Antistaphylococcal Activity of Oritavancin and Its Synergistic Effect in Combination with Other Antimicrobial Agents

Lin, Gengrong; Pankuch, Glenn A.; Appelbaum, Peter C.; Kosowska-Shick, Klaudia

doi:10.1128/aac.02932-14

Cited by 19 publications

(10 citation statements)

References 15 publications

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“…In the case of standard MRSA, all isolates in the present study were inhibited by ORI at a concentration not exceeding 0.063 g/ml, a value that corresponds to the published MIC 90 from surveillance of over 9,000 S. aureus isolates (6). With regard to strains of the more resistant phenotypes, such as hVISA, VISA, and DNS MRSA, the ORI MIC values obtained in our study were lower than those reported previously, where the ORI MICs against hVISA, VISA, and DNS MRSA isolates ranged up to 2 g/ml (6,18). In our study, 12 of 15 (80%) hVISA, VISA, or DNS MRSA isolates were susceptible to ORI, with MIC values being 0.25 g/ml for only three VISA isolates.…”

Section: Discussioncontrasting

confidence: 54%

“…However, only CPT in combination with ORI was able to demonstrate synergy against standard MRSA and hVISA strains as well. Previously, a study evaluated the activity of ORI in combination with gentamicin, rifampin, and linezolid against MRSA, and the authors demonstrated synergistic effects between ORI and each of these agents (18). However, ours is the first study to evaluate ORI in combination with beta-lactam antibiotics.…”

Section: Discussionmentioning

confidence: 70%

“…ORI possesses antibacterial activity against these organisms along with an ability to be administered by a novel, singledose regimen. In vitro time-kill experiments have demonstrated the concentration-dependent bactericidal activity of ORI against daptomycin-nonsusceptible (DNS) MRSA, VAN-intermediate S. aureus (VISA), heteroresistant VISA (hVISA), and VRE in 24-h time-kill experiments (17)(18)(19)(20). Recent data suggest that lipopeptides and glycopeptides demonstrate enhanced activity against these resistant, Gram-positive organisms when beta-lactams are added (9,13,15,16,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

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confidence: 99%

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Oritavancin Combinations with β-Lactams against Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci

Smith

Yim

Raut

et al. 2016

Antimicrob Agents Chemother

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Oritavancin possesses activity against vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). In vitro data suggest synergy between beta-lactams (BLs) and vancomycin or daptomycin, agents similar to oritavancin. We evaluated the activities of BLs combined with oritavancin against MRSA and VRE. Oritavancin MICs were determined for 30 strains, 5 each of MRSA, daptomycin-nonsusceptible (DNS) MRSA, vancomycin-intermediate MRSA (VISA), heteroresistant VISA (hVISA), vancomycin-resistant Enterococcus faecalis, and vancomycin-resistant Enterococcus faecium. Oritavancin MICs were determined in the presence of subinhibitory concentrations of BLs. Oritavancin combined with ceftaroline, cefazolin, or nafcillin was evaluated for lethal synergy against MRSA, and oritavancin combined with ceftaroline, ampicillin, or ertapenem was evaluated for lethal synergy against VRE in 24-h time-kill assays. Oritavancin at 0.5؋ the MIC was combined with BLs at 0.5؋ the MIC or the biological free peak concentration, whichever one was lower. Synergy was defined as a >2-log 10 -CFU/ml difference between the killing achieved with the combination and that achieved with the most active single agent at 24 h. Oritavancin MICs were <0.125 g/ml for all MRSA isolates except three VISA isolates with MICs of 0.25 g/ml. Oritavancin MICs for VRE ranged from 0.03 to 0.125 g/ml. Oritavancin in combination with ceftaroline was synergistic against all MRSA phenotypes and statistically superior to all other combinations against DNS MRSA, hVISA, and MRSA isolates (P < 0.02). Oritavancin in combination with cefazolin and oritavancin in combination with nafcillin were also synergistic against all MRSA strains. Synergy between oritavancin and all BLs was revealed against VRE strain 8019, while synergy between oritavancin and ampicillin or ertapenem but not ceftaroline was demonstrated against VRE strain R7164. The data support the potential use of oritavancin in combination with BLs, especially oritavancin in combination with ceftaroline, for the treatment of infections caused by MRSA. The data from the present study are not as strong for oritavancin in combination with BLs for VRE. Further study of both MRSA and VRE in more complex models is warranted. O ritavancin (ORI) is a novel lipoglycopeptide antibiotic recently approved by the Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) (1-3). Unique to ORI among the agents approved for use for the treatment of ABSSSIs, the antibiotic is administered as a single dose of 1,200 mg as the entire treatment course. ORI is active against a wide range of Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) (4). It possesses three mechanisms of action, acting via inhibition of both transglycosylation and transpeptidation at the cell wall, along with disruption of the cell membrane (5). ORI is a potent agent against Gram-positive organisms. Against ov...

