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1.
Antimicrob Agents Chemother ; 65(8): e0055221, 2021 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-34001510

RESUMEN

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 ß-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 ß-lactamases (ESBLs) and serine carbapenemases. VNRX-5236 is a reversible covalent inhibitor of serine ß-lactamases, with inactivation efficiencies on the order of 104 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 ß-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.


Asunto(s)
Cefalosporinas , Inhibidores de beta-Lactamasas , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Proteínas Bacterianas , Carbapenémicos/farmacología , Ceftibuteno , Cefalosporinas/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Serina , Inhibidores de beta-Lactamasas/farmacología , beta-Lactamasas/genética
2.
Diagn Microbiol Infect Dis ; 89(2): 168-171, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28733126

RESUMEN

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.


Asunto(s)
Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple/genética , Enterococcus faecalis/efectos de los fármacos , Enterococcus faecium/efectos de los fármacos , Glicopéptidos/farmacología , Aminoglicósidos/farmacología , Proteínas Bacterianas/genética , Ligasas de Carbono-Oxígeno/genética , Daptomicina/farmacología , Enterococcus faecalis/clasificación , Enterococcus faecalis/genética , Enterococcus faecium/clasificación , Enterococcus faecium/genética , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Lipoglucopéptidos , Pruebas de Sensibilidad Microbiana , Teicoplanina/análogos & derivados , Teicoplanina/farmacología , Vancomicina/farmacología , Resistencia a la Vancomicina/genética
5.
Diagn Microbiol Infect Dis ; 87(4): 349-356, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28159446

RESUMEN

Gram-positive bacterial pathogens isolated from patient specimens submitted to 15 Canadian hospital laboratories from 2011 to 2015 were tested in the coordinating laboratory for susceptibility to oritavancin and comparative antimicrobial agents using the Clinical and Laboratory Standards Institute M07-A10 (2015) broth microdilution method. Oritavancin's in vitro activity was equivalent to, or more potent than, vancomycin, daptomycin, linezolid, and tigecycline against methicillin-susceptible Staphylococcus aureus (n=2680; oritavancin MIC90, 0.12µg/mL; 99.9% oritavancin-susceptible), methicillin-resistant S. aureus (n=728; oritavancin MIC90, 0.12µg/mL; 99.7% oritavancin-susceptible), Streptococcus pyogenes (n=218; oritavancin MIC90, 0.25µg/mL; 100% oritavancin-susceptible), Streptococcus agalactiae (n=269; oritavancin MIC90, 0.12µg/mL; 100% oritavancin-susceptible), and vancomycin-susceptible Enterococcus faecalis (n=508; oritavancin MIC90, 0.06µg/mL; 100% oritavancin-susceptible). Oritavancin, dalbavancin, and telavancin demonstrated equivalent in vitro activities (MIC90, µg/mL) against 602 isolates of MSSA (0.06, 0.06, 0.06, respectively) and 144 isolates of MRSA (0.12, 0.06, 0.06, respectively) collected in 2015.


Asunto(s)
Antibacterianos/uso terapéutico , Glicopéptidos/uso terapéutico , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/aislamiento & purificación , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Canadá , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Laboratorios de Hospital , Lipoglucopéptidos , Pruebas de Sensibilidad Microbiana/métodos
6.
Int J Antimicrob Agents ; 46(6): 674-81, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26541881

RESUMEN

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 ß-haemolytic streptococci (ßHS) 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 ßHS (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 ßHS. Oritavancin exhibited potent in vitro activity against the most common pathogens associated with ABSSSIs in the USA and Europe.


