Microbiology, University of Leeds and Leeds Teaching Hospitals, Leeds General Infirmary, Old Medical School, Leeds LS1 3EX, UK.
J Antimicrob Chemother. 2011 Jul;66(7):1537-46. doi: 10.1093/jac/dkr155. Epub 2011 Apr 18.
Therapeutic options in Clostridium difficile infection (CDI) are limited. We examined linezolid activity in vitro and potential therapeutic efficacy using a gut model of CDI.
MICs were determined by agar incorporation for 118 diverse C. difficile faecal isolates, including epidemic strains and strains with reduced susceptibility to metronidazole. CDI was established in two gut model experiments using C. difficile epidemic strains (ribotypes 027 and 106) and linezolid was dosed to achieve human gut concentrations.
Linezolid demonstrated good in vitro activity against 98% of the isolates. Two isolates (PCR ribotypes 023 and 067) demonstrated resistance to linezolid, although supplementary susceptibility testing of ribotype 023 isolates did not detect further resistance. In a gut model that simulates CDI, linezolid reduced the duration of cytotoxin production by C. difficile PCR ribotype 027 without influencing viable counts of vegetative forms of the organism. C. difficile PCR ribotype 106 viable counts declined at a faster rate than those of PCR ribotype 027 following dosing with linezolid, but cytotoxin titres declined at a similar rate to an untreated control. Gut flora perturbation occurring on linezolid exposure reversed after drug cessation. Recrudescence of spore germination with subsequent cytotoxin was seen with the C. difficile ribotype 106 strain. Resistance to linezolid was not detected either during linezolid instillation or post-dosing.
Linezolid may reduce toxin levels, as reported in staphylococci and streptococci. Further evaluation is warranted of the effect of linezolid on expression of C. difficile toxin, and to investigate potential recurrence of CDI following cessation of linezolid.
艰难梭菌感染（CDI）的治疗选择有限。我们研究了利奈唑胺在体外的活性和使用 CDI 肠道模型的潜在治疗效果。
通过琼脂掺入法测定了 118 种不同艰难梭菌粪便分离株的 MIC，包括流行株和对甲硝唑敏感性降低的菌株。使用艰难梭菌流行株（027 型和 106 型）建立了两个肠道模型实验，对利奈唑胺进行了给药，以达到人体肠道浓度。
利奈唑胺对 98%的分离株表现出良好的体外活性。有两个分离株（PCR 型 023 和 067）对利奈唑胺表现出耐药性，尽管对 023 型分离株的补充药敏试验未检测到进一步的耐药性。在模拟 CDI 的肠道模型中，利奈唑胺降低了 PCR 型 027 艰难梭菌细胞毒素产生的持续时间，而不影响该生物体的营养体形式的活菌计数。与 PCR 型 027 相比，利奈唑胺给药后 PCR 型 106 的艰难梭菌活菌计数下降更快，但细胞毒素滴度下降速度与未处理的对照组相似。在停止用药后，暴露于利奈唑胺时发生的肠道菌群扰动会逆转。用 PCR 型 106 艰难梭菌菌株观察到孢子发芽和随后细胞毒素的复发。在利奈唑胺灌注或给药后均未检测到对利奈唑胺的耐药性。
利奈唑胺可能会降低毒素水平，如在葡萄球菌和链球菌中报道的那样。需要进一步评估利奈唑胺对艰难梭菌毒素表达的影响，并研究停止利奈唑胺治疗后 CDI 复发的可能性。
