90 results on '"Moeck, G."'
Search Results
2. New osteotropic prodrugs prevent bone infection in a rat model of osteomyelitis: O337
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Lehoux, D., Ostiguy, V., Fadhil, I., Laquerre, K., Tanaka, K. S.E., Kang, T., Lafontaine, Y., Houghton, T. J., Reddy, R., Moeck, G., Far, A. Rafai, and Parr, T. R., Jr.
- Published
- 2008
3. Glycopeptides and Lipoglycopeptides.
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Arhin, F. F., Belley, A., Far, A. Rafai, Lehoux, D., Moeck, G., and Parr Jr., T. R.
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- 2012
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4. 252 Efficacy Outcomes by Lesion Type in Studies of a Single Dose of Oritavancin Compared to 7 to 10 Days of Vancomycin
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Pollack, C.V., Jr., Corey, G.R., Good, S., Jiang, H., Moeck, G., and Wikler, M.W.
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- 2014
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5. 99 A Single Dose of Oritavancin Compared to 7 to 10 Days of Vancomycin: Lesion Size Reduction in Phase 3 Studies of Acute Bacterial Skin and Skin Infections
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Pollack, C.V., Jr., Corey, G.R., Good, S., Jiang, H., Moeck, G., and Wikler, M.W.
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- 2014
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6. Oritavancin does not induce Clostridium difficile germination and toxin production in hamsters or a human gut model.
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Freeman J, Marquis M, Crowther GS, Todhunter SL, Fawley WN, Chilton CH, Moeck G, Lehoux D, and Wilcox MH
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- 2012
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7. Cefepime-Taniborbactam in Complicated Urinary Tract Infection.
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Wagenlehner, Florian M., McGovern, Paul C., and Moeck, G. reg
- Subjects
- *
URINARY tract infections - Abstract
The article focuses on comparing the efficacy of cefepime-taniborbactam with meropenem for treating complicated urinary tract infections, indicating superior clinical success with cefepime-taniborbactam. Concerns are raised regarding unbalanced dosing between the drugs, the exclusion of certain bacterial strains, and the choice of comparator, which may affect the trial's interpretation and applicability to current treatment guidelines.
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- 2024
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8. Construction of umu-fhuA operation fusions to detect genotoxic potential by an antibody-cell surface reaction
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Hartmann, A., Schloter, M., Stubner, S., Moeck, G. S., Coulton, J. W., and Ahne, F.
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ESCHERICHIA coli ,IMMUNOGLOBULINS - Published
- 1994
9. P1781 Efficacy of oritavancin in a mouse model of Streptococcus pneumoniae pneumonia
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Lehoux, D., McKay, G., Fadhil, I., Laquerre, K., Malouin, M., Ostiguy, V., Moeck, G., and Parr, T.
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- 2007
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10. P1112 Effect of polysorbate 80 on oritavancin binding to plastic surfaces-implications for susceptibility testing
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Arhin, F.F., Sarmiento, I., Parr, T.J., and Moeck, G.
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- 2007
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11. P827 Infiuence of polysorbate 80 on susceptibility of Gram-positive bacteria to oritavancin
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Arhin, F.F., Sarmiento, I., Belley, A., McKay, G., Draghi, D., Grover, P., Sahm, D., Parr, T.J., and Moeck, G.
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- 2007
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12. Cefepime-taniborbactam demonstrates potent in vitro activity vs Enterobacterales with bla OXA-48 .
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Mojica MF, Zeiser ET, Becka SA, Six DA, Moeck G, and Papp-Wallace KM
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- Humans, Drug Combinations, beta-Lactamase Inhibitors pharmacology, Azabicyclo Compounds pharmacology, Boronic Acids pharmacology, Enterobacteriaceae drug effects, Enterobacteriaceae enzymology, Ceftazidime pharmacology, Bacterial Proteins genetics, Bacterial Proteins metabolism, Meropenem pharmacology, Enterobacteriaceae Infections microbiology, Enterobacteriaceae Infections drug therapy, Borinic Acids, Carboxylic Acids, Escherichia coli Proteins, Cefepime pharmacology, Microbial Sensitivity Tests, Anti-Bacterial Agents pharmacology, beta-Lactamases metabolism, beta-Lactamases genetics
- Abstract
Taniborbactam (formerly VNRX-5133) is a novel, investigational boronic acid β-lactamase inhibitor. The combination of cefepime (FEP) with taniborbactam is active against Enterobacterales carrying class A, B, C, and/or D enzymes. We assessed the activity of FEP-taniborbactam against Enterobacterales clinical strains carrying bla
OXA-48 ( N = 50, 100%), of which 78% harbored at least one extended-spectrum β-lactamase (ESBL). CLSI-based agar dilution susceptibility testing was conducted using FEP-taniborbactam and comparators FEP, meropenem-vaborbactam (MVB), and ceftazidime-avibactam (CZA). The addition of taniborbactam lowered FEP MICs to the provisionally susceptible range of ≤16 µg/mL; the MIC90 value decreased from ≥64 µg/mL for FEP to 4 µg/mL for FEP-taniborbactam. Notably, FEP-taniborbactam MIC50 /MIC90 values (0.5/4 µg/mL) were lower than those for MVB (1/16 µg/mL) and comparable to those for CZA (0.5/1 µg/mL). Time-kill assays with E. coli clinical strains DOV ( blaOXA-48 , blaCTX-M-15 , blaTEM-1 , and blaOXA-1 ) and MLI ( blaOXA-48 , blaVEB , blaTEM-1 , and blaCMY-2 ) revealed that FEP-taniborbactam at concentrations 1×, 2×, and 4× MIC displayed time-dependent reductions in the number of CFU/mL from 0 to 6 h, and at 4× MIC demonstrated bactericidal activity (3 log10 reduction in CFU/mL at 24 h). Therefore, taniborbactam in combination with FEP was highly active against this diverse panel of Enterobacterales with blaOXA-48 and represents a potential addition to our antibiotic arsenal.IMPORTANCEOXA-48-like β-lactamases are class D carbapenemases widespread in Klebsiella pneumoniae and other Enterobacterales and are associated with carbapenem treatment failures. As up to 80% of OXA-48-like positive isolates coproduce extended-spectrum β-lactamases, a combination of β-lactams with broad-spectrum β-lactamase inhibitors is required to counteract all OXA-48-producing strains effectively. Herein, we evaluated the activity of cefepime-taniborbactam against 50 clinical strains producing OXA-48. We report that adding taniborbactam shifted the minimum inhibitory concentration (MIC) toward cefepime's susceptible range, restoring its antimicrobial activity. Notably, cefepime-taniborbactam MIC50 /MIC90 values (0.5/4 µg/mL) were comparable to ceftazidime-avibactam (0.5/1 µg/mL). Finally, time-kill assays revealed sustained bactericidal activity of cefepime-taniborbactam for up to 24 h. In conclusion, cefepime-taniborbactam will be a welcome addition to the antibiotic arsenal to combat Enterobacterales producing OXA-48., Competing Interests: This project was sponsored by Venatorx Pharmaceuticals, Inc. David A. Six and Greg Moeck are employees of Venatorx Pharmaceuticals.- Published
- 2024
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13. ARGONAUT-IV: susceptibility of carbapenemase-producing Klebsiella pneumoniae to the oral bicyclic boronate β-lactamase inhibitor ledaborbactam combined with ceftibuten.
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Jacobs MR, Good CE, Abdelhamed AM, Mack AR, Bethel CR, Marshall SH, Hujer AM, Hujer KM, Patel R, van Duin D, Fowler VG, Rhoads DD, Six DA, Moeck G, Uehara T, Papp-Wallace KM, and Bonomo RA
- Abstract
Ledaborbactam (formerly VNRX-5236), a bicyclic boronate β-lactamase inhibitor with activity against class A, C, and D β-lactamases, is under development as an orally bioavailable etzadroxil prodrug (VNRX-7145) in combination with ceftibuten for the treatment of urinary tract infections. At ceftibuten breakpoints of ≤1 mg/L (EUCAST) and ≤8 mg/L (CLSI), 92.5% and 99.0%, respectively, of 200 carbapenem-resistant Klebsiella pneumoniae isolates, predominantly K. pneumoniae carbapenemase producing, were susceptible to ceftibuten-ledaborbactam (ledaborbactam tested at a fixed concentration of 4 mg/L) compared to 4.5% and 30.5%, respectively, to ceftibuten alone.
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- 2024
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14. Cefepime-taniborbactam activity against antimicrobial-resistant clinical isolates of Enterobacterales and Pseudomonas aeruginosa: GEARS global surveillance programme 2018-22.
