Wilcox Mark H, Rahav Galia, Dubberke Erik R, Gabryelski Lori, Davies Kerrie, Berry Claire, Eves Karen, Ellison Misoo C, Guris Dalya, Dorr Mary Beth
Leeds Teaching Hospitals & University of Leeds, Leeds, West Yorkshire, UK.
Sheba Medical Center, Tel Hashomer, & Sackler Medical School, Tel Aviv University, Israel.
Open Forum Infect Dis. 2019 Aug 1;6(8). doi: 10.1093/ofid/ofz293.
The optimum diagnostic test method for Clostridioides difficile infection (CDI) remains controversial due to variation in accuracy in identifying true CDI. This post hoc analysis examined the impact of CDI diagnostic testing methodology on efficacy outcomes in phase 3 MODIFY I/II trials.
In MODIFY I/II (NCT01241552/NCT01513239), participants received bezlotoxumab (10 mg/kg) or placebo during anti-CDI treatment for primary/recurrent CDI (rCDI). Using MODIFY I/II pooled data, initial clinical cure (ICC) and rCDI were assessed in participants diagnosed at baseline using direct detection methods (enzyme immunoassay [EIA]/cell cytotoxicity assay [CCA]) or indirect methods to determine toxin-producing ability (toxin gene polymerase chain reaction [tgPCR]/toxigenic culture).
Of 1554 participants who received bezlotoxumab or placebo in MODIFY I/II, 781 (50.3%) and 773 (49.7%) were diagnosed by tgPCR/toxigenic culture and toxin EIA/CCA, respectively. Participants diagnosed by toxin EIA/CCA were more likely to be inpatients, older, and have severe CDI. In bezlotoxumab recipients, ICC rates were slightly higher in the toxin EIA/CCA subgroup (81.7%) vs tgPCR/toxigenic culture (78.4%). Bezlotoxumab significantly reduced the rCDI rate vs placebo in both subgroups; however, the magnitude of reduction was substantially larger in participants diagnosed by toxin EIA/CCA (relative difference, -46.6%) vs tgPCR/toxigenic culture (-29.1%). In bezlotoxumab recipients, the rCDI rate was lower in the toxin EIA/CCA subgroup (17.6%) vs tgPCR/toxigenic culture (23.6%; absolute difference, -6.0%; 95% confidence interval, -12.4 to 0.3; relative difference, -25.4%).
Diagnostic tests that detect fecal C. difficile toxins are of fundamental importance to accurately diagnosing CDI, including in clinical trial design, ensuring that therapeutic efficacy is not underestimated.
由于在识别真正的艰难梭菌感染（CDI）方面准确性存在差异，CDI的最佳诊断测试方法仍存在争议。这项事后分析研究了CDI诊断测试方法对3期MODIFY I/II试验疗效结果的影响。
在MODIFY I/II（NCT01241552/NCT01513239）中，参与者在接受抗CDI治疗原发性/复发性CDI（rCDI）期间接受贝佐托昔单抗（10mg/kg）或安慰剂。使用MODIFY I/II汇总数据，对在基线时使用直接检测方法（酶免疫测定[EIA]/细胞毒性测定[CCA]）或间接方法确定产毒能力（毒素基因聚合酶链反应[tgPCR]/产毒培养）诊断的参与者评估初始临床治愈（ICC）和rCDI。
在MODIFY I/II中接受贝佐托昔单抗或安慰剂的1554名参与者中，分别有781名（50.3%）和773名（49.7%）通过tgPCR/产毒培养和毒素EIA/CCA诊断。通过毒素EIA/CCA诊断的参与者更有可能是住院患者、年龄较大且患有严重CDI。在接受贝佐托昔单抗的参与者中，毒素EIA/CCA亚组的ICC率（81.7%）略高于tgPCR/产毒培养亚组（78.4%）。与安慰剂相比，贝佐托昔单抗在两个亚组中均显著降低了rCDI率；然而，毒素EIA/CCA诊断的参与者的降低幅度（相对差异，-46.6%）远大于tgPCR/产毒培养亚组（-29.1%）。在接受贝佐托昔单抗的参与者中，毒素EIA/CCA亚组的rCDI率（17.6%）低于tgPCR/产毒培养亚组（23.6%；绝对差异，-6.0%；95%置信区间，-12.4至0.3；相对差异，-25.4%）。
检测粪便艰难梭菌毒素的诊断测试对于准确诊断CDI至关重要，包括在临床试验设计中，确保治疗效果不被低估。