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Section: Discussioncontrasting

confidence: 54%

Section: Discussionmentioning

confidence: 70%

mentioning

confidence: 99%

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Oritavancin Combinations with β-Lactams against Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci

Smith

Yim

Raut

et al. 2016

Antimicrob Agents Chemother

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“…Synergy has been demonstrated in vitro between oritavancin and aminoglycosides, b-lactams, linezolid, or rifampin against MRSA or enterococci [90][91][92][93] as well as between telavancin and b-lactams, aminoglycosides, or rifampin against MRSA [94,95], or dalbavancin and oxacillin against MRSA [96].…”

Section: In Vitro Pharmacodynamicsmentioning

confidence: 99%

Lipoglycopeptide Antibacterial Agents in Gram-Positive Infections: A Comparative Review

Bambeke

2015

Drugs

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Oritavancin, telavancin, and dalbavancin are recently marketed lipoglycopeptides that exhibit remarkable differences to conventional molecules. While dalbavancin inhibits the late stages of peptidoglycan synthesis by mainly impairing transglycosylase activity, oritavancin and telavancin anchor in the bacterial membrane by the lipophilic side chain linked to their disaccharidic moiety, disrupting membrane integrity and causing bacteriolysis. Oritavancin keeps activity against vancomycin-resistant enterocococci, being a stronger inhibitor of transpeptidase than of transglycosylase activity. These molecules have potent activity against Grampositive organisms, most notably staphylococci (including methicillin-resistant Staphylococcus aureus and to some extent vancomycin-intermediate S. aureus), streptococci (including multidrug-resistant pneumococci), and Clostridia. All agents are indicated for the treatment of acute bacterial skin and skin structure infections, and telavancin, for hospitalacquired and ventilator-associated bacterial pneumonia. While telavancin is administered daily at 10 mg/kg, the remarkably long half-lives of oritavancin and dalbavancin allow for infrequent dosing (single dose of 1200 mg for oritavancin and 1000 mg at day 1 followed by 500 mg at day 8 for dalbavancin), which could be exploited in the future for outpatient therapy. Among possible safety issues evidenced during clinical development were an increased risk of developing osteomyelitis with oritavancin; taste disturbance, nephrotoxicity, and risk of corrected QT interval prolongation (especially in the presence of at-risk co-medications) with telavancin; and elevation of hepatic enzymes with dalbavancin. Interference with coagulation tests has been reported with oritavancin and telavancin. These drugs proved non-inferior to conventional treatments in clinical trials but their advantages may be better evidenced upon future evaluation in more severe infections. Key PointsNew lipoglycopeptides (telavancin, oritavancin, dalbavancin) differ from vancomycin by the presence of a lipophilic side chain, which profoundly modifies their pharmacokinetic and/or pharmacodynamic profile.Among these agents, telavancin and oritavancin have multiple modes of action and are highly bactericidal.Oritavancin and dalbavancin have prolonged halflives, allowing for their use a single-dose or twodose (once-a-week) regimen, respectively. These three drugs are indicated for the treatment of acute bacterial skin and skin structure infections, and telavancin is indicated for hospital-acquired and ventilator-associated bacterial pneumonia.

