肠球菌

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肠球菌
感染肺部組織的Enterococcus sp.
感染肺部組織的Enterococcus sp.
科學分類
界: Bacteria
門: Firmicutes
綱: Bacilli
目: Lactobacillales
科: Enterococcaceae
屬: 肠球菌屬 Enterococcus
(ex Thiercelin & Jouhaud 1903)
Schleifer & Kilpper-Bälz 1984
Species

E. malodoratus
E. avium
E. durans
E. faecalis
E. faecium
E. gallinarum
E. hirae
E. solitarius
etc.

腸球菌屬(學名:Enterococcus),革蘭氏陽性球菌。經常以成對(雙球菌)或短鏈方式存在,故從形態上與鏈球菌屬很難區分[1]。在人類腸道裡有兩種常見的偏利共生腸球菌:糞腸球菌Enterococcus faecalis)約佔90-95%和屎腸球菌Enterococcus faecium)約佔5-10%。其他人體中較少見的菌群還有E. casseliflavusE. gallinarumE. raffinosus[1]腸球菌因為能生成抵抗藥物的物質,使它們不容易被抗生素殺死,且容易散播抗藥性並可在惡劣環境中生存,故近年來已成為臨床感染的重要致病菌之一[2][3][4][5][6][7]。尤其是E. faecium經常對氨苄青黴素(ampicillin)及萬古黴素(vancomycin)具有抗藥性,是所有腸球菌感染症中最難治療的。

分類[编辑]

腸球菌是一種移生在腸道的革蘭氏陽性菌,故名腸球菌。在19世紀末發現,早期歸為鏈球菌屬。1930年代中期,依蘭斯菲爾德血清分型(Lancefield classification),腸球菌被歸類為D群鏈球菌(Group D Streptococcus),但是與非腸球菌的D群鏈球菌,如Streptococcus bovis, 在生化特性上有相當大的差異。直到1984年,基因體DNA分析指出腸球菌和鏈球菌的不同,而將腸球菌獨立成為一屬。[8]

生理學[编辑]

腸球菌在顯微鏡下典型的排列為成對或短鏈狀,很難與肺炎鏈球菌區別。腸球菌是兼性厭氧菌,可在有氧和無氧的環境中生長[9]。 雖然腸球菌不能形成孢子,但他們對於生長環境卻有很高的耐受性,例如可在下列環境中生長:溫度10-45℃、酸鹼度pH 4.5-10.0、高鹽濃度6.5%NaCl或40%膽汁[10]。最適宜生長溫度為35℃,24小時培養可以形成白色菌落。

病理學[编辑]

腸球菌在臨床上引起的重要感染包括泌尿道感染菌血症、心內膜炎、憩室炎和腦膜炎[10][11] 。敏感性菌株的感染可用氨苄青黴素(ampicillin)、青黴素(penicillin)和萬古黴素(vancomycin)治療[12]。 泌尿道感染則可用呋喃妥因(nitrofurantoin)進行特異性治療,即使在萬古黴素抗藥性的情況下[13]

從醫學觀點來看,腸球菌的一個重要特性是具有高度的先天抗藥性。一些腸球菌對β-內醯胺類抗生素(β-lactam,如青黴素、頭孢菌素(cephalosporin)、碳青黴烯(carbapenem)及許多氨基糖苷類抗生素(aminoglycoside)具有抗藥性[11]。尤其是過去20多年來,抗萬古黴素腸球菌(Vancomycin-Resistant Enterococcus,VRE)在院內感染患者逐漸被檢出,尤其是在美國[10]抗萬古黴素腸球菌可用奎奴普丁/達福普丁(quinupristin/dalfopristin)來治療,約有70%的患者會達到治療效果[14],若與去氧羥四環素(doxycycline)合併治療,可降低抗藥性發生的機會。老虎黴素類抗生素(tigecycline)也已證明能用來治療腸球菌感染,如利福平(rifampicin)[15]

