Objective: To evaluate the efficacy and safety of Saccharomyces boulardii in the prevention of antibiotic-associated diarrhea (AAD) in infants and young children. Method: From November 2012 to September 2013, ten research units of large teaching hospitals or children's hospitals participated in this multicenter randomized controlled clinical trial. Hospitalized young children aged between 1 month and 3 years (nongastrointestinal infection and antibiotic therapy required)were involved in our study. The children were randomly divided into control group and prevention group by means of block random allocation method. The control group received antibiotic therapy and other conventional treatment. The prevention group was given additional Saccharomyces boulardii (250 mg/d) orally. Diarrhea rates of two groups were compared both during the usage of antibiotics and within 14 days after the antibiotics withdrawal. The adverse reactions of Saccharomyces boulardii were observed all through this study. The results were analyzed by χ(2) test or Kruskal-Wallis test or t test. Result: Totally 408 cases (213 cases in prevention group and 195 cases in control group) were enrolled. The age ranged from 1 month to 3 years, with an average age of 1.14 years. The basic diseases were parenteral infections: 368 cases with different kinds of respiratory tract infections or pneumonia, 10 cases of bacterial meningitis, 9 cases with septicemia or sepsis, 6 cases with pertussis or pertussis like syndrome, 5 cases with urinary infection, 5 cases with skin or subcutaneous tissue infections, 3 cases of Kawasaki disease, one with scarlet fever and one with congenital syphilis. During the administration of antibiotics, the incidence of AAD in prevention group was 10.3% (22 cases), which was significantly lower than that of control group (57 cases, 29.2%, χ(2)=23.296, P<0.05). Within 14 days after the discontinuation of antibiotics, the percent of new diarrhea cases in prevention group (2.4%, 5/213) was also significantly lower than that in control group (16.4%, 32/195, χ(2)=23.4, P<0.05). Further analysis revealed that the rate of AAD in children less than or equal to 1 year old (25.1%, 52/207) was significantly higher than that of over 1 year old (13.4%, 27/201, χ(2)=8.922, P<0.05). The incidence of AAD in children treated with antibiotics for more than 5 days was 22.2%(60/270), which was significantly higher than that of less than or equal to 5 days (13.8%, 19/138, χ(2)=4.180, P<0.05). Although no significant difference was observed, the AAD rate of patients with combined use of two antibiotics was higher than that of using one. During the antibiotic therapy, compared with the control group, the risk of AAD in children under 1 year old was reduced by 52% (χ(2)=9.217, P<0.05), and 91% (χ(2)=20.35, P<0.05) in the children over 1 year old in prevention group. The risk of AAD of prevention group decreased by 66% (χ(2)=13.67, P<0.05) in patients treated with one antibiotics, and 65% in children with combined use of antibiotics (χ(2)=10.57, P<0.05). In patients treated with antibiotics for less than or equal to 5 days, the risk of AAD decreased by 74% in prevention group (χ(2)=7.38, P<0.05); and 63% if the course lasted for over 5 days (χ(2)=16.87, P<0.05). Within 14 days after the withdrawal of antibiotics, compared with the control group, the risk of diarrhea in the prevention group decreased by 82% (χ(2)=13.35, P<0.05) in infants (≤1 year old) and 93% (χ(2)=12.00, P<0.05) in children (>1 year old); the risk of diarrhea was reduced by 86% (χ(2)=9.57, P<0.05) and 87% (χ(2)=17.71, P<0.05) respectively in prevention group with single and combined use of antibiotics. In patients treated with antibiotics for more than 5 days, the risk of diarrhea in prevention group was reduced by 63% (χ(2)=22.79, P<0.05), while there was no significant difference if the antibiotics course was less than or equal to 5 days (χ(2)=2.97, P>0.05). No adverse effects related with Saccharomyces boulardii were observed in our study. Conclusion:Saccharomyces boulardii is effective and safe to prevent AAD of infants and young children both during the usage of antibiotics and up to 14 days after drug discontinuance. It can be one of the drugs of for choice prevention of AAD in infants and young children. Trial registration Chinese Clinical Trial Tegister, ChiECRCT-2012-25.
