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 ~  Abstract
 ~  Clostridium diff...
 ~  Clostridium perf...
 ~  Staphylococcus a...
 ~  Klebsiella oxytoca
 ~  Salmonella species
 ~  Candida species
 ~  Treatment
 ~  References

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REVIEW ARTICLE
Year : 2003  |  Volume : 21  |  Issue : 1  |  Page : 6-11
 

Antibiotic associated diarrhoea: Infectious causes


Department of Microbiology, Sanjay Gandhi Post graduate Institute of Medical Sciences, Lucknow - 226014, UP, India

Correspondence Address:
Department of Microbiology, Sanjay Gandhi Post graduate Institute of Medical Sciences, Lucknow - 226014, UP, India

 ~ Abstract 

Nearly 25% of antibiotic associated diarrhoeas (AAD) is caused by Clostridium difficile, making it the commonest identified and treatable pathogen. Other pathogens implicated infrequently include Clostridium perfringens, Staphylococcus aureus, Klebsiella oxytoca, Candida spp. and Salmonella spp. Most mild cases of AAD are due to non-infectious causes which include reduced break down of primary bile acids and decrease metabolism of carbohydrates, allergic or toxic effects of antibiotic on intestinal mucosa and pharmacological effect on gut motility. The antibiotics most frequently associated with C. difficile associated diarrhoea are clindamycin, cephalosporin, ampicillin and amoxicillin. Clinical presentation may vary from mild diarrhoea to severe colitis and pseudomembranous colitis associated with high morbidity and mortality. The most sensitive and specific diagnostic test for C. difficile infection is tissue culture assay for cytotoxicity of toxin B. Commercial ELISA kits are available. Though less sensitive, they are easy to perform and are rapid. Withdrawal of precipitating antibiotic is all that is needed for control of mild to moderate cases. For severe cases of AAD, oral metronidazole is the first line of treatment, and oral vancomycin is the second choice. Probiotics have been used for recurrent cases.

How to cite this article:
Ayyagari A, Agarwal J, Garg A. Antibiotic associated diarrhoea: Infectious causes. Indian J Med Microbiol 2003;21:6-11


How to cite this URL:
Ayyagari A, Agarwal J, Garg A. Antibiotic associated diarrhoea: Infectious causes. Indian J Med Microbiol [serial online] 2003 [cited 2014 Oct 22];21:6-11. Available from: http://www.ijmm.org/text.asp?2003/21/1/6/8307


Diarrhoea is a frequent adverse effect of antibiotic therapy; incidence varying between 5-25%, differing with the antibiotic used.[1] Antibiotic associated diarrhoea (AAD) is considered clinically significant when there are three mushy or watery stools per day.[2] Diarrhoea is reported to develop from within a few hours up to 2 months after antibiotic intake.[3] Various mechanisms have been attributed to development of diarrhoea following antibiotic therapy. Disturbed composition and function of normal intestinal flora leads to decreased metabolism of carbohydrates, which in turn causes osmotic diarrhoea. Reduced break down of primary bile acids further adds on as these are potent colonic secretory agents. Other mechanisms include lower concentrations of faecal anaerobes thus decrease in colonization resistance, overgrowth of pathogenic microbes which may produce toxins; allergic or toxic effects of antibiotic on intestinal mucosa and pharmacological effect on gut motility.[4],[5] Nearly 25% of AAD cases are caused by Clostridium difficile and it is the most commonly identified and treatable pathogen.6 Other pathogens that have been linked with AAD include Clostridium perfringens, Staphylococcus aureus, Klebsiella oxytoca, Candida spp. and  Salmonella More Details spp.[4],[5]