2008年的一研究分析了歐洲各國(北歐、英國、愛爾蘭、法國、中歐、南歐、東歐、荷蘭)抗萬古黴素腸球菌的發生與流行,並對臨床上預防抗萬古黴素腸球菌的方式提出建議。此篇文獻認為,E. faecium的氨苄青黴素(ampicillin)抗藥性可做為抗萬古黴素腸球菌風險一個很好的篩檢方法;對於分析E. faecium的基因差異(如esp基因、pruK基因)則屬次要的方式,因為這些基因學的特徵並非在所有抗氨苄青黴素(ampicillin)的E. faecium皆有一致的表現。也就是說,若沒有檢測出這些基因變異,並不能證明E. faecium菌株不會有擴散或導致疾病的風險[16]世界衛生組織(WHO)在2017年初將抗萬古黴素腸球菌列為「高度威脅」的致病菌[17]

腸球菌性腦膜炎是神經外科上罕見的併發症。它一般需要透過靜脈或鞘內萬古黴素來進行治療,但是治療效果仍有爭議[18]。新的流行病學證據顯示,腸球菌亦是慢性細菌性攝護腺炎的主要感染因子,腸球菌會在攝護腺中形成生物膜,使其難以治療。

除了抗藥性,腸球菌也會生成許多毒性因子,毒性因子是作用於人體且會引發許多病灶,甚至造成嚴重疾病的物質;這些因子皆增加了腸球菌對人體的致病力[19][20][21]

美國國家院內感染監視系統(NNIS)所建置的國家健康照護安全網路(NHSN)[22]統計發現,腸球菌是院內感染的第二大病原菌[23],且位居醫療照護相關血液感染比例的第三位[24],顯示腸球菌抗藥性所隱藏的致病風險。

Enterococcus
分类和外部资源
ICD-9-CM 041.04

食品應用[编辑]

做為益生菌食用[编辑]

腸球菌是人類和許多動物的一種腸道共生菌,糞腸球菌和屎腸球菌是最常見的菌種,這兩種腸球菌已有許多研究證明其促進人體和動物(豬、家禽等)健康的功效,因此在保健食品的應用上普遍被作為益生菌使用[25][26][27][28][29][30]。在腸道中,腸球菌會搶奪病原菌的生存空間,所以當不小心吃入了病原菌,這些病原菌也沒有辦法留在腸道中,大幅減低了它們的致病力。此外,腸球菌具有抵抗消化液的能力,作為益生菌食用時,因不容易被消化液分解,所以能有更多的菌量到達腸道,使其更容易發揮改善腸道健康的作用;因為這些特性,所以腸球菌是常見的益生菌選擇之一[31]

早在1980年代,腸球菌就被使用來治療細菌性的腹瀉[32][33][34],當時被認為是藥物治療以外的另一種選擇,主要因為腸球菌在腸道內生長快速,並可抑制其它致病菌,例如大腸桿菌的生長,因此能減緩腹瀉的症狀。除了細菌性腹瀉,腸球菌也被證實能用來預防藥物型腹瀉[35][36];當服用抗生素時,腸道的菌群會因此失衡,一些致病菌就會趁機繁殖,進而造成腹瀉等症狀,腸球菌可避免服用抗生素時的不良反應發生。所以將具有抗藥性的腸球菌作為藥品,連同抗生素一同使用,達到治療效果的同時,也可以避免副作用的發生[37]

中華民國食品藥物管理署於2017年10月19日公告:預告訂定「糞腸球菌(Enterococcus faecalis)及屎腸球菌(Enterococcus faecium)不得作為食品原料使用」草案,預定2018年7月實施。因腸球菌菌株變異性大,若要作為食品原料使用,業者必須要提出數據證實安全無虞,經個案審議才有機會使用。屆時規定若正式施行後,經查獲食品使用的原料不符規定者,將可依法開罰[38]

食用的健康風險[编辑]

1998年,美國的一項研究就發現,腸球菌在腸道聚集生長的過程會產生相當可觀的自由基,這些自由基很可能導致腸黏膜細胞的不正常增生,進而引發大癌直腸癌的風險[39]

腸球菌具有很強的抗藥性散播能力[40][41][42],造成原本可以被殺死的細菌變成殺不死,因此不被認為是一般公認安全(Generally Recognized as Safe,GRAS)的菌種[43][44],作為益生菌使用仍有安全上的問題,特別是在細菌感染、免疫低下的患者和老年人身上[43][45][46]。除了抗藥性的散播能力,腸球菌也可能散播毒性因子[45][46][47][48][49],增加了腸球菌在食品應用上的疑慮,故腸球菌作為益生菌原料的安全性必須審慎評估。

