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J Antimicrob Chemother. 2009 Apr;63(4):716-20. doi: 10.1093/jac/dkp021. Epub 2009 Feb 13.

TR-700 in vitro activity against and resistance mutation frequencies among Gram-positive pathogens.

Author information

  • 1JMI Laboratories, North Liberty, IA 52317, USA. ronald-jones@jmilabs.com

Abstract

BACKGROUND:

TR-700, the active component of the oxazolidinone prodrug TR-701, has demonstrated potent activity against numerous Gram-positive species. In this study, single-step mutation frequencies, passaging and the activity of TR-700 were tested against a worldwide collection of linezolid-non-susceptible organisms and matched controls.

METHODS:

One hundred and twenty linezolid-non-susceptible and 120 controls matched by genus/species, geographic origin, site of infection and time were susceptibility tested by reference broth microdilution methods. Species of isolates were: Enterococcus faecalis (16 linezolid non-susceptible/16 wild-type strains); Enterococcus faecium (55/55), Staphylococcus aureus (8/8); coagulase-negative staphylococci (at least 7 spp., 40/40) and viridans group streptococci (2 spp., 1/1). 23S rRNA target mutations or cfr genes were detected by PCR and sequencing.

RESULTS:

Among linezolid-non-susceptible strains, the resistance mechanisms were G2576T (109), cfr (4) and unknown (7), with strains originating from Europe, Far East and North and South America. Most strains were multidrug-resistant and cfr isolates exhibited co-resistance to phenicols, clindamycin, linezolid, pleuromutilins and streptogramin B. TR-700 MIC values, regardless of species, were 4-32-fold lower than those of linezolid. TR-700 MIC results were < or = 4, < or = 8 or < or = 16 mg/L for 88%, 96% and > 99% of linezolid-non-susceptible strains, respectively. Spontaneous single-step mutations were undetected (<1.1 x 10(-9)) and 14 day passaging studies produced modest TR-700 MIC elevations compared with linezolid controls.

CONCLUSIONS:

TR-700 exhibited enhanced activity against linezolid-non-susceptible and wild-type control strains of Gram-positive cocci. A significant number (nearly 90%) of linezolid-non-susceptible strains were inhibited by potentially achievable levels (< or = 4 mg/L) of TR-700. All strains with the emerging cfr-mediated resistance determinant had TR-700 MIC results at < or = 8 mg/L.

PMID:
19218276
[PubMed - indexed for MEDLINE]
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