Gentry-Nielsen Martha J, Olsen Keith M, Preheim Laurel C
Research Service, Veterans Affairs Medical Center, Omaha, Nebraska 68105, USA.
Antimicrob Agents Chemother. 2002 May;46(5):1345-51. doi: 10.1128/AAC.46.5.1345-1351.2002.
Linezolid is a new oxazolidinone antibiotic with potent activity against gram-positive bacteria, including Streptococcus pneumoniae. The pharmacodynamic activity and in vivo efficacy of linezolid were compared to those of ceftriaxone in an immunocompetent rat model of pneumococcal pneumonia. Rats infected intratracheally with 8 x 10(7) CFU of a penicillin-sensitive (MIC, 0.032 microg/ml) strain of S. pneumoniae were treated for 5 days beginning 18 h postinfection. Groups of rats were sham treated with oral phosphate-buffered saline or received oral liquid linezolid at 25 or 50 mg/kg of body weight twice a day (b.i.d.) or subcutaneous ceftriaxone at 100 mg/kg once daily. Mortality was monitored for 10 days postinfection; blood culturing was performed on day 1 (pretreatment) and on days 3, 5, and 10 postinfection for the determination of bacteremia. Serum also was collected for the determination of pharmacokinetic and pharmacodynamic parameters at 30 min and at 3, 5, and 12 h (linezolid) or 3, 5, and 24 h (ceftriaxone) postdose. The cumulative mortality rates were 100% for the sham-treated group, 58.3% for the low-dose linezolid group, 8.3% for the high-dose linezolid group, and 0% for the ceftriaxone group. Rats in each of the antibiotic treatment groups had significantly fewer bacteria (P < 0.00001) in their bronchoalveolar lavage fluid (BALF) on day 3 postinfection than sham-treated rats. There also were significantly fewer organisms in the BALF of rats treated with ceftriaxone than in the BALF of rats treated with either dose of linezolid. Oral linezolid at 50 mg/kg b.i.d. therefore was as effective as ceftriaxone in experimental pneumococcal pneumonia, whereas the 25-mg/kg b.i.d. dose was significantly less effective. All pharmacodynamic parameters reflected efficacy and were significantly different for the two dosage regimens of linezolid (P < 0.01). However, the free-fraction pharmacodynamic parameters predictive of outcome were a value of >39% for the percentage of time in the experimental dosing interval during which the linezolid concentration exceeded the MIC and a value of >147 for the ratio of the area under the serum concentration-time curve to the MIC.
利奈唑胺是一种新型恶唑烷酮类抗生素，对包括肺炎链球菌在内的革兰氏阳性菌具有强大活性。在免疫功能正常的大鼠肺炎链球菌肺炎模型中，将利奈唑胺的药效学活性和体内疗效与头孢曲松进行了比较。用8×10⁷CFU对青霉素敏感（MIC，0.032μg/ml）的肺炎链球菌菌株经气管内感染大鼠，在感染后18小时开始治疗5天。大鼠组分别用口服磷酸盐缓冲盐水进行假治疗，或每天两次（bid）接受25或50mg/kg体重的口服液体利奈唑胺，或每天一次接受100mg/kg的皮下头孢曲松。感染后监测10天的死亡率；在感染后第1天（治疗前）以及第3、5和10天进行血培养以确定菌血症。给药后30分钟以及3、5和12小时（利奈唑胺）或3、5和24小时（头孢曲松）还收集血清以测定药代动力学和药效学参数。假治疗组的累积死亡率为100%，低剂量利奈唑胺组为58.3%，高剂量利奈唑胺组为8.3%，头孢曲松组为0%。在感染后第3天，各抗生素治疗组大鼠支气管肺泡灌洗液（BALF）中的细菌数量均显著少于假治疗组大鼠（P<0.00001）。头孢曲松治疗的大鼠BALF中的微生物数量也显著少于两种剂量利奈唑胺治疗的大鼠BALF中的微生物数量。因此，50mg/kg bid的口服利奈唑胺在实验性肺炎链球菌肺炎中与头孢曲松一样有效，而25mg/kg bid的剂量效果明显较差。所有药效学参数均反映了疗效，利奈唑胺的两种给药方案的药效学参数有显著差异（P<0.01）。然而，预测结果的游离分数药效学参数为：利奈唑胺浓度超过MIC的实验给药间隔时间百分比>39%，血清浓度-时间曲线下面积与MIC的比值>147。