腸球菌因抗藥因子和毒性因子的高度散播能力,使腸球菌容易獲得或傳遞這些對健康有風險的因子,最後衍生出藥物殺不死的病菌,造成了治療上的困難,顯示腸球菌對人體健康的潛在危害[41][44][47][48][49]。因此,考慮到腸球菌感染在人類流行病學上的進展,以及腸球菌對人體健康可能具有的風險, 世界衛生組織(WHO)在2002年提出報告不建議腸球菌作為益生菌提供給人類使用[50],2007年歐洲食品安全局(EFSA)也認為腸球菌並非屬於合格認定安全(Qualified Presumption of Safety,QPS)的菌種[51][52],2011年美國食品藥品監督管理局(FDA)的乳製品指導方針草案[53]也不建議將腸球菌作為益生菌使用。中國[54][55] 、加拿大[56][57]等國也禁止或不建議腸球菌作為益生菌成分。根據許多研究結果及主要國家的安全評估,腸球菌作為益生菌對人體健康的不良影響實無法完全排除,因此禁止或有條件的使用是有其必要性的。

腸球菌專家、美國哈佛大學醫學院的Michael S. Gilmore博士團隊在其所撰寫的《Enterococci》一書中,除了提及美國FDA與歐洲食品安全局不建議使用腸球菌作為益生菌給人類食用之外,更寫到腸球菌必須確定無毒性因子以及必須以活體試驗(in vivo)證明不具有基因水平轉移的能力(會導致抗藥性的散播)才可以作為益生菌食用;然而,到2014年為止,科學界並沒有發現不具基因轉移能力的腸球菌菌株[40]。令人擔心的是,在高劑量的情況下,作為益生菌食用的腸球菌可能在腸道系統中參與基因轉移作用而產生有問題的菌株[41]。因此,腸球菌作為益生菌使用仍有相當大的爭議,想藉由食用這類益生菌來促進健康的同時,也不應忽視腸球菌對人體健康的不良影響。

作為飼料添加物[编辑]

目前歐洲食品安全局規定腸球菌E. faecium使用在動物飼料,須通過相關的安全評估,包括了不得檢出三種毒性因子和DNA標記:IS16、Esp、hyl-like,以及氨苄青黴素(ampicillin)的最低抑菌濃度(MIC)不得超過2 mg/L,若不符合上述的檢驗標準,則認定為不安全,此腸球菌不可使用於飼料添加物當中[58]

水質標準評估[编辑]

水質中的腸球菌標準非常嚴格,例如在夏威夷州和美國的大部分地區,其海灘周圍的水域是每100毫升水中,五個星期的平均值不得超過35菌落形成單位(CFU)的腸球菌,否則該地區可能會發布警告,要求民眾遠離海灘[59]。2004年,腸球菌更取代了糞大腸菌群和大腸桿菌,成為新的美國聯邦公共鹽水和淡水海域水質標準[60]

中華民國的海灘水質也是參考香港及美國,主要以甲類海域之海洋環境品質標準—大腸桿菌群之菌落數在1000 CFU/100mL以下(以下簡稱「符合甲類」)為判定依據。符合甲類者,再以腸球菌群區分為「優良」或「普通」。當大腸桿菌群 ≦ 1000 CFU/100mL,且腸球菌群 ≦ 50 CFU/100mL,水質標準為「優良」。當大腸桿菌群 ≦1000 CFU/100mL,但腸球菌群>50 CFU/100mL,水質標準為「普通」。若大腸桿菌群>1000 CFU/100mL,則「不宜親水活動[61]

實驗室檢驗[编辑]

腸球菌通常會在羊血瓊脂(sheep's blood agar)上呈現γ-溶血反應[11]

參考資料[编辑]