- Author
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Karlowsky JA, Wise MG, Hackel MA, Six DA, Uehara T, Daigle DM, Pevear DC, Moeck G, and Sahm DF
- Abstract
Objectives: Taniborbactam is a boronate-based β-lactamase inhibitor in clinical development in combination with cefepime., Methods: Cefepime-taniborbactam and comparator broth microdilution MICs were determined for patient isolates of Enterobacterales (n = 20 725) and Pseudomonas aeruginosa (n = 7919) collected in 59 countries from 2018 to 2022. Taniborbactam was tested at a fixed concentration of 4 mg/L. Isolates with cefepime-taniborbactam MICs ≥ 16 mg/L underwent WGS. β-Lactamase genes were identified in additional meropenem-resistant isolates by PCR/Sanger sequencing., Results: Taniborbactam reduced the cefepime MIC90 value for all Enterobacterales from >16 to 0.25 mg/L (>64-fold). At ≤16 mg/L, cefepime-taniborbactam inhibited 99.5% of all Enterobacterales isolates; >95% of isolates with MDR and ceftolozane-tazobactam-resistant phenotypes; ≥ 89% of isolates with meropenem-resistant and difficult-to-treat-resistant (DTR) phenotypes; >80% of isolates with meropenem-vaborbactam-resistant and ceftazidime-avibactam-resistant phenotypes; 100% of KPC-positive, 99% of OXA-48-like-positive, 99% of ESBL-positive, 97% of acquired AmpC-positive, 95% of VIM-positive and 76% of NDM-positive isolates. Against P. aeruginosa, taniborbactam reduced the cefepime MIC90 value from 32 to 8 mg/L (4-fold). At ≤16 mg/L, cefepime-taniborbactam inhibited 96.5% of all P. aeruginosa isolates; 85% of meropenem-resistant phenotype isolates; 80% of isolates with MDR and meropenem-vaborbactam-resistant phenotypes; >70% of isolates with DTR, ceftazidime-avibactam-resistant and ceftolozane-tazobactam-resistant phenotypes; and 82% of VIM-positive isolates. Multiple potential mechanisms of resistance, including carriage of IMP, or alterations in PBP3 (ftsI), porins (decreased permeability) and efflux (up-regulation) were present in most isolates with cefepime-taniborbactam MICs ≥ 16 mg/L., Conclusions: Cefepime-taniborbactam exhibited potent in vitro activity against Enterobacterales and P. aeruginosa, and inhibited most carbapenem-resistant isolates, including those carrying serine carbapenemases or NDM/VIM MBLs., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)
- Published
- 2024
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15. ARGONAUT-III and -V: susceptibility of carbapenem-resistant Klebsiella pneumoniae and multidrug-resistant Pseudomonas aeruginosa to the bicyclic boronate β-lactamase inhibitor taniborbactam combined with cefepime.
- Author
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Jacobs MR, Abdelhamed AM, Good CE, Mack AR, Bethel CR, Marshall S, Hujer AM, Hujer KM, Patel R, van Duin D, Fowler VG, Rhoads DD, Six DA, Moeck G, Uehara T, Papp-Wallace KM, and Bonomo RA
- Subjects
- Cephalosporins pharmacology, Humans, beta-Lactamases metabolism, beta-Lactamases genetics, Boronic Acids pharmacology, Carbapenems pharmacology, Bacterial Proteins genetics, Bacterial Proteins metabolism, Ceftazidime pharmacology, Borinic Acids pharmacology, Drug Combinations, Azabicyclo Compounds pharmacology, Carboxylic Acids, Cefepime pharmacology, Pseudomonas aeruginosa drug effects, Microbial Sensitivity Tests, Klebsiella pneumoniae drug effects, Anti-Bacterial Agents pharmacology, beta-Lactamase Inhibitors pharmacology, Drug Resistance, Multiple, Bacterial drug effects
- Abstract
Taniborbactam, a bicyclic boronate β-lactamase inhibitor with activity against Klebsiella pneumoniae carbapenemase (KPC), Verona integron-encoded metallo-β-lactamase (VIM), New Delhi metallo-β-lactamase (NDM), extended-spectrum beta-lactamases (ESBLs), OXA-48, and AmpC β-lactamases, is under clinical development in combination with cefepime. Susceptibility of 200 previously characterized carbapenem-resistant K. pneumoniae and 197 multidrug-resistant (MDR) Pseudomonas aeruginosa to cefepime-taniborbactam and comparators was determined by broth microdilution. For K. pneumoniae (192 KPC; 7 OXA-48-related), MIC
90 values of β-lactam components for cefepime-taniborbactam, ceftazidime-avibactam, and meropenem-vaborbactam were 2, 2, and 1 mg/L, respectively. For cefepime-taniborbactam, 100% and 99.5% of isolates of K. pneumoniae were inhibited at ≤16 mg/L and ≤8 mg/L, respectively, while 98.0% and 95.5% of isolates were susceptible to ceftazidime-avibactam and meropenem-vaborbactam, respectively. For P. aeruginosa , MIC90 values of β-lactam components of cefepime-taniborbactam, ceftazidime-avibactam, ceftolozane-tazobactam, and meropenem-vaborbactam were 16, >8, >8, and >4 mg/L, respectively. Of 89 carbapenem-susceptible isolates, 100% were susceptible to ceftolozane-tazobactam, ceftazidime-avibactam, and cefepime-taniborbactam at ≤8 mg/L. Of 73 carbapenem-intermediate/resistant P. aeruginosa isolates without carbapenemases, 87.7% were susceptible to ceftolozane-tazobactam, 79.5% to ceftazidime-avibactam, and 95.9% and 83.6% to cefepime-taniborbactam at ≤16 mg/L and ≤8 mg/L, respectively. Cefepime-taniborbactam at ≤16 mg/L and ≤8 mg/L, respectively, was active against 73.3% and 46.7% of 15 VIM- and 60.0% and 35.0% of 20 KPC-producing P. aeruginosa isolates. Of all 108 carbapenem-intermediate/resistant P. aeruginosa isolates, cefepime-taniborbactam was active against 86.1% and 69.4% at ≤16 mg/L and ≤8 mg/L, respectively, compared to 59.3% for ceftolozane-tazobactam and 63.0% for ceftazidime-avibactam. Cefepime-taniborbactam had in vitro activity comparable to ceftazidime-avibactam and greater than meropenem-vaborbactam against carbapenem-resistant K. pneumoniae and carbapenem-intermediate/resistant MDR P. aeruginosa ., Competing Interests: Robert A. Bonomo reports grants from Venatorx, Entasis, Merck, Wockhardt, and Shionogi outside the submitted work. David A. Six, Greg Moeck, and Tsuyoshi Uehara are employees of Venatorx Pharmaceuticals, Inc.- Published
- 2024
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16. Patient outcomes by baseline pathogen resistance phenotype and genotype in CERTAIN-1, a Phase 3 study of cefepime-taniborbactam versus meropenem in adults with complicated urinary tract infection.
- Author
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Moeck G, Gasink LB, Mendes RE, Woosley LN, Dorr M, Chen H, Wagenlehner FM, Henkel T, and McGovern PC
- Subjects
- Humans, Adult, Female, Male, Pseudomonas aeruginosa drug effects, Pseudomonas aeruginosa genetics, Middle Aged, Double-Blind Method, Bacterial Proteins genetics, Genotype, Phenotype, Aged, Escherichia coli drug effects, Escherichia coli genetics, Treatment Outcome, Borinic Acids, Carboxylic Acids, Meropenem therapeutic use, Meropenem pharmacology, Cefepime therapeutic use, Cefepime pharmacology, Anti-Bacterial Agents therapeutic use, Anti-Bacterial Agents pharmacology, Urinary Tract Infections drug therapy, Urinary Tract Infections microbiology, Cephalosporins therapeutic use, Cephalosporins pharmacology, Microbial Sensitivity Tests, beta-Lactamases genetics
- Abstract
CERTAIN-1 was a Phase 3, double-blind, randomized, parallel group study of the efficacy and safety of cefepime-taniborbactam versus meropenem in the treatment of adults with complicated urinary tract infection (cUTI), including acute pyelonephritis. We determined susceptibility of Enterobacterales and Pseudomonas aeruginosa baseline pathogens to cefepime-taniborbactam and comparators and characterized β-lactam resistance mechanisms. Microbiologic response and clinical response were assessed in patient subsets defined by baseline pathogens that were of cefepime-, multidrug-, or carbapenem-resistant phenotype or that carried β-lactamase genes. Among Enterobacterales baseline pathogens, 26.8%, 4.1%, and 3.0% carried genes for extended-spectrum β-lactamases (ESBLs), AmpC, and carbapenemases, respectively. Within each treatment group, while composite success rates at Test of Cure in resistant subsets by pathogen species were similar to those by pathogen overall, composite success rates in meropenem patients were numerically lower for cefepime-resistant Escherichia coli (9/19; 47.4%) and ESBL E. coli (13/25; 52.0%) compared with E. coli overall (62/100; 62.0%). Cefepime-taniborbactam achieved composite success in 7/8 (87.5%) patients with carbapenem-resistant Enterobacterales and 8/9 (88.9%) patients with Enterobacterales with a carbapenemase gene (5 OXA-48-group; 2 KPC-3; 2 NDM-1). Cefepime-taniborbactam also achieved composite success in 8/16 (50.0%) patients and clinical success in 13/16 (81.3%) patients with P. aeruginosa ; corresponding rates were 4/7 (57.1%) and 6/7 (85.7%) for meropenem. Cefepime-taniborbactam demonstrated efficacy in adult cUTI patients with cefepime-, multidrug-, and carbapenem-resistant pathogens including pathogens with ESBL, AmpC, and carbapenemase genes., Clinical Trials: This study is registered with ClinicalTrials.gov as NCT03840148.
