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非达霉素用于治疗儿科人群艰难梭菌感染——尚需时日。

Fidaxomicin for the Treatment of Clostridium Difficile Infection in the Pediatric Population - Not Quite So Soon Yet.

作者信息

Daniels Tanya, So Tsz-Yin

机构信息

University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.

Department of Pharmacy, Moses H. Cone Hospital, Greensboro, NC 27401, USA.

出版信息

Gastroenterology Res. 2011 Jun;4(3):93-96. doi: 10.4021/gr318e. Epub 2011 May 20.

Abstract

Fidaxomicin is a new narrow spectrum macrocyclic antibiotic. It inhibits bacterial RNA polymerase and eradicates with minimal effect on normal intestinal flora. The US FDA granted orphan drug designation for all formulations of fidaxomicin for the treatment of infections in pediatric patients on January 10, 2011. Fidaxomicin has bactericidal activity against with a prolonged post-antibiotic effect. Even though this medication has an orphan designation for pediatrics, all the available pharmacokinetic and pharmacodynamic data were in subjects ≥ 18 years old. The MIC for fidaxomicin against varies from 0.0078 to 0.25 mcg/ml. Fidaxomicin is poorly absorbed. The highest peak plasma concentration in patients treated with fidaxomicin was 0.191 mcg/ml. Fecal levels of fidaxomicin after oral administration are extremely high. The average fecal concentrations in patients were 255.6 mcg/g, 441.7 mcg/g, and 1443.3 mcg/g in the 100, 200, and 400 mg/day groups, respectively. At a dose of 400 mg/day the average fecal concentration was 5700 times higher than the highest MIC of fidaxomicin against . In a phase III clinical trial fidaxomicin 200 mg twice daily was compared with vancomycin 125 mg four times per day orally for 10 days. Only two patients were 18 years old, and no patients younger than 18 years old participated in the study. The rates of clinical cure with fidaxomicin were noninferior to those with vancomycin. Patients who were infected with non-North American Pulsed Field type 1 strains had fewer recurrences in the fidaxomicin group than patients in the vancomycin group. Side effects were similar between both therapies. Most patients experienced mild gastro-intestinal symptoms. Fidaxomicin is a good therapeutic alternative to vancomycin and metronidazole, especially in patients with recurrence of infection. Patients rarely experience systemic side effects which improves compliance. The dose of fidaxomicin is expected to be 200 mg given orally twice a day for patients 16 years and older. At this point, Optimer Pharmaceuticals Inc has conducted clinical trials in adults only. Additional clinical trials in pediatric patients are needed before therapeutic recommendations can be made in this population.

摘要

非达霉素是一种新型窄谱大环内酯类抗生素。它抑制细菌RNA聚合酶,对正常肠道菌群的影响最小,能根除感染。2011年1月10日,美国食品药品监督管理局授予非达霉素所有剂型孤儿药资格,用于治疗儿科患者的感染。非达霉素对艰难梭菌具有杀菌活性,且抗生素后效应延长。尽管这种药物在儿科有孤儿药资格认定,但所有可用的药代动力学和药效学数据均来自18岁及以上的受试者。非达霉素对艰难梭菌的最低抑菌浓度为0.0078至0.25 mcg/ml。非达霉素吸收较差。接受非达霉素治疗的患者的最高血浆峰浓度为0.191 mcg/ml。口服后非达霉素的粪便水平极高。在100、200和400 mg/天组中,艰难梭菌感染患者的平均粪便浓度分别为255.6 mcg/g、441.7 mcg/g和1443.3 mcg/g。在400 mg/天的剂量下,平均粪便浓度比非达霉素对艰难梭菌的最高最低抑菌浓度高5700倍。在一项III期临床试验中,将每日两次口服200 mg非达霉素与每日四次口服125 mg万古霉素进行了10天的比较。只有两名患者年龄为18岁,没有18岁以下的患者参与该研究。非达霉素的临床治愈率不低于万古霉素。感染非北美脉冲场1型菌株的患者,非达霉素组的复发率低于万古霉素组。两种治疗方法的副作用相似。大多数患者出现轻度胃肠道症状。非达霉素是万古霉素和甲硝唑的良好治疗替代品,尤其是在艰难梭菌感染复发的患者中。患者很少出现全身副作用,这提高了依从性。对于16岁及以上的患者,非达霉素的剂量预计为每日两次口服200 mg。目前,Optimer制药公司仅在成人中进行了临床试验。在能够对该人群提出治疗建议之前,还需要在儿科患者中进行更多的临床试验。

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