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クロストリジオイデス・ディフィシル感染症

著者: 岸田直樹 感染症コンサルタント/北海道科学大学・東京薬科大学 客員教授

監修: 大曲貴夫 国立国際医療研究センター

著者校正/監修レビュー済:2022/08/17
参考ガイドライン:
  1. 日本化学療法学会、日本感染症学会:Clostridioides(Clostridium)difficile感染症診療ガイドライン(2018年)
  1. International Society for Infectious Diseases(ISID):Position paper on the prevention of Clostridioides difficile in hospitals (2020)
  1. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN): Joint position paper on fecal microbiota transplantation for recurrent Clostridium difficile infection and other conditions in children (2019)
  1. World Society of Emergency Surgery (WSES):Guidelines for management of Clostridioides (Clostridium) difficile infection in surgical patients, update (2019)
  1. American Society of Clinical Oncology(ASCO):Guideline for the management of Clostridium difficile infection in children and adolescents with cancer and pediatric hematopoietic stem-cell transplantation recipients (2018)
患者向け説明資料

概要・推奨   

  1. クロストリジオイデス・ディフィシル(Clostridioides difficile:CD)感染症では、再発なのか再感染なのかを明確に分けることはできない。しかし、病歴や症状の程度などから再発を積極的に疑うことが推奨される(推奨度2)
  1. 説明がつかない白血球増多症に院内で出合う機会は意外に多い。その白血球増多症の原因としてクロストリジオイデス感染症で説明可能かもしれない。消化器症状が軽微であってもクロストリジオイデス感染症を疑うことは大切であり、CD toxinチェックを行うことが推奨される(推奨度2)
  1. 海外のガイドラインでは、重症度によらずクロストリジオイデス感染症ではバンコマイシン(塩酸バンコマイシン)やフィダキソマイシン(ダフクリア)を第1選択にすべきとされている。特に欧米では重症患者でのメトロニダゾール(フラジール)による治療失敗が問題となっている。日本ではまだ重症例は多くないとされるが、院内で集団発生している場合などは注意が必要である。重症例や再発例などの場合は、バンコマイシンやフィダキソマイシンによる加療を検討することが推奨される(推奨度3)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
岸田直樹 : 特に申告事項無し[2022年]
監修:大曲貴夫 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 定期レビューを行い、主に下記の内容について加筆した。
  1. 再発予防に対するアプローチ
  1. 抗トキシンB抗体であるベズロトクスマブ(ジーンプラバ)
  1. トキシンPCR検査
  1. 治療薬における海外の推奨と国内の状況の違い

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 抗菌薬の使用中または使用歴のある下痢症患者では積極的に疑うべきだが、すべての院内下痢症がクロストリジオイデス・ディフィシルによるものではない。
  1. 抗菌薬使用としては、第3、4世代セファロスポリン、フルオロキノロン、 カルバペネム、クリンダマイシン、βラクタマーゼ阻害薬配合ペニシリンなどがリスクとなる。
  1. 下痢を来し得るほかの原因を除外することが重要(下剤過剰服用、化学療法、経腸栄養開始など)。PPIも下痢の原因となる(collagenous colitis)。
  1. クロストリジオイデス・ディフィシルは偽膜性大腸炎の原因菌としてよく知られているが、クロストリジオイデス・ディフィシルによる下痢症や腸炎のすべての症例で消化管に偽膜形成が認められるわけではない。
  1. 症状は軽度の下痢症状から腸閉塞や中毒性巨大結腸、さらに死に至るような重篤な腸管壊死まで幅が広いと認識する。
  1. 消化器症状に加えて酵素抗体法(トキシンAとトキシンBの同時検出キット)で確定診断となる。酵素抗体法の感度が不十分(60~70%程度)なため、疑いが高い場合は治療を検討する。
  1. クロストリジオイデス・ディフィシルの抗原であるグルタミン酸脱水素酵素(GDH)を検出する迅速検査を実施してもよい。感度は高いが(80~90%)抗原のみ陽性の場合にはトキシン産生株かは不明であり、確定診断とは至らない。しかし疑いが高い場合は治療を検討する。
  1. GDH抗原検査のみが陽性の場合はNAAT検査(Nucleic acid amplification test:毒素遺伝子検査)で確定診断をしてもよいが、疑いが高い場合はNAAT検査を行わず治療開始としてもよい。
  1. 遺伝子検査へのアクセスが良くなってきており、NAAT検査ができる施設も増えてきている。確認検査にNAAT を使わないアルゴリズムでの感度は40~93%、特異度は97~100% であったのに対し、NAAT を含んだアルゴリズムは感度の面で優れており、感度は68~100%、特異度は92~100% であった[1]
病歴・診察のポイント  
  1. 抗菌薬使用の経過で起こる下痢、腹痛、発熱が典型的である。このような場合は本症を考える。