- Published
- 2024
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17. Examining the activity of cefepime-taniborbactam against Burkholderia cepacia complex and Burkholderia gladioli isolated from cystic fibrosis patients in the United States.
- Author
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Mojica MF, Zeiser ET, Becka SA, LiPuma JJ, Six DA, Moeck G, and Papp-Wallace KM
- Subjects
- Humans, United States, Cefepime pharmacology, Anti-Bacterial Agents pharmacology, beta-Lactamase Inhibitors pharmacology, beta-Lactamases, Microbial Sensitivity Tests, Burkholderia gladioli, Burkholderia cepacia complex, Cystic Fibrosis microbiology
- Abstract
The novel clinical-stage β-lactam-β-lactamase inhibitor combination, cefepime-taniborbactam, demonstrates promising activity toward many Gram-negative bacteria producing class A, B, C, and/or D β-lactamases. We tested this combination against a panel of 150 Burkholderia cepacia complex (Bcc) and Burkholderia gladioli strains. The addition of taniborbactam to cefepime shifted cefepime minimum inhibitory concentrations toward the provisionally susceptible range in 59% of the isolates tested. Therefore, cefepime-taniborbactam possessed similar activity as first-line agents, ceftazidime and trimethoprim-sulfamethoxazole, supporting further development., Competing Interests: D.A.S. and G.M. are employees of Venotorx Pharmaceuticals, Inc. Venatorx Pharmaceuticals, Inc., provided funding as a research grant to K.M.P-W. to conduct this study.
- Published
- 2023
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18. In Vitro Activity of Cefepime-Taniborbactam and Comparators against Clinical Isolates of Gram-Negative Bacilli from 2018 to 2020: Results from the Global Evaluation of Antimicrobial Resistance via Surveillance (GEARS) Program.
- Author
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Karlowsky JA, Hackel MA, Wise MG, Six DA, Uehara T, Daigle DM, Cusick SM, Pevear DC, Moeck G, and Sahm DF
- Subjects
- Cefepime pharmacology, Meropenem pharmacology, Tazobactam pharmacology, beta-Lactamases genetics, Pseudomonas aeruginosa, Gram-Negative Bacteria, Azabicyclo Compounds pharmacology, Microbial Sensitivity Tests, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Drug Resistance, Bacterial
- Abstract
Taniborbactam is a novel cyclic boronate β-lactamase inhibitor in clinical development in combination with cefepime. We assessed the in vitro activity of cefepime-taniborbactam and comparators against a 2018-2020 collection of Enterobacterales ( n = 13,731) and Pseudomonas aeruginosa ( n = 4,619) isolates cultured from infected patients attending hospitals in 56 countries. MICs were determined by CLSI broth microdilution. Taniborbactam was tested at a fixed concentration of 4 μg/mL. Isolates with cefepime-taniborbactam MICs of ≥16 μg/mL underwent whole-genome sequencing. β-lactamase genes were identified in meropenem-resistant isolates by PCR/Sanger sequencing. Against Enterobacterales , taniborbactam reduced the cefepime MIC
90 value by >64-fold (from >16 to 0.25 μg/mL). At ≤16 μg/mL, cefepime-taniborbactam inhibited 99.7% of all Enterobacterales isolates; >97% of isolates with multidrug-resistant (MDR) and ceftolozane-tazobactam-resistant phenotypes; ≥90% of isolates with meropenem-resistant, difficult-to-treat-resistant (DTR), meropenem-vaborbactam-resistant, and ceftazidime-avibactam-resistant phenotypes; 100% of VIM-positive, AmpC-positive, and KPC-positive isolates; 98.7% of extended-spectrum β-lactamase (ESBL)-positive; 98.8% of OXA-48-like-positive; and 84.6% of NDM-positive isolates. Against P. aeruginosa, taniborbactam reduced the cefepime MIC90 value by 4-fold (from 32 to 8 μg/mL). At ≤16 μg/mL, cefepime-taniborbactam inhibited 97.4% of all P. aeruginosa isolates; ≥85% of isolates with meropenem-resistant, MDR, and meropenem-vaborbactam-resistant phenotypes; >75% of isolates with DTR, ceftazidime-avibactam-resistant, and ceftolozane-tazobactam-resistant phenotypes; and 87.4% of VIM-positive isolates. Multiple potential mechanisms, including carriage of IMP, certain alterations in PBP3, permeability (porin) defects, and possibly, upregulation of efflux were present in most isolates with cefepime-taniborbactam MICs of ≥16 μg/mL. We conclude that cefepime-taniborbactam exhibited potent in vitro activity against Enterobacterales and P. aeruginosa and inhibited most carbapenem-resistant isolates, including those carrying serine carbapenemases or NDM/VIM metallo-β-lactamases (MBLs).- Published
- 2023
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19. Ceftibuten-Ledaborbactam Activity against Multidrug-Resistant and Extended-Spectrum-β-Lactamase-Positive Clinical Isolates of Enterobacterales from a 2018-2020 Global Surveillance Collection.
- Author
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Karlowsky JA, Wise MG, Hackel MA, Pevear DC, Moeck G, and Sahm DF
- Subjects
- Ceftibuten therapeutic use, Microbial Sensitivity Tests, Serine, Azabicyclo Compounds pharmacology, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, beta-Lactamases genetics
- Abstract
Ceftibuten-ledaborbactam etzadroxil is a cephalosporin-boronate β-lactamase inhibitor prodrug combination under development as an oral treatment for complicated urinary tract infections caused by multidrug-resistant (MDR) Enterobacterales producing serine β-lactamases (Ambler class A, C, and D). In vivo , ledaborbactam etzadroxil (formerly VNRX-7145) is cleaved to the active inhibitor ledaborbactam (formerly VNRX-5236). To more completely define the breadth of ceftibuten-ledaborbactam's activity against important antimicrobial-resistant pathogens, we assessed its in vitro activity against phenotypic and genotypic subsets from a 2018-2020 global culture collection of 3,889 clinical isolates of Enterobacterales , including MDR organisms, extended-spectrum-β-lactamase (ESBL)-positive organisms, and organisms that are nonsusceptible and resistant to other antimicrobials. MICs were determined by CLSI broth microdilution and interpreted using both CLSI and EUCAST breakpoints. Ledaborbactam was tested at a fixed concentration of 4 μg/mL. β-Lactamase genes were characterized by PCR followed by Sanger sequencing or whole-genome sequencing for selected β-lactam-resistant isolate subsets. At ≤1 μg/mL, ceftibuten-ledaborbactam (MIC
90 , 0.25 μg/mL) inhibited 89.7% of MDR isolates, 98.3% of isolates with a presumptive ESBL-positive phenotype, and 92.6% of trimethoprim-sulfamethoxazole-nonsusceptible, 91.7% of levofloxacin-nonsusceptible, 88.1% of amoxicillin-clavulanate-nonsusceptible, 85.7% of ceftibuten-resistant (MIC >1 μg/mL), and 54.1% of carbapenem-nonsusceptible isolates. Against specific ESBL genotype-positive isolates (AmpC negative, serine carbapenemase negative, and metallo-β-lactamase negative), ceftibuten-ledaborbactam inhibited 96.3% of CTX-M-9 group (MIC90 , 0.25 μg/mL), 91.5% of CTX-M-1 group (MIC90 , 0.5 μg/mL), and 88.2% of SHV-positive (MIC90 , 2 μg/mL) isolates at ≤1 μg/mL. Against specific serine carbapenemase genotype-positive isolates, ceftibuten-ledaborbactam inhibited 85.9% of KPC-positive (MIC90 , 2 μg/mL) and 82.9% of OXA-48-group-positive (MIC90 , 2 μg/mL) isolates at ≤1 μg/mL. Continued development of ceftibuten-ledaborbactam appears warranted.- Published
- 2022
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20. Discovery of VNRX-7145 (VNRX-5236 Etzadroxil): An Orally Bioavailable β-Lactamase Inhibitor for Enterobacterales Expressing Ambler Class A, C, and D Enzymes.