  1. ^ 1.0 1.1 Gilmore MS; 等. The Enterococci: Pathogenesis, Molecular Biology, and Antibiotic Resistance. Washington, D.C.: ASM Press. 2002. ISBN 978-1-55581-234-8. 
  2. ^ Arias, Cesar A.; Murray, Barbara E. The rise of the Enterococcus: beyond vancomycin resistance. Nature Reviews. Microbiology. 2012-03-16, 10 (4): 266–278. ISSN 1740-1534. PMC 3621121. PMID 22421879. doi:10.1038/nrmicro2761. 
  3. ^ Hultin, T. A.; Weber, W. W. Genetic differences in inhibition of 2-aminofluorene N-acetyltransferase activity between C57BL/6J and A/J mice. Biochemical Pharmacology. 1986-04-01, 35 (7): 1214–1216. ISSN 0006-2952. PMID 3485979. 
  4. ^ Mohammadi, F.; Ghafourian, S.; Mohebi, R.; Taherikalani, M.; Pakzad, I.; Valadbeigi, H.; Hatami, V.; Sadeghifard, N. Enterococcus faecalis as multidrug resistance strains in clinical isolates in Imam Reza Hospital in Kermanshah, Iran. British Journal of Biomedical Science. 2015, 72 (4): 182–184. ISSN 0967-4845. PMID 26738400. 
  5. ^ Li, Bin; Ma, Chuan-Ling; Yu, Xiao; Sun, Yao; Li, Mei-Mei; Ye, Jian-Zhong; Zhang, Ya-Pei; Wu, Qing; Zhou, Tie-Li. Investigation of mechanisms and molecular epidemiology of linezolid nonsusceptible Enterococcus faecalis isolated from a teaching hospital in China. Journal of Microbiology, Immunology, and Infection = Wei Mian Yu Gan Ran Za Zhi. August 2016, 49 (4): 595–599. ISSN 1995-9133. PMID 26210761. doi:10.1016/j.jmii.2015.05.010. 
  6. ^ de Kraker, M. E. A.; Jarlier, V.; Monen, J. C. M.; Heuer, O. E.; van de Sande, N.; Grundmann, H. The changing epidemiology of bacteraemias in Europe: trends from the European Antimicrobial Resistance Surveillance System. Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. September 2013, 19 (9): 860–868. ISSN 1469-0691. PMID 23039210. doi:10.1111/1469-0691.12028. 
  7. ^ Daniel, Diane Sunira; Lee, Sui Mae; Dykes, Gary A.; Rahman, Sadequr. Public Health Risks of Multiple-Drug-Resistant Enterococcus spp. in Southeast Asia. Applied and Environmental Microbiology. September 2015, 81 (18): 6090–6097. ISSN 1098-5336. PMC 4542241. PMID 26150452. doi:10.1128/AEM.01741-15. 
  8. ^ Schleifer KH; Kilpper-Balz R. Transfer of Streptococcus faecalis and Streptococcus faecium to the genus Enterococcus nom. rev. as Enterococcus faecalis comb. nov. and Enterococcus faecium comb. nov.. Int. J. Sys. Bacteriol. 1984, 34: 31–34. doi:10.1099/00207713-34-1-31. 
  9. ^ Fischetti VA, Novick RP, Ferretti JJ, Portnoy DA, Rood JI (编). Gram-Positive Pathogens. ASM Press. 2000. ISBN 1-55581-166-3. 
  10. ^ 10.0 10.1 10.2 Fisher K, Phillips C. The ecology, epidemiology and virulence of Enterococcus. Microbiology. 2009, 155 (Pt6): 1749–57. PMID 19383684. doi:10.1099/mic.0.026385-0. 
  11. ^ 11.0 11.1 11.2 Ryan KJ, Ray CG (编). Sherris Medical Microbiology 4th. McGraw Hill. 2004: 294–5. ISBN 0-8385-8529-9. 
  12. ^ Pelletier LL Jr. Microbiology of the Circulatory System. in: Baron's Medical Microbiology (Baron S et al., eds.) 4th. Univ of Texas Medical Branch. 1996. ISBN 0-9631172-1-1. 
  13. ^ Zhanel GG, Hoban DJ, Karlowsky JA. Nitrofurantoin is active against vancomycin-resistant enterococci. Antimicrob. Agents Chemother. January 2001, 45 (1): 324–6. PMC 90284. PMID 11120989. doi:10.1128/AAC.45.1.324-326.2001. 
  14. ^ Tünger A, Aydemir S, Uluer S, Cilli F. In vitro activity of linezolid & quinupristin/dalfopristin against Gram-positive cocci. Indian J Med Res. 2004, 120 (6): 546–52. PMID 15654141. 