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文献 

David Baur, Beryl Primrose Gladstone, Francesco Burkert, Elena Carrara, Federico Foschi, Stefanie Döbele, Evelina Tacconelli
Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis.
Lancet Infect Dis. 2017 Sep;17(9):990-1001. doi: 10.1016/S1473-3099(17)30325-0. Epub 2017 Jun 16.
Abstract/Text BACKGROUND: Antibiotic stewardship programmes have been shown to reduce antibiotic use and hospital costs. We aimed to evaluate evidence of the effect of antibiotic stewardship on the incidence of infections and colonisation with antibiotic-resistant bacteria.
METHODS: For this systematic review and meta-analysis, we searched PubMed, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and Web of Science for studies published from Jan 1, 1960, to May 31, 2016, that analysed the effect of antibiotic stewardship programmes on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infections in hospital inpatients. Two authors independently assessed the eligibility of trials and extracted data. Studies involving long-term care facilities were excluded. The main outcomes were incidence ratios (IRs) of target infections and colonisation per 1000 patient-days before and after implementation of antibiotic stewardship. Meta-analyses were done with random-effect models and heterogeneity was calculated with the I2 method.
FINDINGS: We included 32 studies in the meta-analysis, comprising 9 056 241 patient-days and 159 estimates of IRs. Antibiotic stewardship programmes reduced the incidence of infections and colonisation with multidrug-resistant Gram-negative bacteria (51% reduction; IR 0·49, 95% CI 0·35-0·68; p<0·0001), extended-spectrum β-lactamase-producing Gram-negative bacteria (48%; 0·52, 0·27-0·98; p=0·0428), and meticillin-resistant Staphylococcus aureus (37%; 0·63, 0·45-0·88; p=0·0065), as well as the incidence of C difficile infections (32%; 0·68, 0·53-0·88; p=0·0029). Antibiotic stewardship programmes were more effective when implemented with infection control measures (IR 0·69, 0·54-0·88; p=0·0030), especially hand-hygiene interventions (0·34, 0·21-0·54; p<0·0001), than when implemented alone. Antibiotic stewardship did not affect the IRs of vancomycin-resistant enterococci and quinolone-resistant and aminoglycoside-resistant Gram-negative bacteria. Significant heterogeneity between studies was detected, which was partly explained by the type of interventions and co-resistance patterns of the target bacteria.
INTERPRETATION: Antibiotic stewardship programmes significantly reduce the incidence of infections and colonisation with antibiotic-resistant bacteria and C difficile infections in hospital inpatients. These results provide stakeholders and policy makers with evidence for implementation of antibiotic stewardship interventions to reduce the burden of infections from antibiotic-resistant bacteria.
FUNDING: German Center for Infection Research.

Copyright © 2017 Elsevier Ltd. All rights reserved.
PMID 28629876
Fekety R R, McFarland L V LV, Surawicz C M CM, Greenberg R N RN, Elmer G W GW, Mulligan M E ME
Recurrent Clostridium difficile diarrhea: characteristics of and risk factors for patients enrolled in a prospective, randomized, double-blinded trial.
Clin Infect Dis. 1997 Mar;24(3):324-33.
Abstract/Text Recurrent Clostridium difficile diarrhea (RCDD) occurs in 20% of patients after they have received standard antibiotic treatment with vancomycin or metronidazole, but the reasons for the recurrences are largely unknown. Patients receiving vancomycin or metronidazole for active C. difficile diarrhea (CDD) were referred to our study centers for treatment and a 2-month follow-up as part of a randomized placebo-controlled trial. Sixty patients had RCDD (median number of episodes, 3.0; range, 2-9 episodes) and 64 were having their first episode of CDD. Patients with RCDD had more-severe abdominal pain and were more likely to have fever but initially responded well to antibiotic therapy. Data on sequential episodes showed no progression in disease severity. Five factors were associated with a higher risk of RCDD: the number of previous CDD episodes, onset of the initial disease in the spring, exposure to additional antibiotics for treatment of other infections, infection with immunoblot type 1 or 2 strains of C. difficile, and female gender. These factors may help to identify patients who are more likely to develop RCDD and require careful medical supervision.