- Author
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Trout RE, Zulli A, Mesaros E, Jackson RW, Boyd S, Liu B, Hamrick J, Daigle D, Chatwin CL, John K, McLaughlin L, Cusick SM, Weiss WJ, Pulse ME, Pevear DC, Moeck G, Xerri L, and Burns CJ
- Subjects
- Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents chemistry, Dose-Response Relationship, Drug, Enterobacteriaceae enzymology, Microbial Sensitivity Tests, Molecular Structure, Structure-Activity Relationship, beta-Lactamase Inhibitors chemical synthesis, beta-Lactamase Inhibitors chemistry, Anti-Bacterial Agents pharmacology, Drug Discovery, Enterobacteriaceae drug effects, beta-Lactamase Inhibitors pharmacology, beta-Lactamases metabolism
- Abstract
A major antimicrobial resistance mechanism in Gram-negative bacteria is the production of β-lactamase enzymes. The increasing emergence of β-lactamase-producing multi-drug-resistant "superbugs" has resulted in increases in costly hospital Emergency Department (ED) visits and hospitalizations due to the requirement for parenteral antibiotic therapy for infections caused by these difficult-to-treat bacteria. To address the lack of outpatient treatment, we initiated an iterative program combining medicinal chemistry, biochemical testing, microbiological profiling, and evaluation of oral pharmacokinetics. Lead optimization focusing on multiple smaller, more lipophilic active compounds, followed by an exploration of oral bioavailability of a variety of their respective prodrugs, provided 36 (VNRX-7145/VNRX-5236 etzadroxil), the prodrug of the boronic acid-containing β-lactamase inhibitor 5 (VNRX-5236). In vitro and in vivo studies demonstrated that 5 restored the activity of the oral cephalosporin antibiotic ceftibuten against Enterobacterales expressing Ambler class A extended-spectrum β-lactamases, class A carbapenemases, class C cephalosporinases, and class D oxacillinases.
- Published
- 2021
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21. Microbiological Characterization of VNRX-5236, a Broad-Spectrum β-Lactamase Inhibitor for Rescue of the Orally Bioavailable Cephalosporin Ceftibuten as a Carbapenem-Sparing Agent against Strains of Enterobacterales Expressing Extended-Spectrum β-Lactamases and Serine Carbapenemases.
- Author
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Chatwin CL, Hamrick JC, Trout REL, Myers CL, Cusick SM, Weiss WJ, Pulse ME, Xerri L, Burns CJ, Moeck G, Daigle DM, John K, Uehara T, and Pevear DC
- Subjects
- Animals, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Bacterial Proteins, Carbapenems pharmacology, Ceftibuten, Mice, Microbial Sensitivity Tests, Serine, beta-Lactamases genetics, Cephalosporins pharmacology, beta-Lactamase Inhibitors pharmacology
- Abstract
There is an urgent need for oral agents to combat resistant Gram-negative pathogens. Here, we describe the characterization of VNRX-5236, a broad-spectrum boronic acid β-lactamase inhibitor (BLI), and its orally bioavailable etzadroxil prodrug, VNRX-7145. VNRX-7145 is being developed in combination with ceftibuten, an oral cephalosporin, to combat strains of Enterobacterales expressing extended-spectrum β-lactamases (ESBLs) and serine carbapenemases. VNRX-5236 is a reversible covalent inhibitor of serine β-lactamases, with inactivation efficiencies on the order of 10
4 M-1 · sec-1 , and prolonged active site residence times ( t1/2 , 5 to 46 min). The spectrum of inhibition includes Ambler class A ESBLs, class C cephalosporinases, and class A and D carbapenemases (KPC and OXA-48, respectively). Rescue of ceftibuten by VNRX-5236 (fixed at 4 μg/ml) in isogenic strains of Escherichia coli expressing class A, C, or D β-lactamases demonstrated an expanded spectrum of activity relative to oral comparators, including investigational penems, sulopenem, and tebipenem. VNRX-5236 rescued ceftibuten activity in clinical isolates of Enterobacterales expressing ESBLs (MIC90 , 0.25 μg/ml), KPCs (MIC90 , 1 μg/ml), class C cephalosporinases (MIC90 , 1 μg/ml), and OXA-48-type carbapenemases (MIC90 , 1 μg/ml). Frequency of resistance studies demonstrated a low propensity for recovery of resistant variants at 4× the MIC of the ceftibuten/VNRX-5236 combination. In vivo , whereas ceftibuten alone was ineffective (50% effective dose [ED50 ], >128 mg/kg), ceftibuten/VNRX-7145 administered orally protected mice from lethal septicemia caused by Klebsiella pneumoniae producing KPC carbapenemase (ED50 , 12.9 mg/kg). The data demonstrate potent, broad-spectrum rescue of ceftibuten activity by VNRX-5236 in clinical isolates of cephalosporin-resistant and carbapenem-resistant Enterobacterales .- Published
- 2021
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22. VNRX-5133 (Taniborbactam), a Broad-Spectrum Inhibitor of Serine- and Metallo-β-Lactamases, Restores Activity of Cefepime in Enterobacterales and Pseudomonas aeruginosa.
- Author
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Hamrick JC, Docquier JD, Uehara T, Myers CL, Six DA, Chatwin CL, John KJ, Vernacchio SF, Cusick SM, Trout REL, Pozzi C, De Luca F, Benvenuti M, Mangani S, Liu B, Jackson RW, Moeck G, Xerri L, Burns CJ, Pevear DC, and Daigle DM
- Subjects
- Bacterial Proteins chemistry, Bacterial Proteins genetics, Bacterial Proteins metabolism, Cefepime pharmacology, Microbial Sensitivity Tests, Protein Structure, Secondary, Pseudomonas aeruginosa drug effects, Anti-Bacterial Agents pharmacology, Borinic Acids pharmacology, Carboxylic Acids pharmacology, beta-Lactamase Inhibitors pharmacology
- Abstract
As shifts in the epidemiology of β-lactamase-mediated resistance continue, carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are the most urgent threats. Although approved β-lactam (BL)-β-lactamase inhibitor (BLI) combinations address widespread serine β-lactamases (SBLs), such as CTX-M-15, none provide broad coverage against either clinically important serine-β-lactamases (KPC, OXA-48) or clinically important metallo-β-lactamases (MBLs; e.g., NDM-1). VNRX-5133 (taniborbactam) is a new cyclic boronate BLI that is in clinical development combined with cefepime for the treatment of infections caused by β-lactamase-producing CRE and CRPA. Taniborbactam is the first BLI with direct inhibitory activity against Ambler class A, B, C, and D enzymes. From biochemical and structural analyses, taniborbactam exploits substrate mimicry while employing distinct mechanisms to inhibit both SBLs and MBLs. It is a reversible covalent inhibitor of SBLs with slow dissociation and a prolonged active-site residence time (half-life, 30 to 105 min), while in MBLs, it behaves as a competitive inhibitor, with inhibitor constant ( K
i ) values ranging from 0.019 to 0.081 μM. Inhibition is achieved by mimicking the transition state structure and exploiting interactions with highly conserved active-site residues. In microbiological testing, taniborbactam restored cefepime activity in 33/34 engineered Escherichia coli strains overproducing individual enzymes covering Ambler classes A, B, C, and D, providing up to a 1,024-fold shift in the MIC. Addition of taniborbactam restored the antibacterial activity of cefepime against all 102 Enterobacterales clinical isolates tested and 38/41 P. aeruginosa clinical isolates tested with MIC90 s of 1 and 4 μg/ml, respectively, representing ≥256- and ≥32-fold improvements, respectively, in antibacterial activity over that of cefepime alone. The data demonstrate the potent, broad-spectrum rescue of cefepime activity by taniborbactam against clinical isolates of CRE and CRPA., (Copyright © 2020 Hamrick et al.)- Published
- 2020
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23. Single Intravenous Dose of Oritavancin for Treatment of Acute Skin and Skin Structure Infections Caused by Gram-Positive Bacteria: Summary of Safety Analysis from the Phase 3 SOLO Studies.
