In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents

Zurenko, Gary E.; Yagi, Betty H.; Schaadt, Ronda D.; Allison, John W.; Kilburn, James O.; Glickman, Suzanne E.; Hutchinson, Douglas K.; Barbachyn, Michael R.; Brickner, Steven J.

doi:10.1128/aac.40.4.839

Cited by 433 publications

(217 citation statements)

References 13 publications

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“…A recent summary of the results obtained with linezolid and eperezolid together with the relevant literature is given in [7]. Linezolid and eperezolid are active against sensitive and multidrug-resistant Gram-positive organisms, such as Staphylococcus spp., including S. aureus und S. epidermidis, Streptococcus spp., including S. pneumoniae and S. pyogenes, Enterococcus spp., including E. faecalis and E. faecium, Corynebacterium spp., Mycobacterium spp., including M. tuberculosis, Actinomyces spp., Clostridium spp., Lactobacillus spp., Peptostreptococcus spp., Propionibacterium spp., Haemophilus influenzae, Listeria monocytogenes, Moraxella catarrhalis [18,19]. In addition, they show activity against a variety of anaerobic, Gram-negative bacteria such as Bacteroides spp., Bilophila wadworthia, Fusobacterium spp., Mobiluncus spp., Pre6otella spp., Porphyromonas asaccharolyticus, Veillonella alcalescens [19].…”

Section: Activity Spectrum Of Oxazolidinonesmentioning

confidence: 99%

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Oxazolidinones: a novel class of antibiotics

Müller¹,

Schimz²

1999

Cellular and Molecular Life Sciences (CMLS)

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Oxazolidinones are a novel class of synthetic antimicrobial agents which have now entered phase III clinical trials. The most promising feature of these compounds is their oral activity against multidrug-resistant Gram-positive bacteria which have created tremendous therapeutic problems in recent years. In addition, development of resistance in vitro has so far remained below detectable levels. Different from many antibacterial agents used in the treatment of human infections, oxazolidinones do not block bacterial protein synthesis at the level of polypeptide chain elongation but rather seem to interfere with initiation of translation. Both binding of formylmethionine-transfer RNA to initiation complexes as well as release of formylmethioninepuromycin from initiation complexes have been reported to be targets for oxazolidinones. The major binding sites of oxazolidinones are the large (50S) ribosomal subunits.

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Section: Activity Spectrum Of Oxazolidinonesmentioning

confidence: 99%

“…Oxazolidinones have been successfully used to inhibit bacterial strains which were resistant amongst others to methicillin, vancomycin, penicillin, rifampin and other antitubercular agents [7,18]. The lack of crossresistance with other, contemporary antibiotics is explained by the unique mechanism of action of the oxazolidinones.…”

Section: Resistancementioning

confidence: 99%

Oxazolidinones: a novel class of antibiotics

Müller¹,

Schimz²

1999

Cellular and Molecular Life Sciences (CMLS)

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“…We felt this was particularly important with the staphylococci and their propensity for resistance development which is well known. More recently the novel use of a spiral gradient plating technique has resulted in the isolation of S. aureus isolates which are resistant to eperezolid and linezolid [7,9,11]. Over 20 serial transfers in a drug gradient were required to produce one resistant S. aureus with a MIC of 32 mg/l for eperezolid and which was cross-resistant with linezolid.…”

Section: Resistance Developmentmentioning

confidence: 99%

Linezolid, Critical Characteristics

Hamel¹,

Stapert²,

Moermann³

et al. 2000

Infection

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In spite of a constantly expanding information base with the oxazolidinones generally and linezolid specifically, we have elected here to focus on the key characteristics of linezolid. Linezolid is the first member of a new class of antimicrobial agents, the oxazolidinones, to be tested in humans in Phase I, Phase II and Phase III clinical trials. The oxazolidinones have a novel mechanism of action in that they inhibit initiation complex formation in bacterial protein synthesis and, consistent with a novel mechanism of action, they do not exhibit cross-resistance with existing antibacterial agents. Importantly, resistance development as measured in the laboratory occurs very slowly, there is no evidence of rapid resistance development. The spectrum of oxazolidinone activity is principally gram-positive and in vitro studies demonstrate that linezolid is equivalent to vancomycin in vitro. Linezolid is orally as well as intravenously active and orally administered linezolid is as efficacious in mouse models of bacterial disease as is subcutanously administered vancomycin against appropriate pathogens. The exceptional oral behavior of linezolid in mouse models is readily explained by the observation that oral linezolid is 100% bioavilable and that administration of 400- and 600-mg doses of linezolid in humans results in blood level curves which predict that linezolid will be very well suited for bid dosing. Additionally, the blood level concentrations are in significant and very comfortable excess of the MIC90 concentrations for the important gram-positive pathogens for the bulk of the dosing interval.

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“…It appears to act by inhibiting the initiation phase of protein synthesis, probably by binding to the 50S ribosomal subunit during the formation of the initiation complex [14,15,16]. Because of its unique mechanism of action, cross-resistance with other antimicrobial agents is difficult to develop [12,17].…”

Section: Introductionmentioning

confidence: 97%

Efficacy and Safety of Linezolid in the Treatment of Skin and Soft Tissue Infections

2002

European Journal of Clinical Microbiology & Infectious Dise

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The vast majority of community-acquired skin and soft tissue infections (SSTIs) are caused by gram-positive cocci or are polymicrobial in nature. Hospital-acquired SSTIs are caused by gram-positive cocci in more than 50% of patients. Multidrug-resistant gram-positive cocci are rarely associated with community-acquired SSTIs but are frequently found in hospital-acquired SSTIs. Linezolid is the first member of a new class of antibiotics, the oxazolidinones. These antimicrobial agents have a unique mechanism of action and exhibit excellent activity against a variety of gram-positive organisms, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Linezolid is 100% orally absorbed, allowing for easy intravenous-to-oral continuation therapy. There is considerable clinical experience with the use of linezolid in SSTIs in phase II and III clinical trials. In comparative trials, linezolid was as effective as oxacillin-dicloxacillin or flucloxacillin in patients with complicated SSTIs caused by gram-positive organisms. Linezolid was also associated with significantly earlier hospital discharge than comparator agents among patients with SSTIs. It was equally effective as vancomycin in patients with SSTIs caused by methicillin-resistant Staphylococcus aureus and has also demonstrated efficacy in patients with SSTIs caused by vancomycin-resistant enterococci. Linezolid is well tolerated: the most common adverse events (gastrointestinal effects, headache) are reported in frequencies similar to those reported for comparator agents. Myelosuppression has been reported after prolonged administration but is reversible after discontinuation of the drug. Overall, linezolid has favorable efficacy and safety profiles and will be an increasingly useful option for the treatment of SSTIs, particularly those due to multidrug-resistant, gram-positive organisms.

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In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents

Cited by 433 publications

References 13 publications

Oxazolidinones: a novel class of antibiotics

Oxazolidinones: a novel class of antibiotics

Linezolid, Critical Characteristics

Efficacy and Safety of Linezolid in the Treatment of Skin and Soft Tissue Infections

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