PMID 9114180
Wanahita Anna A, Goldsmith Elizabeth A EA, Marino Bernard J BJ, Musher Daniel M DM
Clostridium difficile infection in patients with unexplained leukocytosis.
Am J Med. 2003 Nov;115(7):543-6.
Abstract/Text PURPOSE: To determine whether unrecognized Clostridium difficile infection is responsible for a substantial proportion of cases of unexplained leukocytosis in a tertiary care hospital setting.
METHODS: We prospectively identified 60 patients who had unexplained leukocytosis (white blood cell count > or =15,000/mm3). Fecal specimens were tested for C. difficile toxin using an enzyme immunosorbent assay. We compared the clinical features of patients who had positive or negative assay results, as well as of 26 hospitalized control patients who did not have unexplained leukocytosis.
RESULTS: Thirty-five (58%) of the patients with unexplained leukocytosis had C. difficile toxin in at least one fecal specimen as compared with 3 (12%) of the controls (P <0.001). Symptoms of colitis were often mild or absent at the time the white blood cell count was first elevated or, if present, had not been recognized by the attending physicians. Leukocytosis resolved promptly in most patients who were treated with metronidazole. In the 25 patients (42%) who had a negative test for C. difficile toxin, leukocytosis also tended to resolve during empiric therapy with metronidazole; some of these patients may have had C. difficile infection.
CONCLUSION: The majority of patients in our hospital who had unexplained leukocytosis had C. difficile infection. Unexplained leukocytosis in hospitalized patients should prompt a search for symptoms and signs consistent with C. difficile infection and a study to detect C. difficile. Empiric therapy with metronidazole may be effective in the appropriate epidemiologic setting.

PMID 14599633
Brown Thomas A TA, Rajappannair Lakshmi L, Dalton Arthur B AB, Bandi Ram R, Myers Joseph P JP, Kefalas Costas H CH
Acute appendicitis in the setting of Clostridium difficile colitis: case report and review of the literature.
Clin Gastroenterol Hepatol. 2007 Aug;5(8):969-71. doi: 10.1016/j.cgh.2007.04.016. Epub 2007 Jul 10.
Abstract/Text A 72-year-old man was hospitalized for exacerbation of chronic obstructive pulmonary disease and was treated with oral prednisone and 7 days of moxifloxacin. Five days after completing the antibiotic course, he developed watery diarrhea and diffuse, crampy abdominal pain. On presentation he was afebrile, and abdominal examination revealed diffuse tenderness without peritoneal signs. Stool tested positive for Clostridium difficile toxin A by enzyme-linked immunosorbent assay. Despite starting oral metronidazole, the patient developed a fever of 101.2 degrees F 36 hours after his initial episode of diarrhea, 12 hours after admission. His abdominal pain intensified and became localized to the right and left lower quadrants. Computed tomography scan revealed both a thickened cecal wall and an edematous appendix with ileocecal stranding consistent with appendicitis. Appendectomy was performed, and the appendix was found to be suppurative in appearance and nonperforated. The cecum had mild edema and erythema, whereas the colon and rectum were grossly unaffected. Pathology examination revealed exudative material in the appendiceal lumen and a diffuse transmural inflammatory cell infiltrate. The patient had an uneventful recovery and continued to improve on oral metronidazole. Although Clostridium difficile colitis and appendicitis are each very common independently, C. difficile as an etiology of appendicitis is exceedingly rare. A review of the literature revealed 2 prior cases. We speculate that this association is underdiagnosed, because milder cases might respond to antibiotic therapy alone, and severe cases might involve the entire colon and require total colectomy. In each scenario, the involvement of the appendix might be overlooked.

PMID 17625978
Jacobs A A, Barnard K K, Fishel R R, Gradon J D JD
Extracolonic manifestations of Clostridium difficile infections. Presentation of 2 cases and review of the literature.
Medicine (Baltimore). 2001 Mar;80(2):88-101.
Abstract/Text Clostridium difficile is most commonly associated with colonic infection. It may, however, also cause disease in a variety of other organ systems. Small bowel involvement is often associated with previous surgical procedures on the small intestine and is associated with a significant mortality rate (4 of 7 patients). When associated with bacteremia, the infection is, as expected, frequently polymicrobial in association with usual colonic flora. The mortality rate among patients with C. difficile bacteremia is 2 of 10 reported patients. Visceral abscess formation involves mainly the spleen, with 1 reported case of pancreatic abscess formation. Frequently these abscesses are only recognized weeks to months after the onset of diarrhea or other colonic symptoms. C. difficile-related reactive arthritis is frequently polyarticular in nature and is not related to the patient's underlying HLA-B27 status. Fever is not universally present. The most commonly involved joints are the knee and wrist (involved in 18 of 36 cases). Reactive arthritis begins an average of 11.3 days after the onset of diarrhea and is a prolonged illness, taking an average of 68 days to resolve. Other entities, such as cellulitis, necrotizing fasciitis, osteomyelitis, and prosthetic device infections, can also occur. Localized skin and bone infections frequently follow traumatic injury, implying the implantation of either environmental or the patient's own C. difficile spores with the subsequent development of clinical infection. It is noteworthy that except for cases involving the small intestine and reactive arthritis, most of the cases of extracolonic C. difficile disease do not appear to be strongly related to previous antibiotic exposure. The reason for this is unclear. We hope that clinicians will become more aware of these extracolonic manifestations of infection, so that they may be recognized and treated promptly and appropriately. Such early diagnosis may also serve to prevent extensive and perhaps unnecessary patient evaluations, thus improving resource utilization and shortening length of hospital stay.