  15. ^ Moellering RC Jr, Wennersten C. Therapeutic potential of rifampin in enterococcal infections. Rev Infect Dis. 1983 Jul-Aug,. 5 Suppl 3: S528–32. 
  16. ^ Werner, G.; Coque, T. M.; Hammerum, A. M.; 等. Emergence and spread of vancomycin resistance among enterococci in Europe. Euro Surveillance: Bulletin Europeen Sur Les Maladies Transmissibles = European Communicable Disease Bulletin. 2008-11-20, 13 (47). ISSN 1560-7917. PMID 19021959. 
  17. ^ Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. World Health Organization; 2017 Feb 27. (PDF). 
  18. ^ Guardado R; Asensi V; Torres JM; 等. Post-surgical enterococcal meningitis: clinical and epidemiological study of 20 cases. Scand. J. Infect. Dis. 2006, 38 (8): 584–8. PMID 16857599. doi:10.1080/00365540600606416. 
  19. ^ Dworniczek, Ewa; Piwowarczyk, Justyna; Bania, Jacek; 等. Enterococcus in wound infections: virulence and antimicrobial resistance. Acta Microbiologica Et Immunologica Hungarica. June 2012, 59 (2): 263–269. ISSN 1217-8950. PMID 22750786. doi:10.1556/AMicr.59.2012.2.11. 
  20. ^ Fernandes, Sanal C.; Dhanashree, B. Drug resistance & virulence determinants in clinical isolates of Enterococcus species. The Indian Journal of Medical Research. May 2013, 137 (5): 981–985. ISSN 0971-5916. PMC 3734693. PMID 23760387. 
  21. ^ Yang, Jing-xian; Li, Tong; Ning, Yong-zhong; 等. Molecular characterization of resistance, virulence and clonality in vancomycin-resistant Enterococcus faecium and Enterococcus faecalis: A hospital-based study in Beijing, China. Infection, Genetics and Evolution: Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases. July 2015, 33: 253–260. ISSN 1567-7257. PMID 25976380. doi:10.1016/j.meegid.2015.05.012. 
  22. ^ NHSN Annual Reports. 
  23. ^ Sievert DM; Ricks P; Edwards JR; 等. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010.. Infect Control Hosp Epidemiol. 2013, 34 (1): 1–14. doi:10.1086/668770. 
  24. ^ Dara Torres; Miriam Gonzalez; Adriana Loera; 等. The CDC definition of mucosal barrier injury–associated bloodstream infection improves accurate detection of preventable bacteremia rates at a pediatric cancer center in a low- to middle-income country. Am J Infect Control. 2016, 44 (4): 432–437. doi:10.1016/j.ajic.2015.11.007. 
  25. ^ Sivieri, K.; Spinardi-Barbisan, A. L. T.; Barbisan, L. F.; Bedani, R.; Pauly, N. D.; Carlos, I. Z.; Benzatti, F.; Vendramini, R. C.; Rossi, E. A. Probiotic Enterococcus faecium CRL 183 inhibit chemically induced colon cancer in male Wistar rats. European Food Research and Technology. 2008-12-01, 228 (2): 231–237. ISSN 1438-2377. doi:10.1007/s00217-008-0927-6 (英语). 
  26. ^ Gautschi, J. R.; Clarkson, J. M. Discontinuous DNA replication in mouse P-815 cells. European Journal of Biochemistry. 1975-01-02, 50 (2): 403–412. ISSN 0014-2956. PMID 1168572. 
  27. ^ Kato, Y.; Okazaki, T.; Mochizuki, T.; Tashima, M.; Sawada, H.; Uchino, H.; Obayashi, T. Coexistence of acute leukemia and gastric cancer in advanced ages. [Rinsho Ketsueki] The Japanese Journal of Clinical Hematology. April 1987, 28 (4): 608–615. ISSN 0485-1439. PMID 3476767. 
  28. ^ Griko, S. P. Immediate results of treatment of children with complicated forms of primary tuberculosis. Problemy Tuberkuleza. 1966, 44 (3): 33–37. ISSN 0032-9533. PMID 5300979. 
