Prophylactic Lactobacillus GG reduces antibiotic-associated diarrhea in children with respiratory infections:: A randomized study
Prophylactic Lactobacillus GG reduces antibiotic-associated diarrhea in children with respiratory infections:: A randomized study
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DOI：
10.1542/peds.104.5.e64
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发表时间：
1999-11-01
期刊：
影响因子：
8
通讯作者：
Isolauri, E
中科院分区：
文献类型：
--
作者：
Arvola, T;Laiho, K;Isolauri, E
目标。抗菌药物治疗可能会干扰胃肠道微生物的定植耐药性，从而引起临床症状，最常见的是腹泻。抗生素相关性腹泻的严重程度可能从短暂的自限性疾病到伴有电解质紊乱、脱水、腹痛、假膜性结肠炎、中毒性巨结肠甚至死亡的毁灭性腹泻。接受单一抗菌药物治疗的儿童腹泻发生率尚不清楚。除了更严格地使用抗菌素外，还需要对抗生素相关性腹泻采取辅助预防措施。本研究的目的是评估在过去3个月内没有使用过抗菌药物的儿童在抗菌药物治疗后腹泻的发生率。本研究的另一个目的是评估鼠李糖乳杆菌GG （Lactobacillus GG; American Type Culture Collection 53103）的预防潜力，这是一种有安全记录的益生菌菌株，对病毒性胃肠炎治疗抗生素相关性腹泻有疗效。在芬兰坦佩雷市卫生保健中心或坦佩雷大学医院的诊所里，167名被邀请参加这项研究的病人被开了口服抗菌药物来治疗急性呼吸道感染。其中48例失访；因此，最终的研究人群包括119名2周至12.8岁的儿童（平均4.5岁）。所有研究对象均符合纳入标准：前3个月内未接受任何抗菌药物治疗，未发生胃肠道疾病，不需要静脉抗菌治疗。患者随机接受安慰剂或2 × 10（10）集落形成单位GG乳杆菌胶囊在抗菌治疗期间给予每日两次。GG乳杆菌胶囊和安慰剂胶囊在外观和味道上没有区别。父母每天记录症状日记，并记录3个月的家中大便次数和稠度。腹泻定义为每天至少连续2天出现三次水样或稀便。在腹泻病例中，研究了粪便样本中的病毒（腺病毒、轮状病毒、杯状病毒和星状病毒）和细菌（沙门氏菌、志贺氏菌、耶尔森菌、弯曲杆菌、艰难梭菌、金黄色葡萄球菌和酵母）分析。通过分析粪便脲酶、β -葡萄糖苷酶和β -葡萄糖苷酶活性来评估肠道微生物群的代谢活性。主要结局指标是抗菌药物治疗开始后头2周的腹泻情况，因为这一时期最可能反映了抗菌药物使用的效果。次要观察指标是粪便脲酶、β -葡糖苷酶和β -葡萄糖苷酶的活性。在整个随访过程中，80%的胃肠道症状出现在抗菌药物治疗开始后的前2周。抗生素治疗2周内，GG乳杆菌组腹泻发生率为5%，安慰剂组为16% （chi(2) = 3.82）。乳酸菌GG的治疗效果（95%置信区间）为-11%（-21% ~ 0%）。在腹泻发作中，2例艰难梭菌阳性，3例诺瓦克样杯状病毒阳性。两组患儿腹泻年龄在3个月~ 5岁之间的占75%。各研究组中腹泻的严重程度具有可比性，如大便频率相似（平均每天5次，范围3-6次）和腹泻持续时间相似（平均4天，范围2-8天）。在抗菌治疗开始后，GG乳杆菌组和安慰剂组的粪便脲酶和β -葡萄糖苷酶的活性发生了显著变化，但β -葡萄糖苷酶没有变化。在没有腹泻的患者中，脲酶和β -葡糖醛酸酶活性的下降是可逆的，但在腹泻患者中，肠道菌群的改变更为深刻和持久。这三种酶的活性在3周内恢复正常，与治疗前相比，抗菌治疗开始后3周、1个月和3个月采集的样品中的酶活性稳定。在本研究中，单次抗菌药物治疗后，腹泻发生率为16%。在以前的报告中，抗生素相关性腹泻的发生率较高可能是由于最近的抗菌治疗扰乱了肠道菌群并暴露于并发症。此外，在本研究中，观察到肠道菌群代谢活性的变化，粪便酶活性的短暂下降证明了这一点。不同的益生菌制剂，包括乳酸菌，经常被推荐用于预防抗生素相关性腹泻。虽然益生菌已被证明在预防和治疗病毒性胃肠炎方面是有效的，但它们在儿童抗菌治疗中的作用以前尚未得到阐明。我们观察到，对因呼吸道感染接受抗菌治疗的儿童给予GG乳杆菌可将抗生素相关性腹泻的发生率降低至三分之一。这种有益作用可能是由益生菌的多种功能介导的，即产生抗菌物质、粘附受体和营养物质的局部竞争、刺激肠道抗原特异性和非特异性免疫反应。一种益生菌菌株，乳酸杆菌GG，是有效的预防腹泻的儿童接受抗微生物治疗呼吸道感染。
Objectives. Antimicrobial treatment may disturb the colonization resistance of gastrointestinal microflora, which may induce clinical symptoms, most commonly diarrhea. The severity of antibiotic-associated diarrhea may range from a brief, self-limiting disease to devastating diarrhea with electrolyte disturbances, dehydration, crampy abdominal pain, pseudomembranous colitis, toxic megacolon, or even death. The incidence of diarrhea in children receiving a single antimicrobial treatment is unclear. In addition to more critical use of antimicrobials, adjunctive preventive measures to antibiotic-associated diarrhea are needed. The objective of this study was to evaluate the incidence of diarrhea after antimicrobial treatment in children with no history of antimicrobial use during the previous 3 months. Another aim of this study was to assess the preventive potential of Lactobacillus rhamnosus GG (Lactobacillus GG; American Type Culture Collection 53103), a probiotic strain with a documented safety record and a therapeutic effect in viral gastroenteritis on antibiotic-associated diarrhea.Methods. Oral antimicrobial agents were prescribed for the treatment of acute respiratory infections at the clinics of the Health Care Center of the City of Tampere or Tampere University Hospital, Finland, to 167 patients who were invited to participate in the study. Of the patients, 48 were lost to follow-up; therefore, the final study population consisted of 119 children from 2 weeks to 12.8 years of age (mean: 4.5 years). All study subjects met the inclusion criteria: they had not received any antimicrobial medication during the previous 3 months, they did not suffer from gastrointestinal disorders, and they did not need intravenous antimicrobial treatment.The patients were randomized to receive placebo or 2 x 10(10) colony-forming units of Lactobacillus GG in capsules given