- Author
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Corey GR, Loutit J, Moeck G, Wikler M, Dudley MN, and O'Riordan W
- Subjects
- Administration, Intravenous, Adult, Double-Blind Method, Female, Humans, Male, Middle Aged, Gram-Positive Bacteria drug effects, Gram-Positive Bacteria pathogenicity, Lipoglycopeptides administration & dosage, Lipoglycopeptides therapeutic use, Skin Diseases, Bacterial drug therapy
- Abstract
Oritavancin is a lipoglycopeptide with bactericidal activity against Gram-positive organisms. Its rapid concentration-dependent bactericidal activity and long elimination half-life allow single-dose treatment of acute bacterial skin and skin structure infections (ABSSSI). SOLO I and SOLO II were randomized, double-blind studies evaluating the efficacy and safety of a single 1,200-mg intravenous (i.v.) dose of oritavancin versus twice-daily i.v. vancomycin for 7 to 10 days in ABSSSI patients. Safety data from both studies were pooled for safety analysis. The database comprised pooled safety data for 976 oritavancin-treated patients and 983 vancomycin-treated patients. The incidences of adverse events, serious adverse events, and discontinuations due to adverse events were similar for oritavancin (55.3, 5.8, and 3.7%, respectively) and vancomycin (56.9, 5.9, and 4.2%, respectively). The median time to onset (3.8 days versus 3.1 days, respectively) and the duration (3.0 days for both groups) of adverse events were also similar between the two groups. The most frequently reported events were nausea, headache, and vomiting. Greater than 90% of all events were mild or moderate in severity. There were slightly more infections and infestations, abscesses or cellulitis, and hepatic and cardiac adverse events in the oritavancin group; however, more than 80% of these events were mild or moderate. Subgroup analyses did not identify clinically meaningful differences in the incidence of adverse events attributed to oritavancin. A single 1,200-mg dose of oritavancin was well tolerated and had a safety profile similar to that of twice-daily vancomycin. The long elimination half-life of oritavancin compared to that of vancomycin did not result in a clinically meaningful delay to the onset or prolongation of adverse events. (This study has been registered at ClinicalTrials.gov under registration no. NCT01252719 and NCT01252732.)., (Copyright © 2018 American Society for Microbiology.)
- Published
- 2018
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24. A Real-world Patient Registry for Oritavancin Demonstrates Efficacy and Safety Consistent With the Phase 3 SOLO Program.
- Author
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Redell M, Moeck G, Lucasti C, Durso S, Kennedy C, Fusaro K, Loutit J, and Dudley M
- Abstract
Background: Oritavancin is a lipoglycopeptide used in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in adults. To characterize its use in patients in the postapproval setting, a patient registry was developed., Methods: Data collected in an ongoing retrospective observational registry are used to evaluate the utilization, outcomes, and adverse events (AEs) associated with oritavancin for the treatment of infections presumed or confirmed to be caused by gram-positive (GP) bacteria in clinical practice., Results: Data for 112 patients from 8 sites were collected. All patients received a single 1200-mg dose of oritavancin mostly in an infusion center. Infection type included cellulitis (67.0%), cutaneous abscess (21.4%), and wound (4.5%). Most patients (72.3%) received 1 or more antimicrobial agents for the index GP infection within 28 days prior to oritavancin treatment. Of positive cultures obtained prior to oritavancin administration, methicillin-resistant Staphylococcus aureus was the predominant pathogen (78.4%). A positive clinical response was observed in 92.8% of patients, and microbial eradication was observed in 90.0% of patients with post-therapy cultures. Within 28 days following oritavancin administration, 4 (3.6%) patients were hospitalized for failure of treatment of the index infection. Five (4.5%) patients experienced 1 or more possible drug-related AEs, which were consistent with types previously reported. There were no drug-related serious AEs reported., Conclusions: Clinical and microbiologic outcomes and safety of single-dose oritavancin 1200 mg were similar in this older patient population with multiple comorbid conditions to those observed in the phase 3 SOLO trials.
- Published
- 2018
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25. Evaluation of Oritavancin Dosing Strategies against Vancomycin-Resistant Enterococcus faecium Isolates with or without Reduced Susceptibility to Daptomycin in an In Vitro Pharmacokinetic/Pharmacodynamic Model.
- Author
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Belley A, Arhin FF, and Moeck G
- Subjects
- Daptomycin pharmacokinetics, Glycopeptides pharmacokinetics, Glycopeptides pharmacology, Gram-Positive Bacterial Infections drug therapy, Humans, Lipoglycopeptides pharmacokinetics, Microbial Sensitivity Tests methods, Vancomycin pharmacokinetics, Anti-Bacterial Agents pharmacology, Daptomycin pharmacology, Enterococcus faecium drug effects, Lipoglycopeptides pharmacology, Vancomycin pharmacology, Vancomycin Resistance drug effects, Vancomycin-Resistant Enterococci drug effects
- Abstract
The clinical development of nonsusceptibility to the lipopeptide antibiotic daptomycin remains a serious concern during therapy for infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The long-acting lipoglycopeptide oritavancin exhibits potent in vitro activity against VREfm, although its safety and efficacy for treating clinical VREfm infections have not been established. In this study, novel dosing regimens of daptomycin and oritavancin were assessed against both VREfm and daptomycin-nonsusceptible VREfm isolates in an in vitro pharmacokinetic/pharmacodynamic model., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
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26. In vitro stepwise selection of reduced susceptibility to lipoglycopeptides in enterococci.
- Author
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Arhin FF, Seguin DL, Belley A, and Moeck G
- Subjects
- Aminoglycosides pharmacology, Bacterial Proteins genetics, Carbon-Oxygen Ligases genetics, Daptomycin pharmacology, Enterococcus faecalis classification, Enterococcus faecalis genetics, Enterococcus faecium classification, Enterococcus faecium genetics, Gram-Positive Bacterial Infections drug therapy, Gram-Positive Bacterial Infections microbiology, Humans, Lipoglycopeptides, Microbial Sensitivity Tests, Teicoplanin analogs & derivatives, Teicoplanin pharmacology, Vancomycin pharmacology, Vancomycin Resistance genetics, Anti-Bacterial Agents pharmacology, Drug Resistance, Multiple, Bacterial genetics, Enterococcus faecalis drug effects, Enterococcus faecium drug effects, Glycopeptides pharmacology
- 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., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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27. Comparative Pharmacodynamics of Single-Dose Oritavancin and Daily High-Dose Daptomycin Regimens against Vancomycin-Resistant Enterococcus faecium Isolates in an In Vitro Pharmacokinetic/Pharmacodynamic Model of Infection.
- Author
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Belley A, Lalonde-Séguin D, Arhin FF, and Moeck G
- Subjects
- Anti-Bacterial Agents pharmacokinetics, Daptomycin pharmacokinetics, Daptomycin pharmacology, Enterococcus faecium isolation & purification, Humans, Lipoglycopeptides, Microbial Sensitivity Tests, Vancomycin Resistance physiology, Vancomycin-Resistant Enterococci isolation & purification, Anti-Bacterial Agents pharmacology, Enterococcus faecium drug effects, Glycopeptides pharmacokinetics, Glycopeptides pharmacology, Gram-Positive Bacterial Infections drug therapy, Vancomycin-Resistant Enterococci drug effects
- Abstract
There are limited therapeutic options to treat infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The lipoglycopeptide oritavancin exhibits in vitro activity against this pathogen, although its utility against infections caused by VREfm has not been clinically established. In this study, the pharmacodynamic activity of free-drug levels associated with 12 mg/kg/day of daptomycin and a single 1,200-mg dose of oritavancin were determined against three VanA VREfm isolates in an in vitro pharmacokinetic/pharmacodynamic model., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
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28. Assessment of the potential for oritavancin MIC changes among Staphylococcus aureus nasal carriage isolates following systemic oritavancin treatment in a phase 2 study in patients with acute bacterial skin and skin-structure infections.
- Author
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Arhin FF and Moeck G
- Subjects
- Administration, Intravenous, Anti-Bacterial Agents administration & dosage, Double-Blind Method, Humans, Lipoglycopeptides administration & dosage, Microbial Sensitivity Tests, Staphylococcus aureus isolation & purification, Anti-Bacterial Agents pharmacology, Carrier State microbiology, Drug Resistance, Bacterial, Lipoglycopeptides pharmacology, Nasal Mucosa microbiology, Staphylococcal Skin Infections drug therapy, Staphylococcus aureus drug effects
- Published
- 2017
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29. Agar dilution minimum inhibitory concentrations under-represent oritavancin in vitro activity against staphylococci and enterococci.
- Author
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Arhin FF and Moeck G
- Subjects
- Humans, Microbial Sensitivity Tests methods, Vancomycin pharmacology, Anti-Bacterial Agents pharmacology, Diagnostic Errors, Enterococcus drug effects, Lipoglycopeptides pharmacology, Staphylococcus drug effects
- Published
- 2017
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30. In vitro activity of Oritavancin against gram-positive pathogens isolated in Canadian hospital laboratories from 2011 to 2015.