Asunto(s)
Antibacterianos/farmacología , Daptomicina/farmacología , Enterococcus/efectos de los fármacos , Glicopéptidos/farmacología , Linezolid/farmacología , Staphylococcus/efectos de los fármacos , Streptococcus/efectos de los fármacos , Vancomicina/farmacología , Farmacorresistencia Bacteriana Múltiple , Enterococcus/aislamiento & purificación , Europa (Continente) , Humanos , Lipoglucopéptidos , Pruebas de Sensibilidad Microbiana , América del Norte , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Enfermedades Cutáneas Bacterianas/microbiología , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus/aislamiento & purificación , Infecciones Estreptocócicas/tratamiento farmacológico , Streptococcus/aislamiento & purificación
7.
Int J Antimicrob Agents ; 44(1): 65-8, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24906505

RESUMEN

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.


Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas/genética , Glicopéptidos/farmacología , Resistencia a la Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Acetamidas/farmacología , Daptomicina/farmacología , Expresión Génica , Linezolid , Lipoglucopéptidos , Staphylococcus aureus Resistente a Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/crecimiento & desarrollo , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Oxazolidinonas/farmacología , Vancomicina/farmacología
9.
J Antimicrob Chemother ; 67(12): 2919-26, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22899803

RESUMEN

OBJECTIVES: To evaluate the relative propensities of oritavancin and vancomycin to induce Clostridium difficile infection (CDI) in hamster and in vitro human gut models. METHODS: Hamsters received clindamycin (100 mg/kg orally or subcutaneously), oritavancin (50 mg/kg orally) or vancomycin (50 mg/kg orally). C. difficile spores were administered orally the next day. Control hamsters received vehicle only (polyethylene glycol 400) plus spores or clindamycin but no spores. Hamsters were monitored for clinical signs for 20 days. Caecal contents were analysed for C. difficile cells, spores and the presence of (cyto)toxin. Oritavancin and vancomycin were instilled over 7 days into separate in vitro gut models primed with pooled human faeces and inoculated with C. difficile ribotype 027 spores. Gut flora, C. difficile total viable and spore counts, toxin titres and antimicrobial concentrations were determined. RESULTS: All hamsters treated with oritavancin survived up to 20 days, with no evidence of C. difficile spores, vegetative cells or toxin in their caeca. No hamsters treated with clindamycin or vancomycin survived >6 days after spore administration. Death was associated with high C. difficile counts and toxin in caecal contents. In the gut model, oritavancin dosing elicited a rapid, marked decrease in total viable C. difficile and spore counts to below the limit of detection. Vancomycin did not elicit germination or toxin production in the gut model, but C. difficile remained present as spores throughout. CONCLUSIONS: Oritavancin exposure, unlike exposure to vancomycin or clindamycin, did not lead to CDI in hamsters. In both models, oritavancin reduced C. difficile total counts and spores to below detectable limits. The data indicate the potential of oritavancin for CDI treatment, since exposure did not induce C. difficile germination and toxin production, which are known to exacerbate the disease state.


Asunto(s)
Antibacterianos/metabolismo , Toxinas Bacterianas/biosíntesis , Clostridioides difficile/efectos de los fármacos , Clostridioides difficile/crecimiento & desarrollo , Glicopéptidos/metabolismo , Esporas Bacterianas/efectos de los fármacos , Esporas Bacterianas/crecimiento & desarrollo , Anciano , Anciano de 80 o más Años , Animales , Carga Bacteriana , Ciego/química , Ciego/microbiología , Infecciones por Clostridium/microbiología , Infecciones por Clostridium/patología , Cricetinae , Modelos Animales de Enfermedad , Heces/química , Heces/microbiología , Humanos , Lipoglucopéptidos , Vancomicina/metabolismo
11.
Int J Antimicrob Agents ; 39(2): 159-62, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22070858

RESUMEN

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.


Asunto(s)
Antibacterianos/farmacología , Glicopéptidos/farmacología , Staphylococcus aureus/efectos de los fármacos , Humanos , Lipoglucopéptidos , Pruebas de Sensibilidad Microbiana/métodos , Pruebas de Sensibilidad Microbiana/normas , Viabilidad Microbiana/efectos de los fármacos , Factores de Tiempo
13.
Antimicrob Agents Chemother ; 54(12): 5369-71, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20876372

RESUMEN

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.