PMID 11307591
Dansinger M L ML, Johnson S S, Jansen P C PC, Opstad N L NL, Bettin K M KM, Gerding D N DN
Protein-losing enteropathy is associated with Clostridium difficile diarrhea but not with asymptomatic colonization: a prospective, case-control study.
Clin Infect Dis. 1996 Jun;22(6):932-7.
Abstract/Text A prospective, case-control study was performed in which enteric protein loss and nutritional status were measured in patients with symptomatic and asymptomatic infections due to Clostridium difficile. Enteric protein loss, measured by elevated levels of fecal alpha1-antitrypsin, was detected in 14 of 20 cases and controls with diarrhea (9 of 10 cases with C. difficile-associated diarrhea and 5 of 10 age-matched control with diarrhea not associated with C. difficile) compared with none of 20 asymptomatic cases and controls (10 colonized cases and 10 noncolonized controls without diarrhea who were matched by age and clinical diagnosis) (P < .0001). Cases and controls with diarrhea had higher prognostic nutritional index values (P = 0.005) and lower levels of serum albumin, transferrin, and cholesterol than did the asymptomatic cases and controls. Decreased nutritional status, measured by increased prognostic nutritional index values, was associated with the presence of diarrhea but not with the presence of C. difficile. Protein-losing enteropathy was associated with C. difficile only in the presence of diarrhea, and we did not detect an increased risk of protein-losing enteropathy or malnutrition as a consequence of asymptomatic colonization with C difficile.

PMID 8783689
Issa Mazen M, Vijayapal Aravind A, Graham Mary Beth MB, Beaulieu Dawn B DB, Otterson Mary F MF, Lundeen Sarah S, Skaros Susan S, Weber Lydia R LR, Komorowski Richard A RA, Knox Josh F JF, Emmons Jeanne J, Bajaj Jasmohan S JS, Binion David G DG
Impact of Clostridium difficile on inflammatory bowel disease.
Clin Gastroenterol Hepatol. 2007 Mar;5(3):345-51. doi: 10.1016/j.cgh.2006.12.028.
Abstract/Text BACKGROUND & AIMS: Clostridium difficile-associated disease has increased significantly in North American medical centers. The impact of C difficile on patients with IBD (Crohn's disease, ulcerative colitis) at the present time is unknown.
METHODS: A retrospective, observational study evaluating IBD patients followed in a referral center to evaluate the impact of C difficile was performed. Diagnosis was confirmed with stool toxin analysis. Demographic information, diagnosis, anatomic location, IBD therapy, antibiotic exposure, hospitalizations, and surgeries were recorded. Available endoscopic and histologic data were evaluated.
RESULTS: Rate of C difficile infection increased from 1.8% of IBD patients in 2004 to 4.6% in 2005 (P < .01). Proportion of IBD patients within the total number of C difficile infections at our institution increased from 7% in 2004 to 16% in 2005 (P < .01). IBD colonic involvement was found in the majority of C difficile-infected patients in 2005 (91%), and the majority contracted infection as an outpatient (76%). Antibiotic exposure was identified in 61% of IBD patients with C difficile infection in 2005. Pseudomembranes and fibrinopurulent eruptions were not seen endoscopically or histologically. During 2004-2005 more than half of the infected IBD patients required hospitalization, and 20% required colectomy. Univariate and multivariate analysis identified maintenance immunomodulator use and colonic involvement as independent risk factors for C difficile infection in IBD.
CONCLUSIONS: C difficile infection has increased significantly in IBD patients and negatively impacts clinical outcome. Increased vigilance regarding this infection in IBD patients with colitis activity is warranted.

PMID 17368234
L Clifford McDonald, Dale N Gerding, Stuart Johnson, Johan S Bakken, Karen C Carroll, Susan E Coffin, Erik R Dubberke, Kevin W Garey, Carolyn V Gould, Ciaran Kelly, Vivian Loo, Julia Shaklee Sammons, Thomas J Sandora, Mark H Wilcox
Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).
Clin Infect Dis. 2018 Mar 19;66(7):987-994. doi: 10.1093/cid/ciy149.
Abstract/Text A panel of experts was convened by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) to update the 2010 clinical practice guideline on Clostridium difficile infection (CDI) in adults. The update, which has incorporated recommendations for children (following the adult recommendations for epidemiology, diagnosis, and treatment), includes significant changes in the management of this infection and reflects the evolving controversy over best methods for diagnosis. Clostridium difficile remains the most important cause of healthcare-associated diarrhea and has become the most commonly identified cause of healthcare-associated infection in adults in the United States. Moreover, C. difficile has established itself as an important community pathogen. Although the prevalence of the epidemic and virulent ribotype 027 strain has declined markedly along with overall CDI rates in parts of Europe, it remains one of the most commonly identified strains in the United States where it causes a sizable minority of CDIs, especially healthcare-associated CDIs. This guideline updates recommendations regarding epidemiology, diagnosis, treatment, infection prevention, and environmental management.

