of serum. Telavancin and daptomycin were bactericidal against GISS and performed similarly in the presence of serum. Quinupristin/dalfopristin demonstrated bactericidal activity at clinically achievable concentrations, whereas linezolid was bacteriostatic. Conclusions:Telavancindemonstratedconcentration-dependentbactericidalactivityagainstGISS,hGISS andVRSAatconcentrationsequaltoorabove4·MIC,whichcorrespondstotherapeuticlevelsagainstGISS and clinically achieved concentrations against the VRSA. Similar to daptomycin, Telavancin activity was diminished in the presence of serum but bactericidal activity was maintained. Further investigation with Telavancin against GISS, hGISS and VRSA is warranted.
Steven N. Leonard - One of the best experts on this subject based on the ideXlab platform.
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2009. Activity of Telavancin against staphylococcus aureus strains with various vancomycin susceptibilities in an in vitro pharmacokinetic/pharmacodynamic model with simulated endocardial vegetations. Antimicrob. Agents Chemother
2016Co-Authors: Steven N. Leonard, Michael J RybakAbstract:We investigated the activity of Telavancin, a novel lipoglycopeptide, alone and combined with gentamicin or rifampin (rifampicin) against strains of Staphylococcus aureus with various vancomycin susceptibilities. Strains tested included methicillin (meticillin)-resistant S. aureus (MRSA) 494, methicillin-sensitive S. aureus (MSSA) 1199, heteroresistant glycopeptide-intermediate S. aureus (hGISA) 1629, which was confirmed by a population analysis profile, and glycopeptide-intermediate S. aureus (GISA) NJ 992. Regimens of 10 mg/kg Telavancin daily and 1 g vancomycin every 12 h were investigated alone and combined with 5 mg/kg gentamicin daily or 300 mg rifampin every 8 h in an in vitro model with simulated endocardial vegetations over 96 h. Telavancin demonstrated significantly greater killing than did vancomycin (P < 0.01) for all isolates except MRSA 494 (P 0.07). Telavancin absolute reductions, in log10 CFU/g, at 96 h were 2.8 0.5 for MRSA 494, 2.8 0.3 for MSSA 1199, 4.2 0.2 for hGISA 1629, and 4.1 0.3 for GISA NJ 992. Combinations of Telavancin with gentamicin significantly enhanced killing compared to Telavancin alone against all isolates (P < 0.001) except MRSA 494 (P 0.176). This enhancement was most evident against hGISA 1629, where killing to the level of detection (2 log10 CFU/g) was achieved at 48 h (P < 0.001). The addition of rifampin to Telavancin resulted in significant (P < 0.001) enhancement of killing against only MSSA 1199. No changes in Telavancin suscepti-bilities were observed. These results suggest that Telavancin may have therapeutic potential, especially agains
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Comparative Activities of Telavancin Combined with Nafcillin, Imipenem, and Gentamicin against Staphylococcus aureus
Antimicrobial agents and chemotherapy, 2013Co-Authors: Steven N. Leonard, Megan E. Supple, Ronak G. Gandhi, Meghna D. PatelAbstract:Beta-lactams enhance the killing activity of vancomycin. Due to structural and mechanistic similarities between vancomycin and Telavancin, we investigated the activity of Telavancin combined with nafcillin and imipenem compared to the known synergistic combination of Telavancin and gentamicin. Thirty strains of Staphylococcus aureus, 10 methicillin-susceptible S. aureus (MSSA), 10 methicillin-resistant S. aureus (MRSA), and 10 heterogeneously vancomycin-intermediate S. aureus (hVISA), were tested for synergy by time-kill methodology. Six strains (2 each of MSSA, MRSA, and hVISA) were further evaluated in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with simulated regimens of 10 mg/kg of body weight of Telavancin once daily alone and combined with 2 g nafcillin every 4 h, 500 mg imipenem every 6 h, or 5 mg/kg gentamicin once daily over 72 h. In the synergy test, 67% of strains displayed synergy with the combination of Telavancin and gentamicin, 70% with Telavancin and nafcillin, and 63% with Telavancin and imipenem. In the PK/PD model, the activities of all three combinations against MRSA and hVISA were superior to all individual drugs alone (P ≤ 0.002) and were similar to each other (P ≥ 0.187). The activities of all three combinations against MSSA were generally similar to each other except for one strain where the combination of Telavancin and imipenem was superior to all other regimens (P ≤ 0.011). The activity of the combination of Telavancin and beta-lactam agents was similar to that of Telavancin and gentamicin against S. aureus, including resistant strains. Because beta-lactam combinations are less likely to be nephrotoxic than Telavancin plus gentamicin, these beta-lactam combinations may have clinical utility.
