Hilliard Jamese J, Fernandez Jeffrey, Melton John, Macielag Mark J, Goldschmidt Raul, Bush Karen, Abbanat Darren
Johnson & Johnson Pharmaceutical Research and Development, 1000 Route 202, Raritan, NJ 08869, USA.
Antimicrob Agents Chemother. 2009 May;53(5):2028-33. doi: 10.1128/AAC.00833-08. Epub 2009 Mar 9.
RWJ-416457 is an investigational pyrrolopyrazolyl-substituted oxazolidinone with activity against antibiotic-susceptible and -resistant gram-positive pathogens. Efficacies of RWJ-416457, linezolid, and vancomycin against methicillin-susceptible Staphylococcus aureus (MSSA) and community-associated methicillin-resistant S. aureus (CA-MRSA) in murine skin and systemic infections were compared, as were efficacies against Streptococcus pneumoniae in a lower respiratory infection. In staphylococcal systemic infections, RWJ-416457 was equipotent with to twofold more potent than linezolid, with 50% effective dose values ranging from 1.5 to 5 mg/kg of body weight/day. RWJ-416457 was two- to fourfold less potent than vancomycin against MSSA but up to fourfold more potent than vancomycin against CA-MRSA. In MSSA and CA-MRSA skin infections, RWJ-416457 demonstrated an efficacy similar to that of linezolid, reducing CFU/g skin approximately 1.0 log(10) at all doses tested; vancomycin yielded greater reductions than the oxazolidinones, with decreases in CFU/g skin of 3 log(10) (MSSA) and 2 log(10) (CA-MRSA). In the pneumococcal model, RWJ-416457 was two- to fourfold more potent than linezolid. The free-drug area under the concentration-time curves at 24 h (fAUC(24)) were similar for RWJ-416457 and linezolid. The half-life of RWJ-416457 was up to threefold longer than that of linezolid for all routes of administration. The fAUC(24)/MIC ratio, the pharmacodynamic parameter considered predictive of oxazolidinone efficacy, was approximately twofold greater for RWJ-416457 than for linezolid. Since the fAUC values were similar for both compounds, the higher fAUC/MIC ratios of RWJ-416457 appear to result from its greater in vitro potency. These results demonstrate that RWJ-416457 is a promising new oxazolidinone with efficacy in S. aureus or S. pneumoniae mouse infection models.
RWJ - 416457是一种正在研究的吡咯并吡唑基取代的恶唑烷酮，对易感性和耐药性革兰氏阳性病原体均有活性。比较了RWJ - 416457、利奈唑胺和万古霉素在小鼠皮肤和全身感染中对甲氧西林敏感金黄色葡萄球菌（MSSA）和社区获得性耐甲氧西林金黄色葡萄球菌（CA - MRSA）的疗效，以及在肺部感染中对肺炎链球菌的疗效。在葡萄球菌全身感染中，RWJ - 416457与利奈唑胺等效或效力比其高两倍，50%有效剂量值范围为1.5至5毫克/千克体重/天。RWJ - 416457对MSSA的效力比万古霉素低两至四倍，但对CA - MRSA的效力比万古霉素高四倍。在MSSA和CA - MRSA皮肤感染中，RWJ - 416457显示出与利奈唑胺相似的疗效，在所有测试剂量下使每克皮肤的菌落形成单位（CFU）减少约1.0 log(10)；万古霉素比恶唑烷酮类药物产生更大的减少，使每克皮肤的CFU减少3 log(10)（MSSA）和2 log(10)（CA - MRSA）。在肺炎链球菌模型中，RWJ - 416457的效力比利奈唑胺高两至四倍。RWJ - 416457和利奈唑胺在24小时的浓度 - 时间曲线下的游离药物面积（fAUC(24)）相似。RWJ - 416457的半衰期在所有给药途径下比利奈唑胺长至三倍。fAUC(24)/MIC比值（被认为是预测恶唑烷酮疗效的药效学参数），RWJ - 416457比利奈唑胺大约高两倍。由于两种化合物的fAUC值相似，RWJ - 416457较高的fAUC/MIC比值似乎源于其更高的体外效力。这些结果表明，RWJ - 416457是一种有前景的新型恶唑烷酮，在金黄色葡萄球菌或肺炎链球菌小鼠感染模型中具有疗效。