PMID 29562266
Triadafilopoulos G G, Hallstone A E AE
Acute abdomen as the first presentation of pseudomembranous colitis.
Gastroenterology. 1991 Sep;101(3):685-91.
Abstract/Text Acute abdomen was the presenting manifestation of pseudomembranous colitis in six men who had previously been treated with antibiotics and presented with abdominal distention, pain, fever, and leukocytosis with absent or mild diarrhea. Plain abdominal radiographs revealed megacolon in two, combined small and large bowel dilation in three, with one of them showing volvuluslike pattern, and isolated small bowel ileus in one. Emergency colonoscopy was performed successfully in all patients and revealed pseudomembranes in five and nonspecific colitis in one. All patients had positive latex test results for Clostridium difficile, and two tested positive for cytotoxicity. All patients were treated with IV metronidazole, resulting in resolution of symptoms and abdominal findings. In addition, two patients underwent colonoscopic decompression with improvement. Endoscopically, complete resolution of the pseudomembranes occurred at 4 weeks in all cases. No patient had a recurrence. It is concluded that (a) pseudomembranous colitis may present as abdominal distention mimicking small bowel ileus. Ogilvie's syndrome, volvulus, or ischemia; (b) in such cases, emergency colonoscopy is safe and useful for diagnosis and therapeutic decompression and may obviate the need for surgery; and (c) treatment with IV metronidazole is effective. Colitis due to C. difficile should be considered in the differential diagnosis of acute abdomen in patients previously treated with antibiotics.

PMID 1860633
Ciarán P Kelly, J Thomas LaMont
Clostridium difficile--more difficult than ever.
N Engl J Med. 2008 Oct 30;359(18):1932-40. doi: 10.1056/NEJMra0707500.
Abstract/Text
PMID 18971494
Apisarnthanarak Anucha A, Razavi Behzad B, Mundy Linda M LM
Adjunctive intracolonic vancomycin for severe Clostridium difficile colitis: case series and review of the literature.
Clin Infect Dis. 2002 Sep 15;35(6):690-6. doi: 10.1086/342334. Epub 2002 Aug 26.
Abstract/Text Successful treatment of severe Clostridium difficile colitis has been reported with the use of adjunctive intracolonic vancomycin (ICV) therapy. We report a descriptive case series and review the literature on patients with C. difficile colitis who received adjunctive ICV therapy. Nine patients received antibiotics within 6 weeks prior to presentation. Complete resolution of the clinical presentation occurred in 8 patients (88.9%), and eradication of C. difficile cytotoxin production was documented in 3 (75%) of 4 patients who were tested after the completion of adjunctive ICV therapy. One patient (11.1%) died as a result of progressive multisystem organ failure. In the 6 weeks after the completion of treatment for C. difficile colitis, no patient had recurrent disease, required surgical intervention, or experienced complications from adjunctive ICV therapy. In this case series, administration of adjunctive ICV therapy appeared to be a safe, practical, and effective adjunctive therapy for severe C. difficile colitis.

PMID 12203166
Louie Thomas J TJ, Miller Mark A MA, Mullane Kathleen M KM, Weiss Karl K, Lentnek Arnold A, Golan Yoav Y, Gorbach Sherwood S, Sears Pamela P, Shue Youe-Kong YK, OPT-80-003 Clinical Study Group
Fidaxomicin versus vancomycin for Clostridium difficile infection.
N Engl J Med. 2011 Feb 3;364(5):422-31. doi: 10.1056/NEJMoa0910812.
Abstract/Text BACKGROUND: Clostridium difficile infection is a serious diarrheal illness associated with substantial morbidity and mortality. Patients generally have a response to oral vancomycin or metronidazole; however, the rate of recurrence is high. This phase 3 clinical trial compared the efficacy and safety of fidaxomicin with those of vancomycin in treating C. difficile infection.
METHODS: Adults with acute symptoms of C. difficile infection and a positive result on a stool toxin test were eligible for study entry. We randomly assigned patients to receive fidaxomicin (200 mg twice daily) or vancomycin (125 mg four times daily) orally for 10 days. The primary end point was clinical cure (resolution of symptoms and no need for further therapy for C. difficile infection as of the second day after the end of the course of therapy). The secondary end points were recurrence of C. difficile infection (diarrhea and a positive result on a stool toxin test within 4 weeks after treatment) and global cure (i.e., cure with no recurrence).
RESULTS: A total of 629 patients were enrolled, of whom 548 (87.1%) could be evaluated for the per-protocol analysis. The rates of clinical cure with fidaxomicin were noninferior to those with vancomycin in both the modified intention-to-treat analysis (88.2% with fidaxomicin and 85.8% with vancomycin) and the per-protocol analysis (92.1% and 89.8%, respectively). Significantly fewer patients in the fidaxomicin group than in the vancomycin group had a recurrence of the infection, in both the modified intention-to-treat analysis (15.4% vs. 25.3%, P=0.005) and the per-protocol analysis (13.3% vs. 24.0%, P=0.004). The lower rate of recurrence was seen in patients with non–North American Pulsed Field type 1 strains. The adverse-event profile was similar for the two therapies.
CONCLUSIONS: The rates of clinical cure after treatment with fidaxomicin were noninferior to those after treatment with vancomycin. Fidaxomicin was associated with a significantly lower rate of recurrence of C. difficile infection associated with non–North American Pulsed Field type 1 strains. (Funded by Optimer Pharmaceuticals; ClinicalTrials.gov number, NCT00314951.)