 ~ Clostridium difficile Top

Clostridium difficile is an anaerobic, gram-positive spore forming bacillus first isolated in 1935 from faecal flora of healthy neonates. It was not until 1978 that its association with antibiotic induced pseudomembranous colitis (PMC) was established.[7] Isolation rate of C. difficile varies from 90% in PMC to 20-25% in AAD.[6] Major risk factors include advanced age, duration of hospitalization, severity of underlying disease and exposure to antibiotics. The antibiotics most frequently associated are clindamycin, cephalosporin, ampicillin and amoxicillin. In a multivariate analysis, after making adjustments for other risk factors, these agents were found to be associated with highest risk of C. difficile diarrhoea.[8] Almost all antibiotics have been linked with C. difficile diarrhoea and colitis, including vancomycin and metronidazole (which are used for its treatment) and cancer chemotherapy.[9],[10] The frequency of association is related to frequency of use, the route of administration and the impact of that antibiotic on the colonic microflora [Figure:1]. Other reported risk factors include presence of nasogastric tube and gastrointestinal procedures.[8]
World over, the incidence of C. difficile associated infections have increased. In UK, since 1992, the number of toxin positive reports has increased more than nine fold.[11] It is now recognized as the leading cause of nosocomial infectious diarrhoea in developed countries. Several large outbreaks associated with inter-patient transfer of this organism have been documented; hospital environment, infected patients, inanimate objects and hands of health care personnel are implicated as major sources for nosocomial acquisition.[12] Endogenous contamination is only rarely implicated because adult intestinal carriage rates are very low in community, however, this increases dramatically after admission to hospital and antibiotic treatment. C. difficile can be detected in stools of 5% or more healthy adults and up to 63% of patients without diarrhoea in hospital setup.[3] Asymptomatic carriers rarely develop C. difficile associated diarrhoea but can contaminate the hospital environment.[12] Spores of C. difficile may persist for many months in hospital wards and are particularly resistant to oxygen, desiccation and many disinfectants.[13]
Pathogenic strains of C. difficile produce two major toxins: toxin A, an enterotoxin (308 kDa protein) and toxin B, a potent cytotoxin approximately 270 kDa protein. Both toxins are involved in the pathogenesis of C. diffficile disease in humans. Different genes in close proximity on bacterial genome encode these toxins and they show only about 49% structural homology.[14] Both toxins potently activate cell-signaling molecules leading to production and release of proinflammatory cytokines including interleukin-1, TNF- and interleukin-8.15 After internalization into the host cell, toxins mediated glucosylation inactivates cellular rho proteins, which are essential for maintaining the actin cytoskeleton. This results in disorganization of colonocyte structure, disruption of protein synthesis, cell rounding and cell death.[16] Toxin A is an inflammatory enterotoxin that induces fluid secretion, increased mucosal permeability and marked enteritis. Toxin B is a protein cytotoxin and does not have any enterotoxic activity in animal models.[16] Toxin A negative/toxin B positive strains have been recovered from patients with AAD and colitis indicating that toxin B may be pathogenic in humans.[17] Investigators have shown that toxin B is 10 times more potent than toxin A in inducing electrophysiological changes in human colonic strips in vitro.[18] Guinea pig has been used in animal model studies for antibiotic associated colitis, histopathology demonstrated necrosed epithelium and gas filled blebs in the submucosa, with congested blood vessels.[19]
In severe cases, histology shows focal ulceration, eruption of purulent material and necrotic debris. These pseudomembranes appear as yellow plaques that are easily visualized by colonoscopy.
Evidence supports that the ability of the host to mount an antibody response against C. difficile toxins is the key factor in determining whether that individual will continue as asymptomatic carrier, develop mild diarrhoea or go on to suffer severe or recurrent diarrhoea or colitis. Higher levels of serum and intestinal antitoxin antibodies may be associated with mild colitis.[20] Infants, especially newborns, are colonized with C. difficle at a rate of 25-80% but most of them remain asymptomatic despite presence of toxin.[21] This is supposedly due to immaturity of enterocytes with absence of toxin receptors expression.[22]
Clinical presentation may vary from asymptomatic carrier, diarrhoea, and colitis to PMC. C. difficile diarrhoea is associated with passage of frequent loose stools with mucus. Presence of visible blood is rare. Leucocytosis may be evident in stool. For diagnosis, detection of toxin from stool samples is the main stay [Table - 1].
A negative cytotoxicity test, however, does not completely rule out C. difficile as the cause of diarrhoea as 30% of patients may be missed23 if toxin detection alone is employed. Tests should be performed on fresh sample, as storage at ambient temperatures may lead to possible denaturation of toxin.[24] The gold standard diagnostic test for C. difficile toxin in stool is the tissue culture cytotoxicity assay. It is 67 to 100% sensitive and 85-100% specific if performed correctly.[25] It can detect as little as 10 pg of toxin B.21 A number of cell lines have been used by various workers, which include Vero, CHO, HEp2, MRC 526 etc. The main disadvantages are that it requires cell culture facility and requires incubation for 24-48 hrs. Counter current immuno electrophoresis has also been used in the past for direct detection of toxin B in stool.[27] Several commercial kits (EIAs) are available for detection of toxin A or both A and B in stool specimens. The advantages being ease of performance, quicker results and high specificity (75-100%). The main disadvantage however is its low sensitivity (63-99%).25 100 - 1000 pg of toxin A or B must be present for the test to be positive.[28] Testing of non-diarrhoeal stools for C. difficile by culture or toxin assay is not recommended.
Isolation of the organism must be attempted for antibiotic sensitivity pattern and epidemiological typing. Culture however is not specific for toxin producing strains. Culture isolate may be tested for toxin production but whole procedure is time consuming and costly. Selective media used are the cycloserine cefoxitin fructose agar (CCFA) with 5% haemolysed sheep blood agar, with final concentration of 250 g/mL, cycloserine and 8 g/mL cefoxitin or cycloserine cefoxitin egg yolk media (CCEY). Plates are incubated in anaerobic jar with 90% N2 and 10% CO2 at 370 C for 48 hrs.[23] Heat shock or alcohol treatment[29] can be used for spore selection. This includes mixing of stool specimen with equal volume of absolute ethanol and subculture after half an hour on to a non-selective enriched medium like blood or brain heart infusion agar. Sodium taurocholate 0.1% is added to blood agar to enhance germination of spores.[12] Presumptive colonies giving golden yellow fluorescence in long wave UV rays and typical horse manure odour are further identified by Gram stain smear examination and biochemical tests.[30] Second look assay for enterotoxin A and cytotoxin B are performed on cooked meat broth culture supernatant after 2 days incubation at 370C.
A latex agglutination test, which recognises glutamate dehydrogenase, a bacterial protein, is available but is non-specific and is insufficiently sensitive (48-59%).[21] Polymerase chain reaction (PCR) using primers based on genes for toxin A and B have been used to identify toxigenic strains clinical isolates, it is an extremely sensitive technique but is laborious, requires technical expertise and initial cultures of C. difficile.[31] PCR methods have been developed for the direct detection of toxin genes in stool samples.[32]
Radiographic imaging studies can be used to assist in diagnosis, abdominal radiography may reveal dilated colon with thickened mucosa in severe cases. Endoscopy is reserved for special situations when diagnosis is in doubt. Findings may be normal in AAD with out colitis, however finding of colonic pseudomembranes is virtually pathognomonic of C. difficile colitis.
For surveillance of hospital environment, sterile pre-moistened swabs are wiped over selected surfaces including equipment, floor linen etc. and inoculated on to CCFA medium. For personnel taking care of patients with positive cultures hand surface imprints and fingernail impressions on CCFA plate are taken. Rectal swab or faeces obtained are transported in Cary-Blair transport media to laboratory and processed immediately for culture for C. difficile.
Certain markers such as resistance to erythromycin, chloramphenicol or clindamycin, can indicate if more than one strain is present, although molecular techniques for typing are indispensable for establishing outbreaks and identifying the possible source of infection. PCR ribotyping is quicker and simpler than pulsed field gel electrophoresis and is shown to be more discriminatory than arbitrarily primed PCR. One hundred and sixteen different types have been described using ribotyping.[33]

