Optimer Pharmaceuticals, San Diego, CA, USA.
J Med Microbiol. 2011 Aug;60(Pt 8):1213-1217. doi: 10.1099/jmm.0.029470-0. Epub 2011 Feb 24.
The kinetics of bacterial killing for fidaxomicin and its major metabolite, OP-1118, were investigated against Clostridium difficile strains, including two clinical strains belonging to the restriction endonuclease analysis group BI (ORG 1687 and 1698), the ATCC 43255 strain and two laboratory-derived mutant strains with decreased susceptibility to fidaxomicin (ORG 919 and 1620). Both fidaxomicin and OP-1118 demonstrated time-dependent killing of C. difficile strains. Fidaxomicin (at 4× MIC) reduced bacterial counts of the ATCC 43255 strain, clinical strain ORG 1687 and the two laboratory-generated mutant strains by ≥3 logs within 48 h of exposure. The other BI strain, ORG 1698, was tested at 2× MIC fidaxomicin with bacterial counts decreasing 1 log in 48 h. Exposure to OP-1118 (at 4× MIC) also resulted in a ≥3 log drop in c.f.u. counts for the ATCC 43255 strain, the clinical BI strain ORG 1687 and the mutant strain ORG 919. Higher concentrations of OP-1118 (32× MIC) were required for a 3 log reduction in c.f.u. counts for the other BI strain, ORG 1698. In summary, the results indicate that both fidaxomicin and its major metabolite, OP-1118, are bactericidal against C. difficile strains, including the hypervirulent restriction endonuclease analysis group BI strains, at concentrations that are many fold below the detected faecal concentrations of these compounds after oral administration of fidaxomicin.
研究了非达霉素及其主要代谢物 OP-1118 对艰难梭菌菌株的杀菌动力学，包括属于内切酶分析组 BI 的两个临床菌株（ORG 1687 和 1698）、ATCC 43255 菌株和两个对非达霉素敏感性降低的实验室衍生突变株（ORG 919 和 1620）。非达霉素和 OP-1118 均表现出对艰难梭菌菌株的时间依赖性杀菌作用。非达霉素（4×MIC）在暴露 48 小时内可使 ATCC 43255 菌株、临床菌株 ORG 1687 和两个实验室产生的突变株的细菌计数减少≥3 对数级。另一个 BI 菌株 ORG 1698 在 2×MIC 非达霉素的测试中，48 小时内细菌计数减少 1 对数级。暴露于 OP-1118（4×MIC）也导致 ATCC 43255 菌株、临床 BI 菌株 ORG 1687 和突变株 ORG 919 的 c.f.u.计数减少≥3 对数级。需要更高浓度的 OP-1118（32×MIC）才能使另一个 BI 菌株 ORG 1698 的 c.f.u.计数减少 3 对数级。总之，结果表明，非达霉素及其主要代谢物 OP-1118 对艰难梭菌菌株均具有杀菌作用，包括高毒力的内切酶分析组 BI 菌株，其浓度是口服非达霉素后粪便中这些化合物检测浓度的许多倍。