PMID 21288078
Wullt Marlene M, Johansson Hagslätt Marie-Louise ML, Odenholt Inga I, Berggren Anna A
Lactobacillus plantarum 299v enhances the concentrations of fecal short-chain fatty acids in patients with recurrent clostridium difficile-associated diarrhea.
Dig Dis Sci. 2007 Sep;52(9):2082-6. doi: 10.1007/s10620-006-9123-3. Epub 2007 Apr 10.
Abstract/Text Our objective was to document how intake of Lactobacillus plantarum 299v affects the concentrations of fecal organic acids during and after metronidazole treatment in 19 patients with recurrent Clostridium difficile-associated diarrhea. Fecal samples were analyzed by gas-liquid chromatography. After intake of metronidazole a significant decrease in total short-chain fatty acids was seen in the placebo group (from 77.1 to 45.5 micromol/g; P=0.028) but not in the Lactobacillus group (79.8-60.4 micromol/g). In addition, a statistically significant difference between treatment groups was noted for butyrate (5.6-1.2 micromol/g in the placebo group vs. 7.6-5.6 micromol/g in the Lactobacillus group; P=0.047). At the end of the study and after cessation of placebo or Lactobacillus, the total short-chain fatty acids rose to the same levels as before antibiotic treatment in the placebo group. Both treatment groups showed a significant decrease in concentrations of succinate at the end of the study in comparison to the time when metronidazole intake was stopped (6.3-1.5 micromol/g in the placebo group versus 9.3-0.9 micromol/g in the Lactobacillus group; P=0.028). The present study of fecal samples from a clinical trial is the first to demonstrate that administration of Lactobacillus plantarum 299v reduces the negative effects of an antibiotic on colonic fermentation. The intake of this probiotic strain may thereby provide an additional benefit for patients with recurrent Clostridium difficile-associated diarrhea.

PMID 17420953
Paul Naaber, Marika Mikelsaar
Interactions between Lactobacilli and antibiotic-associated diarrhea.
Adv Appl Microbiol. 2004;54:231-60. doi: 10.1016/S0065-2164(04)54009-1.
Abstract/Text
PMID 15251283
Abstract/Text Many elderly subjects are at increased risk of infectious and noninfectious diseases due to an age-related decline in lymphoid cell activity (immunosenescence). Noninvasive means of enhancing cellular immunity are therefore desirable in the elderly. Previous reports have suggested that dietary supplementation could represent an effective means of enhancing the activity of circulating natural killer (NK) cells in the elderly. In the present study, we have conducted a pre-post intervention trial to determine the impact of dietary supplementation with probiotic lactic acid bacteria (LAB) on peripheral blood NK cell activity in healthy elderly subjects. Twenty-seven volunteers consumed low-fat/low-lactose milk supplemented with known immunostimulatory LAB strains (Lactobacillus rhamnosus HN001 or Bifidobacterium lactis HN019) for a period of 3 weeks. A dietary run-in of milk alone was shown to have no significant effect on NK cells. In contrast, the proportion of CD56-positive lymphocytes in peripheral circulation was higher following consumption of either LAB strain, and ex vivo PBMC tumoricidal activity against K562 cells was also increased. Supplementation with HN001 or HN019 increased tumoricidal activity by an average of 101 and 62%, respectively; these increases were significantly correlated with age, with subjects older than 70 years experiencing significantly greater improvements than those under 70 years. These results demonstrate that dietary consumption of probiotic LAB in a milk-based diet may offer benefit to elderly consumers to combat some of the deleterious effects of immunosenescence on cellular immunity.