  29. ^ Rossi, Elizeu Antonio; Vendramini, Regina Célia; Carlos, Iracilda Zeppone; de Oliveira, Maurício Gonçalves; de Valdez, Graciela Font. Effect of a new fermented soy milk product on serum lipid levels in normocholesterolemic adult men. Archivos Latinoamericanos De Nutricion. March 2003, 53 (1): 47–51. ISSN 0004-0622. PMID 12942871. 
  30. ^ Enterococcus organisms and their use as probiotics in alleviating irritable bowel syndrome symptoms. European Patent 0508701 (B1),1996.
  31. ^ Franz, C. M.; Holzapfel, W. H.; Stiles, M. E. Enterococci at the crossroads of food safety?. International Journal of Food Microbiology. 1999-03-01, 47 (1-2): 1–24. ISSN 0168-1605. PMID 10357269. 
  32. ^ Lewenstein A; Frigerio G; Mangiagli A. Biological properties of SF68, a new approach for the treatment of diarrhoeal diseases. Curr Ther Res. 1979, 26: 967–981. 
  33. ^ Bellomo G; Mangiagli A; Nicastro L; Frigerio G. A controlled double-blind study of SF68 strain as a new biological preparation for the treatment of diarrhoea in pediatrics.. Curr Ther Res. 1980, 28: 927–936. 
  34. ^ Canganella, F.; Gasbarri, M.; Massa, S.; 等. A microbiological investigation on probiotic preparations used for animal feeding. Microbiological Research: 167–175. doi:10.1016/s0944-5013(96)80041-3. 
  35. ^ Borgia, M., Sepe, N., Brancato, V., Costa, G., Simone, P., Borgia, R. A controlled clinical study on Streptococcus faecium preparation for the prevention of side reactions during long-term antibiotic treatments. Curr Ther Res. 1982, 31: 265–271. 
  36. ^ Wunderlich, P. F.; Braun, L.; Fumagalli, I.; D'Apuzzo, V.; Heim, F.; Karly, M.; Lodi, R.; Politta, G.; Vonbank, F. Double-blind report on the efficacy of lactic acid-producing Enterococcus SF68 in the prevention of antibiotic-associated diarrhoea and in the treatment of acute diarrhoea. The Journal of International Medical Research. July 1989, 17 (4): 333–338. ISSN 0300-0605. PMID 2676650. doi:10.1177/030006058901700405. 
  37. ^ Hammad, A. M.; Shimamoto, T. Towards a compatible probiotic-antibiotic combination therapy: assessment of antimicrobial resistance in the Japanese probiotics. Journal of Applied Microbiology. October 2010, 109 (4): 1349–1360. ISSN 1365-2672. PMID 20497275. doi:10.1111/j.1365-2672.2010.04762.x. 
  38. ^ 預告訂定「糞腸球菌(Enterococcus faecalis)及屎腸球菌(Enterococcus faecium)不得作為食品原料使用」草案. 
  39. ^ Winters, Michael D.; Schlinke, Tiffany L.; Joyce, Wendy A.; Glore, Stephen R.; Huycke, Mark M. Prospective case-cohort study of intestinal colonization with enterococci that produce extracellular superoxide and the risk for colorectal adenomas or cancer. The American Journal of Gastroenterology: 2491–2500. doi:10.1111/j.1572-0241.1998.00710.x. 
  40. ^ 40.0 40.1 Gilmore, Michael S. (编). Enterococci: From Commensals to Leading Causes of Drug Resistant Infection. Boston: Massachusetts Eye and Ear Infirmary. 2014. PMID 24649510. 
  41. ^ 41.0 41.1 41.2 Franz, Charles M. A. P.; Huch, Melanie; Abriouel, Hikmate; Holzapfel, Wilhelm; Gálvez, Antonio. Enterococci as probiotics and their implications in food safety. International Journal of Food Microbiology. 2011-12-02, 151 (2): 125–140. ISSN 1879-3460. PMID 21962867. doi:10.1016/j.ijfoodmicro.2011.08.014. 
