MIAMI (EGMN) –Varying degrees of success and some caveats come with the use of probiotics to combat or prevent Clostridium difficile infection and antibiotic-associated diarrhea.

Saccharomyces boulardii, lactobacilli, and bifidobacteria are among the better-studied probiotic options for these purposes, Dr. Curtis Danskey said at the International Probiotics Association World Congress.

Many hospitalized patients do not have normal gut flora, but “if we can restore the normal intestinal flora, an effective probiotic may protect [these] patients,” said Dr. Danskey, who is on the medicine faculty at Louis Stokes Cleveland Veterans Affairs Medical Center.

C. difficile can cause up to 30% of nosocomial diarrhea cases in hospitalized patients (Pol. J. Microbiol. 2005;54:111-5). In addition, antibiotic-associated diarrhea (AAD) occurs in 3% to 29% of hospitalized patients and is associated with increased length of stay and costs (J. Hosp. Infect. 2003;54:202-6).

The antibiotics routinely prescribed to fight C. difficile also kill beneficial flora in the gut, which is where probiotic therapy might help. “There is evidence [supporting the] use of probiotics for antibiotic-associated diarrhea if you want to use them,” Dr. Danskey said.

–Saccharomyces boulardii . This organism is a type of yeast and is “probably one of the most well-studied probiotics for C. difficile,” Dr. Danskey said. In one study, patients with C. difficile disease experienced a significant reduction in recurrences when treated with high-dose vancomycin for 10 days followed by S. boulardii for 28 days, compared with a regimen of vancomycin followed by placebo (Clin. Infect. Dis. 2000;31:1012-7).

On the downside, there have been several reports of fungemia associated with S. boulardii treatment, particularly in immunocompromised patients, Dr. Danskey said (Crit. Care 2008;12:414). There is a risk of transfer of fungemia to adjacent patients, so “I will not use it in my ICU, [but I] may use it in an outpatient setting in someone with recurrent infections,” he added.

–Lactobacilli and bifidobacteria. There is some rationale for use of these two probiotic species to prevent C. difficile infection, Dr. Danskey said. Lactobacilli, for example, can inhibit growth of C. difficile in vitro (J. Med. Microbiol. 2004;53:551-4). Also, reduced lactobacilli levels were found in the stool of hospitalized patients with C. difficile (Clin. Infect. Dis. 1997;25[suppl 2]:S189-90). “A lack of these organisms may allow C. difficile to grow.”

Historically, the numbers have been small in many probiotic trials that did not show a reduction in C. difficile infection. “Up to 2005, the data were not very convincing,” Dr. Danskey said.

After that, reports became more robust. For example, in one study, 135 hospitalized patients aged 50 years and older taking antibiotics were randomized to a lactobacillus preparation or placebo (BMJ 2007;335:80). A total of 12% of the probiotic group developed AAD, compared with 34% of placebo patients. In addition, no patient who took the probiotic developed a C. difficile infection vs. 17% of the placebo group.

“The results looked very impressive,” Dr. Danskey said. However, the study received a fair amount of criticism. For example, the placebo group drank a sterile milkshake, which could have caused diarrhea, some said. Other aspects of the study that drew criticism included the highly selected patient population (only 8% of screened patients were enrolled) and the exclusion of patients taking antibiotics most likely to cause diarrhea.

“However, the 8% rate is still higher than a just-published study [of monoclonal antibodies targeted against C. difficile toxins] that only enrolled 3% of screened patients,” Dr. Danskey said (N. Engl. J. Med. 2010;362:197-205). Also, in the 2007 lactobacillus vs. placebo study, 43 of 69 probiotic-treated patients (62%) received a high-risk antibiotic, as did 46 of the 66 placebo patients (70%), he said.

In terms of potential adverse events, there are some concerns about safety, “although we eat yogurt [with lactobacillus species] all the time,” Dr. Danskey said. For example, researchers reported two cases of sepsis associated with probiotic lactobacillus strains (Pediatrics 2005;115:178-810).

He also mentioned a meta-analysis that addresses the advantages and disadvantages of probiotics for AAD and C. difficile infection (Anaerobe 2009;15:274-80).

–Nontoxigenic probiotics. Normally, C. difficile growth and toxin production start shortly after infection in susceptible individuals. A person can be an asymptomatic carrier, but about one-third of patients develop disease, Dr. Danskey said. When this happens, C. difficile toxins bind to the lining of the GI tract, leading to cell death and significant inflammation. Colonoscopy and sigmoidoscopy often show pseudomembranous colitis in these patients.

Nontoxigenic probiotics that compete with C. difficile are in development. “Evidence suggests patients colonized with nontoxigenic strains were protected from infection with toxigenic strains,” Dr. Danskey said. “This makes logical sense: They will compete with toxigenic strains in the GI system.” So far, the evidence primarily comes from animal research. “It is now in phase I trials in patients and will move forward if it is shown to be effective and safe.”