PMID 11506196
Pillai A A, Nelson R R
Probiotics for treatment of Clostridium difficile-associated colitis in adults.
Cochrane Database Syst Rev. 2008 Jan 23;(1):CD004611. doi: 10.1002/14651858.CD004611.pub2. Epub 2008 Jan 23.
Abstract/Text BACKGROUND: Probiotics are live microorganisms consisting of non-pathogenic yeast and bacteria that are believed to restore the microbial balance of the gastrointestinal tract altered by infection with Clostridium difficile (C. difficile).
OBJECTIVES: To assess the efficacy of probiotics in the treatment of antibiotic associated C. difficile colitis.
SEARCH STRATEGY: The databases MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and Cochrane IBD/FBD Specialized Trials register were searched to locate all published reports from 1966 to 2007.
SELECTION CRITERIA: Randomized, prospective studies using probiotics alone or in conjunction with conventional antibiotics for the treatment of documented C. difficile colitis were eligible for inclusion.
DATA COLLECTION AND ANALYSIS: Data extraction and analysis was done independently by two authors.
MAIN RESULTS: Four studies met the inclusion criteria and were included in the review. The four studies examined the use of probiotics in conjunction with conventional antibiotics (vancomycin or metronidazole) for the treatment of recurrence or an initial episode of C. difficile colitis in adults. The studies were small in size and had methodological problems. A statistically significant benefit for probiotics combined with antibiotics was found in one study. McFarland 1994 found that patients receiving S. boulardii were significantly less likely than patients receiving placebo to experience recurrence of C. difficile diarrhea (RR 0.59; 95% CI 0.35 to 0.98). No benefit of probiotics treatment was found in the other studies.
AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend probiotic therapy as an adjunct to antibiotic therapy for C. difficile colitis. There is no evidence to support the use of probiotics alone in the treatment of C. difficile colitis.

PMID 18254055
Gao Xing Wang XW, Mubasher Mohamed M, Fang Chong Yu CY, Reifer Cheryl C, Miller Larry E LE
Dose-response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea prophylaxis in adult patients.
Am J Gastroenterol. 2010 Jul;105(7):1636-41. doi: 10.1038/ajg.2010.11. Epub 2010 Feb 9.
Abstract/Text OBJECTIVES: Standard therapies for antibiotic-associated diarrhea (AAD) and Clostridium difficile-associated diarrhea (CDAD) have limited efficacy. Probiotic prophylaxis is a promising alternative for reduction of AAD and CDAD incidence.
METHODS: In this single-center, randomized, double-blind, placebo-controlled dose-ranging study, we randomized 255 adult inpatients to one of three groups: two probiotic capsules per day (Pro-2, n=86), one probiotic capsule and one placebo capsule per day (Pro-1, n=85), or two placebo capsules per day (n=84). Each probiotic capsule contained 50 billion c.f.u. of live organisms (Lactobacillus acidophilus CL1285 +Lactobacillus casei LBC80R Bio-K+ CL1285). Probiotic prophylaxis began within 36 h of initial antibiotic administration, continued for 5 days after the last antibiotic dose, and patients were followed for an additional 21 days.
RESULTS: Pro-2 (15.5%) had a lower AAD incidence vs. Pro-1 (28.2%). Each probiotic group had a lower AAD incidence vs. placebo (44.1%). In patients who acquired AAD, Pro-2 (2.8 days) and Pro-1 (4.1 days) had shorter symptom duration vs. placebo (6.4 days). Similarly, Pro-2 (1.2%) had a lower CDAD incidence vs. Pro-1 (9.4%). Each treatment group had a lower CDAD incidence vs. placebo (23.8%). Gastrointestinal symptoms were less common in the treatment groups vs. placebo and in Pro-2 vs. Pro-1.
CONCLUSIONS: The proprietary probiotic blend used in this study was well tolerated and effective for reducing risk of AAD and, in particular, CDAD in hospitalized patients on antibiotics. A dose-ranging effect was shown with 100 billion c.f.u., yielding superior outcomes and fewer gastrointestinal events compared to 50 billion c.f.u. (ClinicalTrials.gov number NCT00958308).