- Author
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Karlowsky JA, Walkty AJ, Baxter MR, Arhin FF, Moeck G, Adam HJ, and Zhanel GG
- Subjects
- Canada, Gram-Positive Bacterial Infections microbiology, Humans, Laboratories, Hospital, Lipoglycopeptides, Microbial Sensitivity Tests methods, Anti-Bacterial Agents therapeutic use, Glycopeptides therapeutic use, Gram-Positive Bacteria drug effects, Gram-Positive Bacteria isolation & purification, Gram-Positive Bacterial Infections drug therapy
- Abstract
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 , 0.12μg/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., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2017
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31. Comparative in vitro activity of oritavancin and other agents against vancomycin-susceptible and -resistant enterococci.
- Author
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Sweeney D, Stoneburner A, Shinabarger DL, Arhin FF, Belley A, Moeck G, and Pillar CM
- Subjects
- Cross Infection microbiology, Enterococcus isolation & purification, Enterococcus faecalis drug effects, Gram-Positive Bacterial Infections drug therapy, Humans, Lipoglycopeptides, Microbial Sensitivity Tests methods, Vancomycin pharmacology, Vancomycin Resistance, Anti-Bacterial Agents pharmacology, Enterococcus drug effects, Glycopeptides pharmacology
- Published
- 2017
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32. Comparative in vitro activity of oritavancin and other agents against methicillin-susceptible and methicillin-resistant Staphylococcus aureus.
- Author
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Sweeney D, Shinabarger DL, Arhin FF, Belley A, Moeck G, and Pillar CM
- Subjects
- Lipoglycopeptides, Microbial Sensitivity Tests, Microbial Viability drug effects, Staphylococcus aureus physiology, Anti-Bacterial Agents pharmacology, Glycopeptides pharmacology, Staphylococcus aureus drug effects
- Abstract
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 (fC
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 MIC50/90 . 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 fCmax against MRSA and MSSA at standard inoculum density, though oritavancin exhibited the most rapid bactericidal activity. Oritavancin and daptomycin at their respective fCmax 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., (Copyright © 2016 Elsevier Inc. All rights reserved.)- Published
- 2017
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33. Effects of Oritavancin on Coagulation Tests in the Clinical Laboratory.
- Author
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Belley A, Robson R, Francis JL, Adcock DM, Tiefenbacher S, Rubino CM, Moeck G, Sylvester D, Dudley MN, and Loutit J
- Subjects
- Adult, Blood Coagulation Tests, Female, Hemostasis drug effects, Humans, Lipoglycopeptides, Male, Middle Aged, Young Adult, Anti-Bacterial Agents therapeutic use, Blood Coagulation drug effects, Glycopeptides therapeutic use
- Abstract
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., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
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34. 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.
- Author
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Corey GR, Arhin FF, Wikler MA, Sahm DF, Kreiswirth BN, Mediavilla JR, Good S, Fiset C, Jiang H, Moeck G, Kabler H, Green S, and O'Riordan W
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Double-Blind Method, Female, Gram-Positive Bacteria classification, Gram-Positive Bacteria drug effects, Humans, Lipoglycopeptides, Male, Microbial Sensitivity Tests, Middle Aged, Treatment Outcome, Young Adult, Anti-Bacterial Agents administration & dosage, Glycopeptides administration & dosage, Gram-Positive Bacteria isolation & purification, Gram-Positive Bacterial Infections drug therapy, Skin Diseases, Bacterial drug therapy
- Abstract
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 MIC
90 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., (Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)- Published
- 2016
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35. Comparative In Vitro Activities of Oritavancin, Dalbavancin, and Vancomycin against Methicillin-Resistant Staphylococcus aureus Isolates in a Nondividing State.
- Author
-
Belley A, Lalonde Seguin D, Arhin F, and Moeck G
- Subjects
- Lipoglycopeptides, Microbial Sensitivity Tests, Teicoplanin pharmacology, Anti-Bacterial Agents pharmacology, Glycopeptides pharmacology, Methicillin-Resistant Staphylococcus aureus drug effects, Teicoplanin analogs & derivatives, Vancomycin pharmacology
- Abstract
Antibacterial agents that kill nondividing bacteria may be of utility in treating persistent infections. Oritavancin and dalbavancin are bactericidal lipoglycopeptides that are approved for acute bacterial skin and skin structure infections in adults caused by susceptible Gram-positive pathogens. Using time-kill methodology, we demonstrate that oritavancin exerts bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) isolates that are maintained in a nondividing state in vitro, whereas dalbavancin and the glycopeptide vancomycin do not., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
- Published
- 2016
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36. Results from Oritavancin Resistance Surveillance Programs (2011 to 2014): Clarification for Using Vancomycin as a Surrogate To Infer Oritavancin Susceptibility.
- Author
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Jones RN, Moeck G, Arhin FF, Dudley MN, Rhomberg PR, and Mendes RE
- Subjects
- Gram-Positive Bacteria drug effects, Lipoglycopeptides, Microbial Sensitivity Tests, Anti-Bacterial Agents pharmacology, Glycopeptides pharmacology, Vancomycin pharmacology
- Abstract
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., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
- Published
- 2016
- Full Text
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37. In vitro activity of oritavancin and comparator agents against staphylococci, streptococci and enterococci from clinical infections in Europe and North America, 2011-2014.
- Author
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Biedenbach DJ, Arhin FF, Moeck G, Lynch TF, and Sahm DF
- Subjects
- Drug Resistance, Multiple, Bacterial, Enterococcus isolation & purification, Europe, Humans, Lipoglycopeptides, Microbial Sensitivity Tests, North America, Skin Diseases, Bacterial drug therapy, Skin Diseases, Bacterial microbiology, Staphylococcal Infections drug therapy, Staphylococcus isolation & purification, Streptococcal Infections drug therapy, Streptococcus isolation & purification, Anti-Bacterial Agents pharmacology, Daptomycin pharmacology, Enterococcus drug effects, Glycopeptides pharmacology, Linezolid pharmacology, Staphylococcus drug effects, Streptococcus drug effects, Vancomycin pharmacology
- Abstract
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., (Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)
- Published
- 2015
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38. Use of in vitro vancomycin testing results to predict susceptibility to oritavancin, a new long-acting lipoglycopeptide.
- Author
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Jones RN, Turnidge JD, Moeck G, Arhin FF, and Mendes RE
- Subjects
- Enterococcus drug effects, Gram-Positive Bacteria drug effects, Lipoglycopeptides, Microbial Sensitivity Tests, Predictive Value of Tests, Reference Standards, Staphylococcus aureus drug effects, Streptococcus drug effects, Vancomycin Resistance drug effects, Anti-Bacterial Agents pharmacology, Drug Resistance, Bacterial drug effects, Glycopeptides pharmacology, Vancomycin pharmacology
- Abstract
Oritavancin is a recently approved lipoglycopeptide antimicrobial agent with activity against Gram-positive pathogens. Its extended serum elimination half-life and concentration-dependent killing enable single-dose treatment of acute bacterial skin and skin structure infections. At the time of regulatory approval, new agents, including oritavancin, are not offered in the most widely used susceptibility testing devices and therefore may require application of surrogate testing using a related antimicrobial to infer susceptibility. To evaluate vancomycin as a predictive susceptibility marker for oritavancin, 26,993 recent Gram-positive organisms from U.S. and European hospitals were tested using reference MIC methods. Organisms included Staphylococcus aureus, coagulase-negative staphylococci (CoNS), beta-hemolytic streptococci (BHS), viridans group streptococci (VGS), and enterococci (ENT). These five major pathogen groups were analyzed by comparing results with FDA-approved susceptible breakpoints for both drugs, as well as those suggested by epidemiological cutoff values and supported by pharmacokinetic/pharmacodynamic analyses. Vancomycin susceptibility was highly accurate (98.1 to 100.0%) as a surrogate for oritavancin susceptibility among the indicated pathogen species. Furthermore, direct MIC comparisons showed high oritavancin potencies, with vancomycin/oritavancin MIC90 results of 1/0.06, 2/0.06, 0.5/0.12,1/0.06, and >16/0.06 μg/ml for S. aureus, CoNS, BHS, VGS, and ENT, respectively. In conclusion, vancomycin demonstrated acceptable accuracy as a surrogate marker for predicting oritavancin susceptibility when tested against the indicated pathogens. In contrast, 93.3% of vancomycin-nonsusceptible enterococci had oritavancin MIC values of ≤0.12 μg/ml, indicating a poor predictive value of vancomycin for oritavancin resistance against these organisms. Until commercial oritavancin susceptibility testing devices are readily available, isolates that when tested show vancomycin susceptibility can be inferred to be susceptible to oritavancin by using FDA-approved breakpoints., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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39. Single-dose oritavancin versus 7-10 days of vancomycin in the treatment of gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study.
