Departments of Medicine, Chi Mei Medical Center, Tainan, Taiwan.
Antimicrob Agents Chemother. 2012 Jun;56(6):2916-22. doi: 10.1128/AAC.00110-12. Epub 2012 Apr 2.
The emergence of multidrug-resistant Salmonella isolates has created the need for new therapeutic agents. We evaluated the intracellular activity of four carbapenem compounds against clinical nontyphoid Salmonella (NTS) isolates in vitro and ex vivo. Subsequently, the efficacy of carbapenem treatment against selected Salmonella isolates in vivo was assessed using a murine peritonitis model. The MIC(50) and MIC(90) for doripenem, ertapenem, imipenem, and meropenem against 126 NTS isolates were found to be 0.062 and 0.062, 0.015 and 0.015, 0.5 and 1, and 0.031 and 0.031 μg/ml, respectively. The intracellular killing effect of ertapenem was sustained for 24 h and was superior to that of imipenem, meropenem, and doripenem; its effect was comparable to that of ceftriaxone. Ertapenem demonstrated an excellent pharmacokinetic profile with a percent time above the MIC of 75.5% and an area under the concentration-time curve/MIC ratio of 20,733. When peritoneal exudate cells were examined directly ex vivo from mice with Salmonella-induced peritonitis, cells from mice treated with ertapenem and ceftriaxone had intracellular and extracellular bacterial counts reduced 10(2)- to 10(4)-fold and exhibited killing effects similar to each other. The survival rates of mice inoculated with 1 × 10(5) and 10(6) CFU of a ceftriaxone-susceptible Salmonella isolate that were subsequently treated with ertapenem or ceftriaxone were 100% and 90%, respectively. When mice were inoculated with 5 × 10(4) and 10(5) CFU of a ceftriaxone-resistant and ciprofloxacin-resistant Salmonella isolate, mice treated with ertapenem had a higher survival rate than mice treated with ceftriaxone (70% versus 0% and 50% versus 0%, respectively; P < 0.001). Our results suggest that ertapenem is at least as effective as ceftriaxone in treating murine Salmonella infections and show that further clinical investigations on the potential use of ertapenem in treatment of human Salmonella infections are warranted.
耐多药沙门氏菌分离株的出现催生了对新型治疗药物的需求。我们评估了四种碳青霉烯类化合物对临床非伤寒沙门氏菌（NTS）分离株的体外和体内细胞内活性。随后，使用鼠腹膜炎模型评估了碳青霉烯类药物对选定沙门氏菌分离株的体内治疗效果。发现多利培南、厄他培南、亚胺培南和美罗培南对 126 株 NTS 分离株的 MIC50 和 MIC90 分别为 0.062 和 0.062、0.015 和 0.015、0.5 和 1、0.031 和 0.031 μg/ml。厄他培南的细胞内杀菌效果持续 24 小时，优于亚胺培南、美罗培南和多利培南；其效果与头孢曲松相当。厄他培南具有出色的药代动力学特性，超过 MIC 的时间百分比为 75.5%，浓度-时间曲线下面积/MIC 比值为 20733。当直接从患有沙门氏菌性腹膜炎的小鼠的腹膜渗出液细胞中进行离体检测时，用厄他培南和头孢曲松治疗的小鼠的细胞内和细胞外细菌计数减少了 10(2)-10(4)倍，并且具有相似的杀菌效果。用头孢曲松敏感的沙门氏菌分离株接种 1×10(5)和 10(6)CFU 的小鼠，随后用厄他培南或头孢曲松治疗后，存活率均为 100%；而用头孢曲松耐药和环丙沙星耐药的沙门氏菌分离株接种 5×10(4)和 10(5)CFU 的小鼠，用厄他培南治疗的小鼠的存活率高于用头孢曲松治疗的小鼠（分别为 70%比 0%和 50%比 0%；P<0.001）。我们的结果表明，厄他培南在治疗鼠沙门氏菌感染方面至少与头孢曲松一样有效，并表明进一步开展临床研究以评估厄他培南在治疗人类沙门氏菌感染方面的潜力是合理的。