PMID 20145608
Els van Nood, Anne Vrieze, Max Nieuwdorp, Susana Fuentes, Erwin G Zoetendal, Willem M de Vos, Caroline E Visser, Ed J Kuijper, Joep F W M Bartelsman, Jan G P Tijssen, Peter Speelman, Marcel G W Dijkgraaf, Josbert J Keller
Duodenal infusion of donor feces for recurrent Clostridium difficile.
N Engl J Med. 2013 Jan 31;368(5):407-15. doi: 10.1056/NEJMoa1205037. Epub 2013 Jan 16.
Abstract/Text BACKGROUND: Recurrent Clostridium difficile infection is difficult to treat, and failure rates for antibiotic therapy are high. We studied the effect of duodenal infusion of donor feces in patients with recurrent C. difficile infection.
METHODS: We randomly assigned patients to receive one of three therapies: an initial vancomycin regimen (500 mg orally four times per day for 4 days), followed by bowel lavage and subsequent infusion of a solution of donor feces through a nasoduodenal tube; a standard vancomycin regimen (500 mg orally four times per day for 14 days); or a standard vancomycin regimen with bowel lavage. The primary end point was the resolution of diarrhea associated with C. difficile infection without relapse after 10 weeks.
RESULTS: The study was stopped after an interim analysis. Of 16 patients in the infusion group, 13 (81%) had resolution of C. difficile-associated diarrhea after the first infusion. The 3 remaining patients received a second infusion with feces from a different donor, with resolution in 2 patients. Resolution of C. difficile infection occurred in 4 of 13 patients (31%) receiving vancomycin alone and in 3 of 13 patients (23%) receiving vancomycin with bowel lavage (P<0.001 for both comparisons with the infusion group). No significant differences in adverse events among the three study groups were observed except for mild diarrhea and abdominal cramping in the infusion group on the infusion day. After donor-feces infusion, patients showed increased fecal bacterial diversity, similar to that in healthy donors, with an increase in Bacteroidetes species and clostridium clusters IV and XIVa and a decrease in Proteobacteria species.
CONCLUSIONS: The infusion of donor feces was significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin. (Funded by the Netherlands Organization for Health Research and Development and the Netherlands Organization for Scientific Research; Netherlands Trial Register number, NTR1177.).

PMID 23323867
Mark H Wilcox, Dale N Gerding, Ian R Poxton, Ciaran Kelly, Richard Nathan, Thomas Birch, Oliver A Cornely, Galia Rahav, Emilio Bouza, Christine Lee, Grant Jenkin, Werner Jensen, You-Sun Kim, Junichi Yoshida, Lori Gabryelski, Alison Pedley, Karen Eves, Robert Tipping, Dalya Guris, Nicholas Kartsonis, Mary-Beth Dorr, MODIFY I and MODIFY II Investigators
Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection.
N Engl J Med. 2017 Jan 26;376(4):305-317. doi: 10.1056/NEJMoa1602615.
Abstract/Text BACKGROUND: Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively.
METHODS: We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population.
RESULTS: In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, -10.1 percentage points; 95% confidence interval [CI], -15.9 to -4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, -9.9 percentage points; 95% CI, -15.5 to -4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, -11.6 percentage points; 95% CI, -17.4 to -5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, -10.7 percentage points; 95% CI, -16.4 to -5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea.
CONCLUSIONS: Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239 .).

PMID 28121498
Lamontagne François F, Labbé Annie-Claude AC, Haeck Olivier O, Lesur Olivier O, Lalancette Mathieu M, Patino Carlos C, Leblanc Martine M, Laverdière Michel M, Pépin Jacques J
Impact of emergency colectomy on survival of patients with fulminant Clostridium difficile colitis during an epidemic caused by a hypervirulent strain.
Ann Surg. 2007 Feb;245(2):267-72. doi: 10.1097/01.sla.0000236628.79550.e5.
Abstract/Text OBJECTIVES: To determine whether emergency colectomy reduces mortality in patients with fulminant Clostridium difficile-associated disease (CDAD), and to identify subgroups of patients more likely to benefit from the procedure.
SUMMARY BACKGROUND DATA: Many hospitals in Quebec, Canada, have noted since 2003 a dramatic increase in CDAD incidence and in the proportion of cases severe enough to require intensive care unit (ICU) admission. The decision to perform an emergency colectomy remains largely empirical.
METHODS: Retrospective observational cohort study of 165 cases of CDAD that required ICU admission or prolongation of ICU stay between January 2003 and June 2005 in 2 tertiary care hospitals of Quebec. Multivariate analysis was performed through logistic regression; adjusted odds ratios (AOR) and their 95% confidence intervals (CI) were calculated. The primary outcome was mortality within 30 days of ICU admission.
RESULTS: Eighty-seven (53%) cases resulted in death within 30 days of ICU admission, almost half (38 of 87, 44%) within 48 hours of ICU admission. The independent predictors of 30-day mortality were: leukocytosis >or=50 x 10(9)/L (AOR, 18.6; 95% CI, 3.7-94.7), lactate >or=5 mmol/L (AOR, 12.4; 95% CI, 2.4-63.7), age >or=75 years (AOR, 6.5; 95% CI, 1.7-24.3), immunosuppression (AOR, 7.9; 95% CI, 2.3-27.2) and shock requiring vasopressors (AOR, 3.4; 95% CI, 1.3-8.7). After adjustment for these confounders, patients who had an emergency colectomy were less likely to die (AOR, 0.22; 95% CI, 0.07-0.67, P = 0.008) than those treated medically. Colectomy seemed more beneficial in patients aged 65 years or more, in those immunocompetent, those with a leukocytosis >or=20 x 10(9)/L or lactate between 2.2 and 4.9 mmol/L.
CONCLUSION: Emergency colectomy reduces mortality in some patients with fulminant CDAD.

PMID 17245181

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