Fidaxomicin: A novel agent for the treatment of Clostridium difficile infection.
Fidaxomicin: A novel agent for the treatment of Clostridium difficile infection.
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DOI：
10.1155/2015/934594
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发表时间：
2015-11
期刊：
影响因子：
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通讯作者：
Karlowsky JA
中科院分区：
文献类型：
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作者：
Zhanel GG;Walkty AJ;Karlowsky JA
口服万古霉素和口服甲硝唑在治疗艰难梭菌感染（CDIs）方面有一些局限性;然而，口服万古霉素被认为是临床试验的金标准。2012年6月，非达霉素获得加拿大卫生部批准用于治疗CDIs。它的化学，作用机制和药理学特性进行了讨论，沿着其在CDI治疗的潜在作用。由于艰难梭菌感染（CDI）的现有治疗选择的局限性，需要新的治疗方法。综述非达霉素的化学、作用机制和耐药性、体外活性、药代动力学和药效学特性、临床试验中的疗效和安全性以及治疗中的位置等方面的现有数据。使用术语“非达霉素”、“OPT-80”、“PAR-101”、“OP-1118”、“迪菲米星”、“泰勾霉素”和“lipiarmycin”对PubMed进行了检索。对1983年1月至2014年11月的所有英文文章以及所有文章的参考书目进行了审查。非达霉素是第一个对艰难梭菌具有活性的大环内酯类抗生素。它抑制RNA聚合酶，从而阻止转录。非达霉素（及其活性代谢产物OP-1118）对艰难梭菌具有杀菌作用，并表现出延长的抗生素后效应（约10小时）。除艰难梭菌外，非达霉素对革兰氏阳性菌仅表现出中度抑制活性，对正常结肠植物群（包括厌氧菌和肠道革兰氏阴性杆菌）的抑制作用较差。口服给药（200 mg，每天两次，持续10天）后，非达霉素达到低血清浓度水平，但粪便浓度水平较高（平均约1400 μg/g粪便）。涉及成人CDI患者的3期临床试验表明，在治疗结束时的临床应答方面，200 mg非达霉素每日2次，持续10天不劣于125 mg口服万古霉素每日4次，持续10天。然而，据报道，非达霉素在减少非BI/NAP 1/027菌株感染患者的复发性CDI和实现持续临床应答（在第28天评估）方面上级口服万古霉素。在CDI治疗结束时，非达霉素的临床反应不劣于口服万古霉素。已证明非达霉素与口服万古霉素一样安全，但在非BI/NAP 1/027菌株感染患者中实现CDI的持续临床应答方面上级万古霉素。由于可用数据有限，在使用非达霉素单药治疗重度复杂性CDI时应谨慎。非达霉素是否具有成本效益（由于其购买成本显著高于口服万古霉素）取决于可接受的每质量调整生命年支付意愿阈值，作为评估成本效益的指标。
Oral vancomycin and oral metronidazole have several limitations with regard to their use in the treatment of Clostridium difficile infections (CDIs); however, oral vancomycin has been considered the gold standard in clinical trials. In June 2012, fidaxomicin received Health Canada approval for the treatment of CDIs. Its chemistry, mechanisms of action and pharmacological properties are discussed, along with its potential role in CDI therapy. Due to the limitations of existing treatment options for Clostridium difficile infection (CDI), new therapies are needed. To review the available data on fidaxomicin regarding chemistry, mechanisms of action and resistance, in vitro activity, pharmacokinetic and pharmacodynamic properties, efficacy and safety in clinical trials, and place in therapy. A search of PubMed using the terms “fidaxomicin”, “OPT-80”, “PAR-101”, “OP-1118”, “difimicin”, “tiacumicin” and “lipiarmycin” was performed. All English-language articles from January 1983 to November 2014 were reviewed, as well as bibliographies of all articles. Fidaxomicin is the first macrocyclic lactone antibiotic with activity versus C difficile. It inhibits RNA polymerase, therefore, preventing transcription. Fidaxomicin (and its active metabolite OP-1118) is bactericidal against C difficile and exhibits a prolonged postantibiotic effect (approximately 10 h). Other than for C difficile, fidaxomicin demonstrated only moderate inhibitory activity against Gram-positive bacteria and was a poor inhibitor of normal colonic flora, including anaerobes and enteric Gram-negative bacilli. After oral administration (200 mg two times per day for 10 days), fidaxomicin achieved low serum concentration levels but high fecal concentration levels (mean approximately 1400 μg/g stool). Phase 3 clinical trials involving adults with CDI demonstrated that 200 mg fidaxomicin twice daily for 10 days was noninferior to 125 mg oral vancomycin four times daily for 10 days in regard to clinical response at the end of therapy. Fidaxomicin was, however, reported to be superior to oral vancomycin in reducing recurrent CDI and achieving a sustained clinical response (assessed at day 28) for patients infected with non-BI/NAP1/027 strains. Fidaxomicin was noninferior to oral vancomycin with regard to clinical response at the end of CDI therapy. Fidaxomicin has been demonstated to be as safe as oral vancomycin, but superior to vancomycin in achieving a sustained clinical response for CDI in patients infected with non-BI/NAP1/027 strains. Caution should be exercised in using fidaxomicin monotherapy for treatment of severe complicated CDI because limited data are available. Whether fidaxomicin is cost effective (due to its significantly higher acquisition cost versus oral vancomycin) depends on the acceptable willingness to pay threshold per quality-adjusted life year as a measure of assessing cost effectiveness.