  42. ^ Murray, B. E. Vancomycin-resistant enterococcal infections. The New England Journal of Medicine. 2000-03-09, 342 (10): 710–721. ISSN 0028-4793. PMID 10706902. doi:10.1056/NEJM200003093421007. 
  43. ^ 43.0 43.1 Murlidhar,, Meghwal,; Raj,, Goyal, Megh; S.,, Chavan, Rupesh. Dairy engineering : advanced technologies and their applications. Oakville, ON. ISBN 9781771883801. OCLC 965781424. 
  44. ^ 44.0 44.1 Reidel, W. L.; Clouse, R. E. Variations in clinical presentation of patients with esophageal contraction abnormalities. Digestive Diseases and Sciences. November 1985, 30 (11): 1065–1071. ISSN 0163-2116. PMID 4053917. 
  45. ^ 45.0 45.1 Eaton, Tracy J.; Gasson, Michael J. Molecular Screening of EnterococcusVirulence Determinants and Potential for Genetic Exchange between Food and Medical Isolates. Applied and Environmental Microbiology. 2001-04-01, 67 (4): 1628–1635. ISSN 0099-2240. PMID 11282615. doi:10.1128/AEM.67.4.1628-1635.2001 (英语). 
  46. ^ 46.0 46.1 Lund, B.; Edlund, C. Probiotic Enterococcus faecium strain is a possible recipient of the vanA gene cluster. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America. 2001-05-01, 32 (9): 1384–1385. ISSN 1058-4838. PMID 11303279. doi:10.1086/319994. 
  47. ^ 47.0 47.1 Tamimi, S. O.; Ahmed, A. Stromal changes in early invasive and non-invasive breast carcinoma: an ultrastructural study. The Journal of Pathology. September 1986, 150 (1): 43–49. ISSN 0022-3417. PMID 3023597. doi:10.1002/path.1711500108. 
  48. ^ 48.0 48.1 Franz, Charles M. A. P.; Stiles, Michael E.; Schleifer, Karl Heinz; Holzapfel, Wilhelm H. Enterococci in foods--a conundrum for food safety. International Journal of Food Microbiology. 2003-12-01, 88 (2-3): 105–122. ISSN 0168-1605. PMID 14596984. 
  49. ^ 49.0 49.1 Araújo, Tatiane Ferreira; Ferreira, Célia Lúcia de Luces Fortes. The genus Enterococcus as probiotic: safety concerns. Brazilian Archives of Biology and Technology. June 2013, 56 (3): 457–466. ISSN 1516-8913. doi:10.1590/S1516-89132013000300014. 
  50. ^ Probiotics in food: Health and nutritional properties and guidelines for evaluation. ISSN: 0254-4725.
  51. ^ Introduction of a Qualified Presumption of Safety (QPS) approach for assessment of selected microorganisms referred to EFSA. The EFSA Journal. 2007;587:1–16.
  52. ^ Scientific Opinion on the maintenance of the list of QPS biological agents intentionally added to food and feed (2013 update). EFSA Journal 2013;11(11):3449 [106 pp.].
  53. ^ Dietary Supplements: New Dietary Ingredient Notifications and Related Issues: Guidance for Industry. U.S. FDA, Center for Food Safety and Applied Nutrition; August 2016.
  54. ^ 卫生部关于印发真菌类和益生菌类保健食品评审规定的通知。 (PDF). 
  55. ^ 卫生部关于印发《可用于食品的菌种名单》的通知。. 
  56. ^ Report submitted to the Natural Health Products Directorate, Health Canada. Nutritech Consulting Winnipeg, Manitoba; March 2005.
  57. ^ Health Claims - Probiotic Claims. 
  58. ^ EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP). Guidance on the safety assessment of Enterococcus faecium in animal nutrition. EFSA Journal. 2012-05-01, 10 (5): n/a–n/a. ISSN 1831-4732. doi:10.2903/j.efsa.2012.2682 (英语). 
  59. ^ Clean Water Branch (PDF). Hawaii State Department of Health. [2012-05-18]. (原始内容 (PDF)存档于2011-11-11). 
  60. ^ Water Quality Standards for Coastal and Great Lakes Recreation Waters. EPA. [7/9/2004]. 
  61. ^ 行政院環保署-全國環境水質監測資訊網-海灘水質檢測標準.