 ~ Clostridium perfringens Top

Type A C. perfringens is known to cause food poisoning and more recently a different genotype has been implicated in causing AAD.[34] In one study, workers found C. perfringens enterotoxin in 11 patients with AAD, all cases were sporadic and most serotypes were different from those associated with food poisoning, none had PMC and all cases were self limiting.[35] However, nosocomial C. perfringens diarrhoea has been reported in patients without any antibiotic treatment.

 ~ Staphylococcus aureus Top

Once thought to be the chief cause of AAD, S. aureus may have represented misdiagnosed cases of C. difficile infection.[4] Although a few reports still suggest S. aureus can cause AAD, more recently there are reports on role of methicillin resistant S. aureus (MRSA) in AAD.[37]

 ~ Klebsiella oxytoca Top

Recent studies suggest its involvement in acute segmental haemorrhagic penicillin associated colitis. K. oxytoca strains associated with colitis are found to be ampicillin resistant and cytotoxin producing. In the acute phase of disease they were found to be present in high numbers in stool (107cfu/gm).[38],[39] The toxin caused fluid accumulation in rabbit ileal loop model.[38]

 Salmonella More Details species"> ~  Salmonella More Details species Top

In one report, multi-drug resistant S. newport (resistance to ampicillin, carbenicillin and tetracycline) has been linked with AAD.[40] These patients probably harboured multi resistant S. newport before they took antibiotics and that antibiotic selected the pathogenic drug resistant  Salmonella More Details.[40] Fluroquinolone resistance enteric disease caused by  Salmonella More Details has also been reported; most of the patients had taken fluroquinolone previously.[41]  Salmonella More Details may also cause pseudomembranous colitis.[42]

 ~ Candida species Top

Overgrowth of Candida species (105 cfu/mL) has been associated with AAD in patients who are negative for C. difficile. Most of these patients respond to oral nystatin.[43] Exact mechanism by which Candida causes diarrhoea is not fully understood. Candida can depress lactase activity in rabbit's intestine, which can lead to lactose intolerance, and an endotoxin like substance is shown to stimulate net secretion of water, sodium and potassium in ileum of rats.[44] Though association is still controversial, in selective clinical settings Candida can cause AAD.