Dr. Danskey receives research support from Viral Pharma (which is developing nontoxigenic probiotic strains) and the U.S. Department of Veterans Affairs.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

迈阿密(EGMN)——应用益生菌治疗或预防艰难梭菌感染及抗生素相关腹泻取得了不同程度的成功，但也存在一些不足。

 

Curtis Danskey博士在国际益生菌协会世界大会上表示，布拉酵母菌、乳杆菌和双歧杆菌是在这方面研究较为深入的益生菌。

 

路易斯斯托克斯克里夫兰退伍军人事务部医学中心的Danskey博士表示，许多住院患者的肠道菌群失调，但“如果我们能够恢复正常肠道菌群，那么有效的益生菌就可保护这些患者。”

 

在住院患者中，30%的院内腹泻病例由艰难梭菌引起(Pol. J. Microbiol. 2005;54:111-5)。此外，抗生素相关腹泻(AAD)见于3%~29%的住院患者，并与住院时间延长和费用增加相关(J. Hosp. Infect. 2003;54:202-6)。

 

常规用于治疗艰难梭菌感染的抗生素也会杀死肠道中的有益菌群，而益生菌疗法有助于改善这种情况。Danskey博士说：“有证据支持应用益生菌治疗抗生素相关腹泻，如果你打算应用益生菌的话。”

 

-布拉酵母菌。Danskey博士表示，这种酵母菌“可能是在治疗艰难梭菌感染方面研究最为深入的益生菌之一。” 一项纳入艰难梭菌感染患者的研究显示，高剂量万古霉素治疗10天继以布拉酵母菌治疗28天的方案较万古霉素继以安慰剂的方案更能显著降低感染复发率(Clin. Infect. Dis. 2000;31:1012-7)。

 

Danskey博士指出，有一些报告显示，布拉酵母菌治疗的缺点在于可导致患者(特别是免疫低下的患者)出现真菌血症(Crit Care 2008;12:414)。他补充说，由于存在真菌血症传播至邻近患者的危险，因此“我不会用布拉酵母菌治疗ICU住院患者，但我可能会用其治疗复发性感染的门诊患者。”

 

-乳杆菌和双歧杆菌。 Danskey博士表示，有依据支持应用这两种益生菌预防艰难梭菌感染。例如，乳杆菌可在体外抑制艰难梭菌生长(J. Med. Microbiol. 2004;53:551-4)。此外，还在艰难梭菌感染住院患者的粪便中发现乳杆菌水平降低(Clin. Infect. Dis. 1997;25[suppl 2]:S189-90)。“缺乏这些益生菌，使得艰难梭菌的生长不受控制。”

 

在既往未显示益生菌可减轻艰难梭菌感染的许多益生菌试验中，患者样本量较少。Danskey博士说：“截至2005年的数据还不是非常令人信服。”

 

但此后所报告的数据越来越有说服力。例如，在一项研究中，135例住院患者(年龄≥50岁)在服用抗生素的基础上随机加用乳杆菌制剂或安慰剂(BMJ 2007;335:80)。益生菌组和安慰剂组AAD的发生率分别为12%和34%，艰难梭菌感染的发生率分别为0%和17%。

 

Danskey博士说：“这些结果看起来非常令人振奋。” 然而，该研究也受到不少批评。例如，一些人指出，安慰剂组患者饮用了可引起腹泻的无菌奶昔。该研究招致批评的其他方面还包括高度选择患者人群(仅8%的筛查患者入组)，并且且排除了服用极可能导致腹泻的抗生素的患者。

 

Danskey博士说：“然而，8%的入组率仍高于一项刚发表研究的入组率，后者为一项旨在探讨单克隆抗体靶向治疗艰难梭菌毒素感染的研究，仅3%的筛查患者入组。”(N. Engl. J. Med. 2010;362:197-205) 此外，他表示，在这项2007年进行的旨在比较乳杆菌与安慰剂的研究中，益生菌组和安慰剂组分别有62%(43/69例)和70%(46/66例)的患者服用高风险抗生素。

 

Danskey博士表示，“尽管我们一直都食用含乳杆菌属的酸奶酪，”但在潜在不良事件方面，仍对益生菌的安全性存有一些担忧。例如，有研究者报告了两例益生乳杆菌相关脓毒症病例(Pediatrics 2005;115:178-810)。

 

他还提到了一项旨在探讨益生菌治疗AAD和艰难梭菌感染的利弊的Meta分析(Anaerobe 2009;15:274-80)。

 

-非产毒益生菌。艰难梭菌的生长与毒素的产生一般在易感个体感染后不久即开始。Danskey博士表示，有些人可能为无症状的携带者，但约1/3的患者出现症状。在出现症状的患者中，艰难梭菌毒素粘附于胃肠道内层，导致细胞死亡和明显炎症。结肠镜检和乙状结肠镜检通常能够在这些患者中检出假膜性结肠炎。

 

可与艰难梭菌竞争的非产毒益生菌目前正处于开发阶段。Danskey博士说：“有证据表明，对患者定植非产毒菌株可预防产毒菌株感染。这在逻辑上是行得通的：非产毒菌株将可在胃肠系统中与产毒菌株发生竞争。” 迄今为止，证据主要来自于动物研究。“目前非产毒菌株正处于人体I期试验阶段，如果试验显示其有效且安全，则试验将进入下一阶段。”

 

Danskey博士声明获得来自Viral Pharma(该公司目前正开发非产毒益生菌株)和美国退伍军人事务部的研究支持。

 

爱思唯尔  版权所有