目的： 评价布拉酵母菌预防婴幼儿抗生素相关性腹泻(AAD)的疗效及安全性。 方法： 由10家医院参加的多中心临床随机对照研究，于2012年11月至2013年9月，以非胃肠道感染并需要抗生素治疗的1月龄以上至3岁以下住院婴幼儿为研究对象，采取区组随机分配法入组，干预组在应用抗生素同时加服布拉酵母菌(250 mg/d)，对照组单纯使用抗生素等常规治疗，观察与对比抗生素治疗期间及停用抗生素后14 d内两组腹泻发生率来评价预防效果，同时观察布拉酵母菌不良反应。组间比较采用χ(2)检验或非参数检验、t检验。 结果： 共纳入408例患儿，干预组213例，对照组195例。年龄1月龄至3岁，平均1.14岁。其基础非胃肠道感染性疾病包括各种呼吸道感染或肺炎368例，细菌性脑膜炎10例，败血症或脓毒症9例，百日咳或类百日咳6例，泌尿系感染和皮肤或皮下组织感染各5例，川畸病3例，猩红热和先天性梅毒各1例。在抗生素使用期间，干预组AAD发生率为10.3%(22例)，低于对照组(57例，29.2%，χ(2)＝23.296，P<0.05)。在抗生素停用后14 d内，干预组新发腹泻比率(2.4%，5/213)亦明显低于对照组(16.4%，32/195，χ(2)＝23.4，P<0.05)。进一步分析发现，在抗生素治疗期间，≤1岁患儿AAD发生率(25.1%，52/207)高于>1岁患儿(13.4%，27/201，χ(2)＝8.922，P<0.05)；抗生素使用>5 d患儿AAD发生率(22.2%，60/270)高于抗生素使用≤5 d患儿(13.8%，19/138，χ(2)＝4.180，P<0.05)。联用二种抗生素患儿AAD发生率高于单用抗生素者，但差异无统计学意义(χ(2)＝1.404，P>0.05)。在抗生素治疗期间，与对照组相比，干预组≤1岁患儿AAD患病风险降低了52%(χ(2)＝9.217，P<0.05)；干预组>1岁以上患儿AAD发病风险降低了91%(χ(2)＝20.35，P<0.05)；单用抗生素患儿中，干预组AAD发生风险降低了66%(χ(2)＝13.67，P<0.05)，联用抗生素患儿中，干预组AAD发生风险降低了65%(χ(2)＝10.57，P<0.05)；抗生素使用≤5 d患儿中，干预组腹泻发生风险降低了74%(χ(2)＝7.38，P<0.05)，抗生素使用>5 d患儿中，干预组AAD发病风险降低了63%(χ(2)＝16.87，P<0.05)。在停用抗生素后14 d内，与对照组比较≤1岁患儿中，干预组腹泻发生风险降低了82%(χ(2)＝13.35，P<0.05)，>1岁患儿中干预组腹泻发病风险降低了93%(χ(2)＝12.00，P<0.05)；单用抗生素患儿中，干预组腹泻发生风险降低了86%(χ(2)＝9.57，P<0.05)，联用2种抗生素患儿中，干预组腹泻发病风险降低了87%(χ(2)＝17.71，P<0.05)；抗生素使用>5 d患儿中，干预组腹泻发生风险降低了63%(χ(2)＝22.79，P<0.05)，抗生素使用≤5 d患儿中，干预组腹泻发生率与对照组差异无统计学意义(χ(2)＝2.97，P>0.05)。干预组患儿在研究期间均未观察到布拉酵母菌相关不良反应。 结论： 布拉酵母菌能有效预防婴幼儿抗生素使用期间和停用后14 d内的抗生素相关性腹泻，且无不良反应，可作为预防婴幼儿抗生素相关性腹泻的首选药物之一。临床试验注册 中国临床试验注册中心，ChiECRCT-2012-25。.
Keywords: Anti-bacterial agents; Child; Diarrhea, infantile; Multicenter study; Saccharomyces boulardii.