- Author
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Corey GR, Good S, Jiang H, Moeck G, Wikler M, Green S, Manos P, Keech R, Singh R, Heller B, Bubnova N, and O'Riordan W
- Subjects
- Administration, Intravenous, Adolescent, Adult, Aged, Aged, 80 and over, Double-Blind Method, Female, Gram-Positive Bacterial Infections pathology, Humans, Lipoglycopeptides, Male, Middle Aged, Treatment Outcome, Young Adult, Anti-Bacterial Agents therapeutic use, Glycopeptides therapeutic use, Gram-Positive Bacterial Infections drug therapy, Skin Diseases, Bacterial drug therapy, Soft Tissue Infections drug therapy, Vancomycin therapeutic use
- Abstract
Background: Oritavancin is a lipoglycopeptide antibiotic with rapid bactericidal activity against gram-positive bacteria. Its concentration-dependent activity and long half-life allow for single-dose treatment., Methods: In a randomized, double-blind trial, adults with acute bacterial skin and skin structure infections (ABSSSIs) received either a single intravenous 1200-mg dose of oritavancin or 7-10 days of twice-daily vancomycin. Three efficacy endpoints were tested for noninferiority: (1) primary composite endpoint at 48-72 hours (cessation of spreading or reduction in lesion size, absence of fever, and no rescue antibiotic); (2) investigator-assessed clinical cure 7-14 days after end of treatment; and (3) ≥20% reduction in lesion area at 48-72 hours., Results: A total of 503 and 502 patients comprised the modified intent-to-treat population for oritavancin and vancomycin, respectively. All 3 efficacy endpoints met the 10% noninferiority margin: the primary composite endpoint (80.1% vs 82.9%; 95% confidence interval [CI], -7.5 to 2.0), investigator-assessed clinical cure (82.7% vs 80.5%; 95% CI, -2.6 to 7.0), and proportion of patients attaining ≥20% reduction in lesion area (85.9% vs 85.3%; 95% CI, -3.7 to 5.0) for oritavancin vs vancomycin, respectively. Efficacy outcomes by pathogen, including methicillin-resistant Staphylococcus aureus and the frequency of adverse events, were similar between treatment groups., Conclusions: A single 1200-mg dose of oritavancin was noninferior to 7-10 days of vancomycin in treating ABSSSIs caused by gram-positive pathogens, and was well tolerated. Oritavancin provides a single-dose alternative to multidose therapies for the treatment of ABSSSIs. Clinical Trials Registration. NCT01252732., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2015
- Full Text
- View/download PDF
40. Population pharmacokinetic analysis for a single 1,200-milligram dose of oritavancin using data from two pivotal phase 3 clinical trials.
- Author
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Rubino CM, Bhavnani SM, Moeck G, Bellibas SE, and Ambrose PG
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Humans, Lipoglycopeptides, Middle Aged, Monte Carlo Method, Young Adult, Anti-Bacterial Agents pharmacokinetics, Glycopeptides pharmacokinetics
- Abstract
Oritavancin is a lipoglycopeptide antibiotic with activity against Gram-positive bacteria. Here we describe oritavancin population pharmacokinetics and the impact of patient-specific covariates on drug exposure variability. Concentration-time data were analyzed from two phase 3 clinical trials, SOLO I and SOLO II, in which oritavancin was administered as a single 1,200-mg dose to patients with acute bacterial skin and skin structure infections. A total of 1,337 drug concentrations from 297 patients (90% of whom had 4 or 5 pharmacokinetic samples) were available for analysis. A previously derived population model based on data from 12 phase 1, 2, and 3 oritavancin studies was applied to the SOLO data set. Alterations to the structural model were made, as necessary, based on model fit. Analyses utilized Monte Carlo parametric expectation maximization (S-ADAPT 1.5.6). The previous population pharmacokinetic model fit the data well (r(2) = 0.972), and population pharmacokinetic parameters were estimated with acceptable precision and lack of bias. Covariate evaluations revealed statistically significant relationships between central compartment volume and age and between clearance and height; however, these relationships did not indicate a clinically relevant impact on oritavancin exposure over the range of age and height observed in the SOLO studies. The mean (coefficient of variation [CV]) area under the plasma concentration-time curve from time zero to 72 h (AUC0-72) and maximum plasma concentration (Cmax) were 1,530 (36.9%) μg · h/ml and 138 (23%) μg/ml, respectively. The mean (CV) half-life at alpha phase (t1/2α), t1/2β, and t1/2γ were 2.29 (49.8%), 13.4 (10.5%), and 245 (14.9%) hours, respectively. These analyses are the first to describe oritavancin pharmacokinetics following a single 1,200-mg dose. Covariate analyses suggested that no dose adjustments are required for renal impairment (creatinine clearance, >29 ml/min), mild or moderate hepatic impairment, age, weight, gender, or diabetes status., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
- Full Text
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41. Dalbavancin or oritavancin for skin infections.
- Author
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Corey GR, Jiang H, and Moeck G
- Subjects
- Female, Humans, Male, Anti-Bacterial Agents administration & dosage, Glycopeptides administration & dosage, Skin Diseases, Bacterial drug therapy, Teicoplanin analogs & derivatives, Vancomycin administration & dosage
- Published
- 2014
- Full Text
- View/download PDF
42. In vitro activities of oritavancin and comparators against meticillin-resistant Staphylococcus aureus (MRSA) isolates harbouring the novel mecC gene.
- Author
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Arhin FF, Sarmiento I, and Moeck G
- Subjects
- Acetamides pharmacology, Daptomycin pharmacology, Gene Expression, Linezolid, Lipoglycopeptides, Methicillin-Resistant Staphylococcus aureus genetics, Methicillin-Resistant Staphylococcus aureus growth & development, Methicillin-Resistant Staphylococcus aureus isolation & purification, Microbial Sensitivity Tests, Microbial Viability drug effects, Oxazolidinones pharmacology, Vancomycin pharmacology, Anti-Bacterial Agents pharmacology, Bacterial Proteins genetics, Glycopeptides pharmacology, Methicillin Resistance genetics, Methicillin-Resistant Staphylococcus aureus drug effects
- Abstract
Meticillin-resistant Staphylococcus aureus (MRSA) is routinely detected by amplification of the mecA gene. Recently, MRSA isolates harbouring a novel mec gene (mecC) that is not detected by mecA amplification have been reported. In this study, the activities of the lipoglycopeptide oritavancin as well as the comparators vancomycin, daptomycin and linezolid against 14 mecC MRSA isolates were studied by broth microdilution minimum inhibitory concentration (MIC) and time-kill assays at clinically relevant concentrations of each antibacterial agent. Oritavancin, vancomycin, daptomycin and linezolid MIC90 values (MIC required to inhibit 90% of the isolates) against the mecC isolates were 0.06, 1, 1 and 2mg/L, respectively. In time-kill assays, oritavancin at concentrations reflective of its free peak in plasma of patients receiving a single 1200 mg intravenous dose and the level 24h thereafter was bactericidal against all isolates tested, attaining 3 log kill relative to the starting inoculum between 5 min and 15 min. Vancomycin both at its free peak and free trough concentrations was also bactericidal against all isolates, attaining bactericidal activity between 6h and 24h. Daptomycin was bactericidal only at its free peak concentration, attaining bactericidal activity between 30 min and 4h against the tested isolates. Linezolid was bacteriostatic (<3 log kill relative to the starting inoculum) against the tested isolates. Oritavancin's in vitro activity against mecC MRSA isolates was indistinguishable from that against mecA MRSA isolates both in MIC and time-kill assays., (Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