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comparative in vitro activity of Telavancin vancomycin and linezolid against heterogeneously vancomycin intermediate staphylococcus aureus hvisa
International Journal of Antimicrobial Agents, 2011Co-Authors: Steven N. Leonard, Yong G Szeto, Maria Zolotarev, Ilona V GrigoryanAbstract:Abstract Selective pressure from glycopeptide use has led to non-susceptible strains of Staphylococcus aureus , including heterogeneously vancomycin-intermediate S. aureus (hVISA). Treatment of hVISA infections with vancomycin has been associated with treatment failure, therefore new treatments are required. The objective of this study was to evaluate the activity of Telavancin, vancomycin and linezolid against hVISA clinical strains. Twenty-five hVISA isolates were evaluated for minimum inhibitory concentrations (MICs) by microdilution and for bactericidal activity by time–kill analysis [starting inoculum ca. 10 6 colony-forming units (CFU)/mL and ca. 10 8 CFU/mL] against Telavancin, vancomycin and linezolid. MICs for 50% and 90% of the organisms (MIC 50 and MIC 90 values, respectively) were, respectively, 0.5mg/L and 1mg/L for Telavancin and 2mg/L and 2mg/L for both vancomycin and linezolid. In time–kill studies, Telavancin was bactericidal against all strains at plasma peak and trough concentrations and at low and high inocula. At low inoculum, the time to bactericidal activity (defined as 99.9% kill from initial inoculum) ( T 99.9 ) for Telavancin was 5.6±3.2h at peak concentration and 12.3±5.2h at trough concentration. This was superior to vancomycin ( P T 99.9 of 18.8±2.1h at peak concentration and 19.1±2.2h at trough concentration. At high inoculum, Telavancin had a T 99.9 of 16.3±3.2h at peak concentration and 21.4±2.5h at trough concentration, whilst vancomycin did not consistently achieve bactericidal activity. Linezolid was not bactericidal against any strain at either concentration or inoculum. In conclusion, the killing activity of Telavancin against hVISA was found to be superior to vancomycin and linezolid.
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activity of Telavancin against staphylococcus aureus strains with various vancomycin susceptibilities in an in vitro pharmacokinetic pharmacodynamic model with simulated endocardial vegetations
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Michael J Rybak, Steven N. Leonard, Celine VidaillacAbstract:We investigated the activity of Telavancin, a novel lipoglycopeptide, alone and combined with gentamicin or rifampin (rifampicin) against strains of Staphylococcus aureus with various vancomycin susceptibilities. Strains tested included methicillin (meticillin)-resistant S. aureus (MRSA) 494, methicillin-sensitive S. aureus (MSSA) 1199, heteroresistant glycopeptide-intermediate S. aureus (hGISA) 1629, which was confirmed by a population analysis profile, and glycopeptide-intermediate S. aureus (GISA) NJ 992. Regimens of 10 mg/kg Telavancin daily and 1 g vancomycin every 12 h were investigated alone and combined with 5 mg/kg gentamicin daily or 300 mg rifampin every 8 h in an in vitro model with simulated endocardial vegetations over 96 h. Telavancin demonstrated significantly greater killing than did vancomycin (P < 0.01) for all isolates except MRSA 494 (P = 0.07). Telavancin absolute reductions, in log10 CFU/g, at 96 h were 2.8 ± 0.5 for MRSA 494, 2.8 ± 0.3 for MSSA 1199, 4.2 ± 0.2 for hGISA 1629, and 4.1 ± 0.3 for GISA NJ 992. Combinations of Telavancin with gentamicin significantly enhanced killing compared to Telavancin alone against all isolates (P < 0.001) except MRSA 494 (P = 0.176). This enhancement was most evident against hGISA 1629, where killing to the level of detection (2 log10 CFU/g) was achieved at 48 h (P < 0.001). The addition of rifampin to Telavancin resulted in significant (P < 0.001) enhancement of killing against only MSSA 1199. No changes in Telavancin susceptibilities were observed. These results suggest that Telavancin may have therapeutic potential, especially against strains with reduced susceptibility to vancomycin. Combination therapy, particularly with gentamicin, may improve bacterial killing against certain strains.
Ronald N. Jones - One of the best experts on this subject based on the ideXlab platform.