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“…Additional in vitro investigations support potential future studies regarding use against VRE infections (20), methicillin-resistant S. aureus (MRSA) infections with the novel mecC gene mechanism or infections emerging in the community setting (21,22), some S. aureus strains with elevated vancomycin MIC values or heteroresistant variations (23,24), and uncommonly isolated Gram-positive species (25). Furthermore, favorable in vitro drug combination (synergy) results have been reported for oritavancin testing against staphylococci (26). With this favorable microbiological, PK/PD, and clinical trial background, oritavancin provides a valuable addition to our antimicrobial armamentarium to treat infections caused by resistant Gram-positive cocci.…”

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confidence: 99%

Results from Oritavancin Resistance Surveillance Programs (2011 to 2014): Clarification for Using Vancomycin as a Surrogate To Infer Oritavancin Susceptibility

Jones

Moeck²,

Arhin³

et al. 2016

Antimicrob Agents Chemother

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O ritavancin, a novel lipoglycopeptide, was recently approved for single-dose treatment of acute bacterial skin and skin structure infections (ABSSSIs) in the United States and Europe (1, 2). The compound (formerly LY333328) has a long history of in vitro evaluations and drug development, dating from the late 1990s (3-5) and documenting a broad anti-Gram-positive organism spectrum comparable to those of vancomycin and teicoplanin. Initial worldwide surveillance (5) suggested that oritavancin had activity similar to that of existing glycopeptides; reference methods were subsequently modified to recognize the greater oritavancin activity (8-to 16-fold superior) against Staphylococcus aureus and various streptococcal species (1, 2, 6, 7).The physicochemical characteristics of lipoglycopeptides (oritavancin, dalbavancin, and telavancin) are particularly challenging for the development of standardized in vitro susceptibility testing methods. Poor drug diffusion through agar-based media limits the application of the agar disk diffusion method, as published by several international standards organizations (8), and the binding of drug to various plastics compromises dilution MIC testing (7, 9). Reference broth microdilution methods (10, 11) for oritavancin require the surfactant polysorbate-80 (P-80) (0.002%) to recognize full antimicrobial potency, and adaption of commonly used commercial devices appears to be uncertain. Such delays in the use of commercial susceptibility testing systems to direct oritavancin chemotherapy may necessitate alternative testing strategies, such as the use of vancomycin susceptibility testing results as a surrogate predictive measure (12). In this investigation, (i) we update the analysis of 2011-2013 oritavancin surveillance results (12) for validation of the use of vancomycin MIC results to infer oritavancin susceptibility, following retesting of strains with previous nonsusceptible results, and (ii) we present 2014 oritavancin surveillance data to confirm the high predictive value of surrogate vancomycin testing for oritavancin susceptibility.European and U.S. oritavancin resistance surveillance isolates from 2011 to 2013 (26,993 isolates; 22,606 indicated species) and 2014 (10,002 isolates; 7,688 indicated species) were tested by validated reference broth microdilution methods (10). For species and antimicrobial-resistant subset details, refer to Tables 1 and 2, as well as to reference 12. The interpretive breakpoint criteria used for oritavancin were those selected by the U.S. Food and Drug Administration (FDA) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST), and the criteria for vancomycin were those published by the Clinical and Laboratory Standards Institute (CLSI) (11,(13)(14)(15). All quality control (QC) results were within published ranges (13), using the following QC organisms: S. aureus ATCC 29213, Enterococcus faecalis ATCC 29212, and Streptococcus pneumoniae ATCC 49619.An earlier publication (12) quantified the predictive accuracy of using vancom...

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Antistaphylococcal Activity of Oritavancin and Its Synergistic Effect in Combination with Other Antimicrobial Agents

Cited by 19 publications

References 15 publications

Oritavancin Combinations with β-Lactams against Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci

Oritavancin Combinations with β-Lactams against Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci

Lipoglycopeptide Antibacterial Agents in Gram-Positive Infections: A Comparative Review

Results from Oritavancin Resistance Surveillance Programs (2011 to 2014): Clarification for Using Vancomycin as a Surrogate To Infer Oritavancin Susceptibility

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