twice daily during the antimicrobial treatment. Lactobacillus GG and placebo capsules were indistinguishable in appearance and taste. The parents kept a daily symptom diary and recorded stool frequency and consistency at home for 3 months. Diarrhea was defined as at least three watery or loose stools per day for a minimum of 2 consecutive days. In the case of diarrhea, viral (adenovirus, rotavirus, calicivirus and astrovirus) and bacterial (Salmonella, Shigella, Yersinia, Campylobacter, Clostridium difficile, Staphylococcus aureus, and yeasts) analyses were studied in fecal samples. The metabolic activity of the gut microflora was assessed by analysis of fecal urease, beta-glucosidase, and beta-glucuronidase activities. The primary outcome measure was diarrhea during the first 2 weeks after the beginning of the antimicrobial treatment, because this period most likely reflects the effects of antimicrobial use. Secondary outcome measures were the activities of fecal urease, beta-glucuronidase, and beta-glucosidase.Results. On the entire follow-up, 80% of any gastrointestinal symptoms were reported during the first 2 weeks after the beginning of the antimicrobial treatment. The incidence of diarrhea was 5% in the Lactobacillus GG group and 16% in the placebo group within 2 weeks of antimicrobial therapy (chi(2) = 3.82). The treatment effect (95% confidence interval) of Lactobacillus GG was -11% (-21%-0%). In diarrheal episodes, the viral and bacterial analyses were positive for Clostridium difficile in 2 cases and for Norwalk-like calicivirus in 3 cases. The age of the patients with diarrhea was between 3 months and 5 years in 75% of cases in both groups. The severity of diarrhea was comparable in the study groups, as evidenced by similar stool frequency (mean: 5 per day; range: 3-6) and the duration of diarrhea (mean: 4 days; range: 2-8).The activities of fecal urease and beta-glucuronidase, but not beta-glucosidase, changed significantly after the beginning of the antimicrobial treatment in the Lactobacillus GG group and in the placebo group alike. The decrease in urease and beta-glucuronidase activities was reversible in patients with no diarrhea, but in patients with diarrhea, the modifications in gut microflora were more profound and prolonged. The activities of the three enzymes were normalized within 3 weeks, evidenced by stable enzyme activities in samples collected 3 weeks, 1 month, and 3 months after the beginning of the antimicrobial treatment, compared with those obtained before treatment.Discussion. In the present study, after a single antimicrobial treatment, the incidence of diarrhea was 16%. The higher incidence of antibiotic-associated diarrhea in previous reports may be attributable to a recent antimicrobial therapy that disturbs intestinal flora and exposes to complications. Also, in the present study, changes in the metabolic activity of the intestinal flora were observed, evidenced by a transient decline in fecal enzyme activities.Different probiotic preparations, including lactobacilli, are recommended frequently to prevent antibiotic-associated diarrhea. Although probiotics have been shown to be efficient in the prevention and the treatment of viral gastroenteritis, their usefulness during antimicrobial therapy in children has not been elucidated before. We observed that the administration of Lactobacillus GG to children receiving antimicrobial therapy for respiratory infection reduced the incidence of antibiotic-associated diarrhea to one third. The beneficial effect may be mediated by a number of functions of probiotics, ie, production of antimicrobial substances, local competition of adhesion receptors and nutrients, and stimulation of intestinal antigen specific and nonspecific immune responses.Conclusion. A probiotic strain, Lactobacillus GG, is effective in the prevention of diarrhea in children receiving antimicrobial treatment to respiratory infections.