Asunto(s)
Antibacterianos/farmacología , Membrana Celular/efectos de los fármacos , Enterococcus/efectos de los fármacos , Glicopéptidos/farmacología , Staphylococcus aureus/efectos de los fármacos , Vancomicina/farmacología , Farmacorresistencia Bacteriana , Lipoglucopéptidos
14.
Antimicrob Agents Chemother ; 54(8): 3481-3, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20498314

RESUMEN

Biophysical methods to study the binding of oritavancin, a lipoglycopeptide, to serum protein are confounded by nonspecific drug adsorption to labware surfaces. We assessed oritavancin binding to serum from mouse, rat, dog, and human by a microbiological growth-based method under conditions that allow near-quantitative drug recovery. Protein binding was similar across species, ranging from 81.9% in human serum to 87.1% in dog serum. These estimates support the translation of oritavancin exposure from nonclinical studies to humans.


Asunto(s)
Antibacterianos/metabolismo , Proteínas Sanguíneas/metabolismo , Glicopéptidos/metabolismo , Animales , Antibacterianos/farmacología , Cefalosporinas/metabolismo , Cefalosporinas/farmacología , Daptomicina/metabolismo , Daptomicina/farmacología , Perros , Glicopéptidos/farmacología , Humanos , Lipoglucopéptidos , Ratones , Pruebas de Sensibilidad Microbiana/métodos , Unión Proteica , Ratas , Especificidad de la Especie , Staphylococcus aureus/efectos de los fármacos , Cefpiroma
15.
Curr Protoc Microbiol ; Chapter 17: Unit17.1, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20131224

RESUMEN

The increasing incidence of antibiotic resistance in human pathogens is of significant concern. Resistance to the widely-used and highly effective glycopeptide antibacterial agent vancomycin, which has been in clinical use for over half a century, has emerged in staphylococci and enterococci. This has spurred the development of newer glycopeptide agents, some of which show activity against vancomycin-resistant organisms. The newer agents currently being developed contain lipophilic side-chains, which distinguish them from vancomycin; as such, they are categorized as lipoglycopeptides. Oritavancin, telavancin, and dalbavancin are lipoglycopeptides in late-stage development to combat Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. This unit describes methods that may be used to assess the in vitro activities of lipoglycopeptides. The methods include susceptibility assays, time-kill and time-kill-synergy assays, inhibition of synthesis of macromolecules, membrane perturbation assays, and measurement of activity against biofilms.


Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Glicopéptidos/farmacología , Lipopéptidos/farmacología , Pruebas de Sensibilidad Microbiana/métodos , Antibacterianos/química , Biopelículas/efectos de los fármacos , Glicopéptidos/química , Lipopéptidos/química , Potenciales de la Membrana/efectos de los fármacos , Viabilidad Microbiana/efectos de los fármacos
16.
Bioorg Med Chem Lett ; 20(4): 1355-9, 2010 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-20097069

RESUMEN

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


Asunto(s)
Difosfonatos/síntesis química , Glicopéptidos/síntesis química , Osteomielitis/tratamiento farmacológico , Profármacos/síntesis química , Animales , Antibacterianos/farmacología , Conservadores de la Densidad Ósea/síntesis química , Conservadores de la Densidad Ósea/química , Conservadores de la Densidad Ósea/uso terapéutico , Difosfonatos/química , Difosfonatos/uso terapéutico , Glicopéptidos/química , Glicopéptidos/uso terapéutico , Humanos , Lipoglucopéptidos , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Profármacos/química , Profármacos/uso terapéutico , Ratas , Staphylococcus aureus/efectos de los fármacos , Vancomicina/uso terapéutico
18.
Int J Antimicrob Agents ; 34(6): 550-4, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19818587

