JAC Advance Access originally published online on February 13, 2009
Journal of Antimicrobial Chemotherapy 2009 63(4):716-720; doi:10.1093/jac/dkp021
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Original research |
TR-700 in vitro activity against and resistance mutation frequencies among Gram-positive pathogens
JMI Laboratories, North Liberty, IA 52317, USA
Received 26 November 2008; returned 6 January 2009; revised 7 January 2009; accepted 13 January 2009
* Corresponding author. Tel: +1-319-665-3370; Fax: +1-319-655-3371; E-mail: ronald-jones{at}jmilabs.com
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 
4, 8 or 16 mg/L for 88%, 96% and >99% of linezolid-non-susceptible strains, respectively. Spontaneous single-step mutations were undetected (<1.1x10–9) 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 (4 mg/L) of TR-700. All strains with the emerging cfr-mediated resistance determinant had TR-700 MIC results at 8 mg/L.
Keywords: oxazolidinones , cfr , mutation studies , TR-701
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