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activity of Telavancin against gram positive pathogens isolated from bone and joint infections in north american latin american european and asia pacific nations
Diagnostic Microbiology and Infectious Disease, 2017Co-Authors: Ronald N. Jones, Helio S. Sader, Robert K Flamm, Mariana Castanheira, Jennifer I Smart, Rodrigo E. MendesAbstract:Telavancin was tested against a worldwide collection of Gram-positive pathogens (967) isolated from bone and joint infections (BJI). Most BJI isolates were from the United States (US) (49.9%) followed by Europe (26.4%), Latin America (LATAM; 14.4%), and Asia-Pacific (APAC; 9.3%). Organisms were tested by broth microdilution susceptibility methods. S. aureus (66.4%; range of 48.9% in APAC to 71.2% in LATAM) was the most common pathogen and had a 35.7% methicillin resistance (MRSA) rate and Telavancin MIC50/90 of 0.03/0.06μg/mL (100% susceptible). MRSA isolates that were daptomycin resistant (0.2%) were Telavancin susceptible. CoNS (12.1% of BJI) had Telavancin MIC50/90 at 0.06/0.06μg/mL, and 13.7% were teicoplanin resistant. Enterococci had Telavancin MIC50/90 at 0.12/0.25μg/mL, but Telavancin inhibited vancomycin-susceptible isolates at ≤0.25μg/mL. All streptococci were Telavancin susceptible (MIC90, 0.03-0.06μg/mL). The in vitro results presented here warrant further investigations to access the role of Telavancin for BJI/osteomyelitis treatment caused by Gram-positive cocci.
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Baseline Activity of Telavancin against Gram-Positive Clinical Isolates Responsible for Documented Infections in U.S. Hospitals (2011-2012) as Determined by the Revised Susceptibility Testing Method
2016Co-Authors: Rodrigo E. Mendes, David J. Farrell, Helio S. Sader, Robert K Flamm, Ronald N. JonesAbstract:Telavancin hadMIC50 andMIC90 values of 0.03 and 0.06g/ml (100.0 % susceptible), respectively, against methicillin-resistant and-susceptible Staphylococcus aureus. Telavancin was active against vancomycin-susceptible Enterococcus faecalis (MIC50/90, 0.12/0.12g/ml; 100 % susceptible) and Enterococcus faecium (MIC50/90, 0.03/0.06g/ml), while higher MIC values were ob-tained against vancomycin-resistant E. faecium (MIC50/90, 1/2 g/ml) and E. faecalis (MIC50/90,>2/>2 g/ml). Streptococci showed Telavancin modal MIC results of<0.015g/ml, except against Streptococcus agalactiae (i.e., 0.03g/ml). This study reestablishes the Telavancin spectrum of activity against isolates recovered from the United States (2011-2012) using the revised broth microdilutionmethod. Telavancin is a once-daily parenteral semisynthetic lipoglyco-peptide agent approved in the United States and Canada for the treatment of adult patients with complicated skin and skin structure infections (cSSSI) caused by susceptible Gram-positive pathogens. Telavancin was also approved in the United States and Europe for the treatment of adult patients with hospital-acquired bacterial pneumonia, including ventilator-associated bacterial pneumonia (HABP/VABP) due to susceptible isolates of Staphy-lococcus aureus (methicillin-resistant S. aureus [MRSA] strain
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Telavancin activity tested against gram positive clinical isolates from european russian and israeli hospitals 2011 2013 using a revised broth microdilution testing method redefining the baseline activity of Telavancin
Journal of Chemotherapy, 2016Co-Authors: Rodrigo E. Mendes, David J. Farrell, Helio S. Sader, Robert K Flamm, Ronald N. JonesAbstract:Objectives: To reassess the activity of Telavancin when tested against Gram-positive clinical pathogens recovered from hospitalized patients in European and adjacent regions using a revised broth microdilution method.Methods: 11 601 consecutive, non-duplicate isolates originating from 36 institutions among 18 countries recovered between 2011 and 2013 were tested for susceptibility using a revised broth microdilution method for Telavancin. Interpretive Telavancin breakpoints appropriate for the method were those recently approved by the FDA and EUCAST, as available.Results: Telavancin (MIC50/90, 0.03/0.06 mg/l; 100.0% susceptible) was equally potent against methicillin-susceptible ((MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus. All Enterococcus faecalis was susceptible to Telavancin (MIC50/90, 0.12/0.12 mg/l) and inhibited at the susceptibility breakpoint (i.e. ≤ 0.25 mg/l), except for VanA-phenotype vancomycin-resistant isolates (Telavancin MIC, >1 mg/l). Telavancin ( ≤ 0.015/0.03 mg/l) wa...