RESUMEN

The activity of oritavancin in vitro against recent clinical isolates of Streptococcus pyogenes, including antibiotic-resistant strains, was characterised by determination of broth microdilution minimal inhibitory concentrations as well as time-kill assays. Ten clinical isolates of S. pyogenes, three of which were resistant to erythromycin, as well as one reference S. pyogenes strain were tested. In the time-kill assays, oritavancin and the comparators vancomycin, teicoplanin, linezolid, penicillin, erythromycin and daptomycin were tested at static concentrations approximating their free peak (fC(max)) and free trough (fC(min)) concentrations in plasma when administered at approved doses for skin and skin-structure infections. At its fC(max) predicted from a 200 mg dose in humans, oritavancin exerted bactericidal activity (> or = 3 log kill relative to the starting inoculum) within 15 min to 3 h against all tested strains. Daptomycin exhibited bactericidal activity at its fC(max) for all but one strain; time to cidality was between 15 min and 6 h. At fC(min), only oritavancin was bactericidal against all the tested strains. Oritavancin displayed concentration-dependent killing of all isolates in vitro. Oritavancin was more rapidly bactericidal than the comparators at physiologically relevant concentrations against all strains tested. These data support the potential utility of oritavancin in infections with contemporary isolates of S. pyogenes, including drug-resistant strains.


Asunto(s)
Antibacterianos/farmacología , Glicopéptidos/farmacología , Viabilidad Microbiana/efectos de los fármacos , Streptococcus pyogenes/efectos de los fármacos , Humanos , Lipoglucopéptidos , Pruebas de Sensibilidad Microbiana , Infecciones Estreptocócicas/microbiología , Streptococcus pyogenes/aislamiento & purificación , Factores de Tiempo
19.
Diagn Microbiol Infect Dis ; 65(2): 207-10, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19748436

RESUMEN

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


Asunto(s)
Antibacterianos/antagonistas & inhibidores , Antibacterianos/farmacología , Glicopéptidos/antagonistas & inhibidores , Glicopéptidos/farmacología , Albúmina Sérica , Staphylococcus aureus/efectos de los fármacos , Humanos , Lipoglucopéptidos , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Factores de Tiempo
20.
Int J Antimicrob Agents ; 34(6): 540-3, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19744838

RESUMEN

In this study, we assessed by broth microdilution the in vitro activity of oritavancin, a semisynthetic lipoglycopeptide currently under development, against selected meticillin-resistant Staphylococcus aureus (MRSA) bloodstream isolates (n=56) from Geneva University Hospital, Switzerland, displaying a wide range of vancomycin minimum inhibitory concentrations (MICs) (0.25-4 microg/mL). The MRSA resistance phenotype was confirmed by broth microdilution (oxacillin MIC > or = 4 microg/mL) for all isolates; 89% and 100% of the tested isolates were also resistant to erythromycin and ciprofloxacin, respectively. For 53 MRSA isolates for which vancomycin MICs were in the susceptible range (0.5-2.0 microg/mL), the oritavancin MICs ranged from 0.03 microg/mL to 0.5 microg/mL. For these 53 vancomycin-susceptible isolates, the cumulative distribution of oritavancin MICs was markedly different from those of vancomycin, teicoplanin, daptomycin and linezolid MICs, yielding an oritavancin MIC for 90% of the organisms (MIC(90)) (0.25 microg/mL) that was four times lower than the MIC(90) values (1 microg/mL) of comparators. For three MRSA isolates with a vancomycin-intermediate phenotype (vancomycin MIC=4 microg/mL), oritavancin MICs (0.5-1.0 microg/mL) were 2-4-fold lower than vancomycin, teicoplanin or daptomycin MICs, but were equivalent to linezolid MICs. Pairwise comparison for each bloodstream isolate showed that oritavancin was > or =4-fold more active than vancomycin, teicoplanin and daptomycin, against 86%, 75% and 59% of all MRSA isolates, respectively.


Asunto(s)
Antibacterianos/farmacología , Bacteriemia/microbiología , Glicopéptidos/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Infecciones Estafilocócicas/microbiología , Ciprofloxacina/farmacología , Eritromicina/farmacología , Hospitales de Enseñanza , Humanos , Lipoglucopéptidos , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Suiza , Vancomicina/farmacología
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