43. Single-dose oritavancin in the treatment of acute bacterial skin infections.
- Author
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Corey GR, Kabler H, Mehra P, Gupta S, Overcash JS, Porwal A, Giordano P, Lucasti C, Perez A, Good S, Jiang H, Moeck G, and O'Riordan W
- Subjects
- Acute Disease, Adolescent, Adult, Aged, Aged, 80 and over, Anti-Bacterial Agents adverse effects, Double-Blind Method, Drug Administration Schedule, Female, Glycopeptides adverse effects, Humans, Infusions, Intravenous, Intention to Treat Analysis, Lipoglycopeptides, Male, Methicillin-Resistant Staphylococcus aureus isolation & purification, Middle Aged, Nausea chemically induced, Skin Diseases, Bacterial microbiology, Vancomycin adverse effects, Young Adult, Anti-Bacterial Agents administration & dosage, Glycopeptides administration & dosage, Skin Diseases, Bacterial drug therapy, Vancomycin administration & dosage
- Abstract
Background: Oritavancin is a lipoglycopeptide with bactericidal activity against gram-positive bacteria. Its concentration-dependent activity and prolonged half-life allow for single-dose treatment., Methods: We conducted a randomized, double-blind trial in which adults with acute bacterial skin and skin-structure infections received either a single intravenous dose of 1200 mg of oritavancin or a regimen of intravenous vancomycin twice daily for 7 to 10 days. Three efficacy end points were tested for noninferiority. The primary composite end point was defined as cessation of spreading or reduction in lesion size, absence of fever, and no need for administration of a rescue antibiotic 48 to 72 hours after administration of oritavancin. Secondary end points were clinical cure 7 to 14 days after the end of treatment, as determined by a study investigator, and a reduction in lesion size of 20% or more 48 to 72 hours after administration of oritavancin., Results: The modified intention-to-treat population comprised 475 patients who received oritavancin and 479 patients who received vancomycin. All three efficacy end points met the prespecified noninferiority margin of 10 percentage points for oritavancin versus vancomycin: primary end point, 82.3% versus 78.9% (95% confidence interval [CI] for the difference, -1.6 to 8.4 percentage points); investigator-assessed clinical cure, 79.6% versus 80.0% (95% CI for the difference, -5.5 to 4.7 percentage points); and proportion of patients with a reduction in lesion area of 20% or more, 86.9% versus 82.9% (95% CI for the difference, -0.5 to 8.6 percentage points). Efficacy outcomes measured according to type of pathogen, including methicillin-resistant Staphylococcus aureus, were similar in the two treatment groups. The overall frequency of adverse events was also similar, although nausea was more common among those treated with oritavancin., Conclusions: A single dose of oritavancin was noninferior to twice-daily vancomycin administered for 7 to 10 days for the treatment of acute bacterial skin and skin-structure infections caused by gram-positive pathogens. (Funded by the Medicines Company; SOLO I ClinicalTrials.gov number, NCT01252719.).
- Published
- 2014
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44. Oritavancin retains bactericidal activity in vitro against standard and high inocula of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA).
- Author
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Arhin FF, Sarmiento I, and Moeck G
- Subjects
- Humans, Lipoglycopeptides, Staphylococcal Skin Infections microbiology, Anti-Bacterial Agents pharmacology, Drug Resistance, Bacterial, Glycopeptides pharmacology, Methicillin-Resistant Staphylococcus aureus drug effects, Microbial Sensitivity Tests standards, Staphylococcus aureus drug effects, Vancomycin pharmacology
- Published
- 2013
- Full Text
- View/download PDF
45. Pharmacodynamics of a simulated single 1,200-milligram dose of oritavancin in an in vitro pharmacokinetic/pharmacodynamic model of methicillin-resistant staphylococcus aureus infection.
- Author
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Belley A, Arhin FF, Sarmiento I, Deng H, Rose W, and Moeck G
- Subjects
- Analysis of Variance, Area Under Curve, Clinical Trials, Phase III as Topic, Colony Count, Microbial, Culture Media, Drug Dosage Calculations, Humans, Infusion Pumps, Lipoglycopeptides, Methicillin-Resistant Staphylococcus aureus growth & development, Microbial Sensitivity Tests, Staphylococcal Infections drug therapy, Staphylococcal Infections microbiology, Anti-Bacterial Agents pharmacology, Daptomycin pharmacology, Glycopeptides pharmacology, Methicillin-Resistant Staphylococcus aureus drug effects, Models, Biological, Vancomycin pharmacology
- Abstract
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 (AUBKC(0-24)), 48 h (AUBKC(0-48)), and 72 h (AUBKC(0-72)). The rapid bactericidal activities of oritavancin and daptomycin contributed to lower AUBKC(0-24)s 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 AUBKC(0-48) and AUBKC(0-72) against one MRSA strain and a lower AUBKC(0-48) for another strain than did vancomycin exposure (P < 0.05). Furthermore, daptomycin exposure resulted in a lower AUBKC(0-48) and AUBKC(0-72) for one of the MRSA isolates than did vancomycin exposure (P < 0.05). Lower AUBKC(0-24)s 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.
- Published
- 2013
- Full Text
- View/download PDF
46. Correlation between oritavancin and vancomycin minimum inhibitory concentrations in staphylococci.
- Author
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Arhin FF, Draghi DC, Pillar CM, Moeck G, and Sahm DF
- Subjects
- Humans, Lipoglycopeptides, Microbial Sensitivity Tests, Glycopeptides pharmacology, Staphylococcus drug effects, Vancomycin pharmacology
- Published
- 2012
- Full Text
- View/download PDF
47. Activity of oritavancin and comparators in vitro against standard and high inocula of Staphylococcus aureus.
- Author
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Arhin FF, Sarmiento I, Parr TR Jr, and Moeck G
- Subjects
- Humans, Lipoglycopeptides, Microbial Sensitivity Tests methods, Microbial Sensitivity Tests standards, Microbial Viability drug effects, Time Factors, Anti-Bacterial Agents pharmacology, Glycopeptides pharmacology, Staphylococcus aureus drug effects
- Abstract
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., (Copyright © 2011 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
48. Genome annotation and intraviral interactome for the Streptococcus pneumoniae virulent phage Dp-1.
- Author
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Sabri M, Häuser R, Ouellette M, Liu J, Dehbi M, Moeck G, García E, Titz B, Uetz P, and Moineau S
- Subjects
- Chromatography, Liquid, DNA Replication, DNA, Viral chemistry, DNA, Viral genetics, Gene Order, Genes, Viral, Mass Spectrometry, Molecular Sequence Data, Multigene Family, Open Reading Frames, Promoter Regions, Genetic, Protein Biosynthesis, Sequence Analysis, DNA, Siphoviridae classification, Siphoviridae ultrastructure, Streptococcus Phages classification, Streptococcus Phages ultrastructure, Terminator Regions, Genetic, Viral Structural Proteins analysis, Genome, Viral, Streptococcus Phages genetics, Streptococcus pneumoniae virology
- Abstract
Streptococcus pneumoniae causes several diseases, including pneumonia, septicemia, and meningitis. Phage Dp-1 is one of the very few isolated virulent S. pneumoniae bacteriophages, but only a partial characterization is currently available. Here, we confirmed that Dp-1 belongs to the family Siphoviridae. Then, we determined its complete genomic sequence of 56,506 bp. It encodes 72 open reading frames, of which 44 have been assigned a function. We have identified putative promoters, Rho-independent terminators, and several genomic clusters. We provide evidence that Dp-1 may be using a novel DNA replication system as well as redirecting host protein synthesis through queuosine-containing tRNAs. Liquid chromatography-mass spectrometry analysis of purified phage Dp-1 particles identified at least eight structural proteins. Finally, using comprehensive yeast two-hybrid screens, we identified 156 phage protein interactions, and this intraviral interactome was used to propose a structural model of Dp-1.
- Published
- 2011
- Full Text
- View/download PDF
49. Oritavancin disrupts membrane integrity of Staphylococcus aureus and vancomycin-resistant enterococci to effect rapid bacterial killing.
- Author
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Belley A, McKay GA, Arhin FF, Sarmiento I, Beaulieu S, Fadhil I, Parr TR Jr, and Moeck G
- Subjects
- Drug Resistance, Bacterial, Lipoglycopeptides, Anti-Bacterial Agents pharmacology, Cell Membrane drug effects, Enterococcus drug effects, Glycopeptides pharmacology, Staphylococcus aureus drug effects, Vancomycin pharmacology
- Abstract
Oritavancin is an investigational lipoglycopeptide in clinical development for the treatment of acute bacterial skin and skin structure infections. In this study, we demonstrate that oritavancin causes bacterial membrane depolarization and permeabilization leading to cell death of Gram-positive pathogens and that these effects are attributable to the 4'-chlorobiphenylmethyl group of the molecule.
- Published
- 2010
- Full Text
- View/download PDF
50. Longitudinal analysis of the in vitro activity profile of oritavancin and comparator glycopeptides against Gram-positive organisms from Europe: 2005-2008.
- Author
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Arhin FF, Moeck G, Draghi DC, Pillar CM, and Sahm DF
- Subjects
- Europe, Gram-Positive Bacteria isolation & purification, Humans, Lipoglycopeptides, Microbial Sensitivity Tests, Teicoplanin pharmacology, Vancomycin pharmacology, Anti-Bacterial Agents pharmacology, Glycopeptides pharmacology, Gram-Positive Bacteria drug effects, Gram-Positive Bacterial Infections microbiology
- Published
- 2010
- Full Text
- View/download PDF
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