Redmond Sarah N, Cadnum Jennifer L, Jencson Annette L, Kaple Claire E, Wilson Brigid M, Skinner Andrew M, Gargis Amy S, Hwang Munok, Choi Hosoon, Chatterjee Piyali, Jinadatha Chetan, Donskey Curtis J
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Research Service, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, USA.
Clin Infect Dis. 2025 Jun 4;80(5):984-991. doi: 10.1093/cid/ciaf028.
There have been several recent reports of Clostridioides difficile infection (CDI) due to isolates with reduced fidaxomicin susceptibility (minimum inhibitory concentration [MIC] ≥ 2 µg/mL). However, the clinical implications are uncertain because fidaxomicin achieves high concentrations in the intestinal tract.
In an acute care hospital, we conducted a 3-year cohort study of patients with CDI to determine the frequency of infection with isolates with reduced fidaxomicin susceptibility and the impact on response to fidaxomicin treatment. Stool specimens were cultured for C. difficile, and susceptibility testing was performed using agar dilution. Whole-genome sequencing was used to identify mutations associated with reduced fidaxomicin susceptibility and to determine relatedness of isolates. For genomically related susceptible and reduced susceptibility isolates from the same patient, we compared rates of growth, sporulation, and toxin production.
Of 108 fidaxomicin-treated patients, 6 (5.6%) were infected with isolates that possessed reduced fidaxomicin susceptibility (MICs 8-32 µg/mL), including 3 with initially susceptible isolates followed by clinical failure with subsequent recovery of genomically related isolates with reduced susceptibility. Isolates with reduced fidaxomicin susceptibility harbored mutations in RNA polymerase associated with reduced susceptibility and exhibited reduced toxin production, and 20% to 40% of isolates tested had reduced growth and/or sporulation in comparison with susceptible isolates. Three patients were infected with genomically indistinguishable ribotype 097 isolates with reduced fidaxomicin susceptibility.
Our findings highlight the potential for the emergence on therapy of clinically relevant reduced fidaxomicin susceptibility in C. difficile and its spread via transmission to other patients.
最近有几篇关于艰难梭菌感染（CDI）的报道，感染由对非达霉素敏感性降低（最低抑菌浓度[MIC]≥2μg/mL）的分离株引起。然而，由于非达霉素在肠道中可达到高浓度，其临床意义尚不确定。
在一家急症医院，我们对CDI患者进行了一项为期3年的队列研究，以确定对非达霉素敏感性降低的分离株的感染频率及其对非达霉素治疗反应的影响。对粪便标本进行艰难梭菌培养，并使用琼脂稀释法进行药敏试验。采用全基因组测序来鉴定与非达霉素敏感性降低相关的突变，并确定分离株的相关性。对于来自同一患者的基因组相关的敏感和敏感性降低的分离株，我们比较了其生长、产孢和毒素产生率。
在108例接受非达霉素治疗的患者中，6例（5.6%）感染了对非达霉素敏感性降低的分离株（MIC为8 - 32μg/mL），其中3例最初为敏感分离株，随后临床治疗失败，之后分离出基因组相关的敏感性降低的分离株。对非达霉素敏感性降低的分离株在与敏感性降低相关的RNA聚合酶中存在突变，且毒素产生减少，与敏感分离株相比，20%至40%的受试分离株生长和/或产孢减少。3例患者感染了基因组无法区分的核糖型097且对非达霉素敏感性降低的分离株。
我们的研究结果突出了艰难梭菌临床相关的非达霉素敏感性降低在治疗过程中出现并通过传播感染其他患者的可能性。
