Jones Ronald N, Moet Gary J, Sader Helio S, Mendes Rodrigo E, Castanheira Mariana
JMI Laboratories, North Liberty, IA 52317, USA.
J Antimicrob Chemother. 2009 Apr;63(4):716-20. doi: 10.1093/jac/dkp021. Epub 2009 Feb 13.
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.
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.
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.
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.
恶唑烷酮前药TR - 701的活性成分TR - 700已证明对多种革兰氏阳性菌具有强大活性。在本研究中，针对全球收集的耐利奈唑胺菌株及配对对照菌株，测试了TR - 700的单步突变频率、传代情况及活性。
采用参考肉汤微量稀释法，对120株耐利奈唑胺菌株及按属/种、地理来源、感染部位和时间配对的120株对照菌株进行药敏试验。分离菌株的种类包括：粪肠球菌（16株耐利奈唑胺/16株野生型菌株）；屎肠球菌（55/55）、金黄色葡萄球菌（8/8）；凝固酶阴性葡萄球菌（至少7种，40/40）和草绿色链球菌（2种，1/1）。通过PCR和测序检测23S rRNA靶点突变或cfr基因。
在耐利奈唑胺菌株中，耐药机制为G2576T（109株）、cfr（4株）和未知（7株），这些菌株来自欧洲、远东以及南北美洲。大多数菌株为多重耐药，携带cfr基因的菌株对氯霉素、克林霉素、利奈唑胺、截短侧耳素类和链阳菌素B表现出共同耐药性。无论菌株种类如何，TR - 700的MIC值比利奈唑胺低4 - 32倍。对于88%、96%和>99%的耐利奈唑胺菌株，TR - 700的MIC结果分别≤4 mg/L、≤8 mg/L或≤16 mg/L。未检测到自发单步突变（<1.1×10⁻⁹），与利奈唑胺对照相比，14天传代研究中TR - 700的MIC升高幅度较小。
TR - 700对耐利奈唑胺的革兰氏阳性球菌菌株及野生型对照菌株表现出增强的活性。大量（近90%）耐利奈唑胺菌株可被潜在可达到的TR - 700水平（≤4 mg/L）抑制。所有携带新出现的cfr介导耐药决定簇的菌株，其TR - 700的MIC结果均≤8 mg/L。