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Telavancin activity tested against Gram-positive clinical isolates from European, Russian and Israeli hospitals (2011–2013) using a revised broth microdilution testing method: redefining the baseline activity of Telavancin
Journal of chemotherapy (Florence Italy), 2016Co-Authors: Rodrigo E. Mendes, David J. Farrell, Helio S. Sader, Robert K Flamm, Ronald N. JonesAbstract:Objectives: To reassess the activity of Telavancin when tested against Gram-positive clinical pathogens recovered from hospitalized patients in European and adjacent regions using a revised broth microdilution method.Methods: 11 601 consecutive, non-duplicate isolates originating from 36 institutions among 18 countries recovered between 2011 and 2013 were tested for susceptibility using a revised broth microdilution method for Telavancin. Interpretive Telavancin breakpoints appropriate for the method were those recently approved by the FDA and EUCAST, as available.Results: Telavancin (MIC50/90, 0.03/0.06 mg/l; 100.0% susceptible) was equally potent against methicillin-susceptible ((MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus. All Enterococcus faecalis was susceptible to Telavancin (MIC50/90, 0.12/0.12 mg/l) and inhibited at the susceptibility breakpoint (i.e. ≤ 0.25 mg/l), except for VanA-phenotype vancomycin-resistant isolates (Telavancin MIC, >1 mg/l). Telavancin ( ≤ 0.015/0.03 mg/l) wa...
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Analysis of Vancomycin Susceptibility Testing Results for Presumptive Categorization of Telavancin
Journal of clinical microbiology, 2015Co-Authors: Rodrigo E. Mendes, David J. Farrell, Helio S. Sader, Robert K Flamm, Ronald N. JonesAbstract:Scattergrams between vancomycin and Telavancin demonstrated susceptibility agreement rates of 99.96, 99.65, and 100.00% for Staphylococcus aureus, Enterococcus faecalis, and streptococci, respectively. A single very major error was obtained against E. faecalis, while vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant and teicoplanin-susceptible (VanB phenotype) E. faecalis were responsible for major and minor errors. These results support the use of vancomycin to infer Telavancin susceptibility among indicated pathogens, except VISA, which should be tested for Telavancin susceptibility.
Bret M Benton - One of the best experts on this subject based on the ideXlab platform.
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In vitro activity of Telavancin and comparator antimicrobial agents against a panel of genetically defined staphylococci
Diagnostic microbiology and infectious disease, 2011Co-Authors: David J. Farrell, Kevin M Krause, Bret M BentonAbstract:Abstract The in vitro activity of Telavancin was determined for 94 diverse Staphylococcus spp. Telavancin had MIC 90 values of 0.5 μg/mL for methicillin-susceptible, methicillin-resistant, and vancomycin-susceptible Staphylococcus aureus , and coagulase-negative staphylococci isolates. Telavancin MICs were 0.5–1 μg/mL for vancomycin-intermediate S. aureus isolates and 2–4 μg/mL for vancomycin-resistant S. aureus strains.
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Specificity of induction of the vanA and vanB operons in vancomycin-resistant enterococci by Telavancin.
Antimicrobial agents and chemotherapy, 2010Co-Authors: Craig M. Hill, Mathai Mammen, Patrick P Humphrey, Bret M Benton, Kevin M Krause, Stacey R. Lewis, Johanne Blais, Alfred Dieudonné Kinana, James W. JancAbstract:Telavancin is a bactericidal, semisynthetic lipoglycopeptide indicated in the United States for the treatment of complicated skin and skin structure infections caused by susceptible gram-positive bacteria and is under investigation as a once-daily treatment for nosocomial pneumonia. The related vanA and vanB gene clusters mediate acquired resistance to glycopeptides in enterococci by remodeling the dipeptide termini of peptidoglycan precursors from D-alanyl-D-alanine (D-Ala-D-Ala) to D-alanyl-D-lactate (D-Ala-D-Lac). In this study, we assessed the ability of Telavancin to induce the expression of van genes in VanA- and VanB-type strains of vancomycin-resistant enterococci. Vancomycin, teicoplanin, and Telavancin efficiently induced VanX activity in VanA-type strains, while VanX activity in VanB-type isolates was inducible by vancomycin but not by teicoplanin or Telavancin. In VanA-type strains treated with vancomycin or Telavancin, high levels of D-Ala-D-Lac-containing pentadepsipeptide were measured, while D-Ala-D-Ala pentapeptide was present at very low levels or not detected at all. In VanB-type strains, vancomycin but not Telavancin induced high levels of pentadepsipeptide, while pentapeptide was not detected. Although vancomycin, teicoplanin, and Telavancin induced similar levels of VanX activity in VanA-type strains, these organisms were more sensitive to Telavancin, which displayed MIC values that were 32- and 128-fold lower than those of vancomycin and teicoplanin, respectively.
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activity of Telavancin against heterogeneous vancomycin intermediate staphylococcus aureus hvisa in vitro and in an in vivo mouse model of bacteraemia
Journal of Antimicrobial Chemotherapy, 2010Co-Authors: Sharath S. Hegde, Kevin M Krause, Robert A. Skinner, Stacey R. Lewis, Johanne Blais, Bret M BentonAbstract:Received 19 November 2009; returned 20 December 2009; revised 11 January 2010; accepted 13 January 2010 Objectives: Infections caused by heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) are associated with high rates of vancomycin treatment failure. Telavancin is a bactericidal lipoglycopeptide active in vitro against Gram-positive pathogens including hVISA and vancomycin-intermediate S. aureus (VISA). This study characterizes the microbiological activity of Telavancin against vancomycin-susceptible S. aureus (VSSA), hVISA and VISA strains. Methods: Reference strains of VSSA, hVISA and VISA were assessed for potential Telavancin heteroresistance by population analysis. In addition, the efficacies of Telavancin (40 mg/kg subcutaneously every 12 h for 4 days) and vancomycin (110 mg/kg subcutaneously every 12 h for 8 days) were compared in a neutropenic murine model (immunocompromised female non-Swiss albino mice) of bacteraemia caused by hVISA strain Mu3. Blood and spleen bacterial titres were quantified from cohorts of mice euthanized pre-treatment and at 24 h intervals post-treatment for 8 days. Results: Telavancin was active against all strains of S. aureus tested, with MIC values � 0.5 mg/L. Population analyses revealed no evidence of subpopulations with reduced susceptibility to Telavancin. In the murine bacteraemia model of hVISA infection, all animals were bacteraemic pre-treatment and mortality was 100% within 16‐24 h post-infection in untreated animals. Treatment with Telavancin was associated with lower spleen bacterial titres, lower rates of bacteraemia and lower overall mortality than treatment with vancomycin. Conclusions: These in vitro and pre-clinical in vivo studies demonstrate that Telavancin has the potential to be efficacious in infections caused by hVISA.
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Fluorescence Microscopy Demonstrates Enhanced Targeting of Telavancin to the Division Septum of Staphylococcus aureus
Antimicrobial agents and chemotherapy, 2010Co-Authors: Christopher S Lunde, Stephanie R Hartouni, Charles H. Rexer, Sabine Axt, Bret M BentonAbstract:The cellular binding patterns of fluorescent conjugates of Telavancin and vancomycin were evaluated in Staphylococcus aureus by fluorescence microscopy and ratio imaging analysis. Telavancin showed enhanced binding at the division septum compared to vancomycin. This result is consistent with observations that Telavancin binds with higher affinity to lipid II than to d-Ala-d-Ala residues in the cell wall, thus demonstrating the preferential binding of Telavancin to the site of active cell wall biosynthesis.
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Telavancin disrupts the functional integrity of the bacterial membrane through targeted interaction with the cell wall precursor lipid ii
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Christopher S Lunde, Stephanie R Hartouni, Mathai Mammen, Patrick P Humphrey, James W. Janc, Bret M BentonAbstract:Telavancin is an investigational lipoglycopeptide antibiotic currently being developed for the treatment of serious infections caused by gram-positive bacteria. The bactericidal action of Telavancin results from a mechanism that combines the inhibition of cell wall synthesis and the disruption of membrane barrier function. The purpose of the present study was to further elucidate the mechanism by which Telavancin interacts with the bacterial membrane. A flow cytometry assay with the diethyloxacarbocyanine dye DiOC(2)(3) was used to probe the membrane potential of actively growing Staphylococcus aureus cultures. Telavancin caused pronounced membrane depolarization that was both time and concentration dependent. Membrane depolarization was demonstrated against a reference S. aureus strain as well as phenotypically diverse isolates expressing clinically important methicillin-resistant (MRSA), vancomycin-intermediate (VISA), and heterogeneous VISA (hVISA) phenotypes. The cell wall precursor lipid II was shown to play an essential role in Telavancin-induced depolarization. This was demonstrated both in competition binding experiments with exogenous D-Ala-D-Ala-containing ligand and in experiments with cells expressing altered levels of lipid II. Finally, monitoring of the optical density of S. aureus cultures exposed to Telavancin showed that cell lysis does not occur during the time course in which membrane depolarization and bactericidal activity are observed. Taken together, these data indicate that Telavancin's membrane mechanism requires interaction with lipid II, a high-affinity target that mediates binding to the bacterial membrane. The targeted interaction with lipid II and the consequent disruption of both peptidoglycan synthesis and membrane barrier function provide a mechanistic basis for the improved antibacterial properties of Telavancin relative to those of vancomycin.