 ~ Treatment Top

Discontinuation of antibiotic therapy withdraws the offending agent but is often not appropriate if the indication for such therapy was correct. An alternative is to change the antibiotics to a low risk group for the induction of AAD (parenteral aminoglycosides, trimethoprim, rifampicin or a quinolone).[45]
Patients with mild diarrhoea not caused by C. difficile may not need any specific treatment except substitution of lost fluid and electrolytes. Specific therapy for C. difficile eradication is recommended in patients whose symptoms persist despite discontinuation of antibiotic therapy and these include oral/intravenous metronidazole and oral vancomycin. Metronidazole is suggested as first line drug treatment of C. difficile infection. Other therapies that have been tried are bacitracin, teicoplanin, fusidic acid, colstipol.[46],[1],[2] For severe pseudomembranous colitis intravenous therapy with passive immunoglobulin may be effective. Probiotics eg. S. boulardii, Lactobacillus etc. have been found useful in management of recurrent C. difficile diarrhoea.[47] 

 ~ References Top

1.Barlett JG. Management of Clostridium difficile infection and other antibiotic associated diarrhoea. Eur J Gastroenterol Hepatol 1996;8:1054-1061.  Back to cited text no. 1    
2.Katz DA, Lynch ME, Littenberg B. Clinical prediction rules to optimize cytotoxin testing for Clostridium difficile in hospitalized patients with diarrhoea. Am J Med 1996;100:487-495.  Back to cited text no. 2    
3.Fekety R. Guidelines for the diagnosis and management of Clostridium difficile - associated diarrhoea and colitis. Am J Gastroenterol 1997; 92:739-750.  Back to cited text no. 3    
4.Barlett JG. Antibiotic-associated diarrhoea. N Engl J Med 2002;346:334-339.  Back to cited text no. 4    
5.Hogenauer C, hammer HF. Krejs GJ, Reisinger EC. Mechanism and management of antibiotic-associated diarrhoea. Clin Infect Dis 1998;27:702-710.  Back to cited text no. 5    
6.Barlett JG. Antibiotic associated diarrhoea. Clin Infect Dis 1992;15:573-581.  Back to cited text no. 6    
7.Larson HE, Price AB, Honour P, Borriello SP. Clostridium difficile and the etiology of pseudomembranous colitis. Lancet 1978;1:1063-1066.  Back to cited text no. 7    
8.Bignardi GE, Risk factors for clostridial infection. J Hosp Infect 1998;40:1-15.  Back to cited text no. 8    
9.Hecht JR, Olinger EJ. Clostridium difficile colitis secondary to intravenous vancomycin. Dig Dis Sci 1989;34:148-149.  Back to cited text no. 9    
10.Anand A, Glatt AE. Clostridium difficile infection associated with antineoplastic chemotherapy: A review. Clin Infect Dis 1993;17:109-113.  Back to cited text no. 10    
11.Wilcox MH, Smyth ETM. Incidence and impact of Clostridium difficile infection in the UK, 1993-1996. J Hosp Infect 1998;39:181-187.  Back to cited text no. 11    
12.McFarland LV, Mulligan ME, Kwok RYY, Stamm WE. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med 1989;320:204-210.  Back to cited text no. 12    
13.Fekety R, Kim KH, Brown D, Batts DH, Cudmore M, Silva J Jr. Epidemiology of antibiotic associated colitis: Isolation of Clostridium difficile from the hospital environment. Am J Med 1981;70:906-908.  Back to cited text no. 13    
14.von Eichel-Streiber C, Laufenberg-Feldmann R, Sartingen S, Schulze J, Sauerborn M. Cloning of Clostridium difficile toxin B gene and demonstration of N-terminal homology between toxin A and B. Med Microbiol Immunol 1990;179:271-279.  Back to cited text no. 14    
15.Pathoulakis C. Pathogenesis of Clostridium difficile-associated diarrhoea. Eur J Gastroenterol Hepatol 1996;8:1041-1047.  Back to cited text no. 15    
16.Pathoulakis C, Barone LM, Ely R, Faris B, Clark ME, Franzblau C, KaMont JT. Purification and properties of Clostridium difficile cytotoxin B. J Biol Chem 1986;26:1316-1321.  Back to cited text no. 16    
17.Kato H, Kato N, Watanable K, Iwai N, Nakamura H, Yamamoto T, Suzuki K, Kim SM, Chong Y, Wasito EB. Identification of Toxin A-negative, toxin B-positive Clostridium difficile by PCR. J Clin Microbiol 1998;36:2178-2182.  Back to cited text no. 17    
18.Riegler M, Sedivy R, Pathoulakis C, Hamilton G, Zacherl J, Bischof G, Cosentini E, Feil W, Schiessel R, La Mount JT. Clostridium difficile toxin B is more potent than toxin A in damaging human colonic epithelium in vitro. J Clin Invest 1995;95:2004-2011.  Back to cited text no. 18    
19.Chakrabarti A, Ayyagari A, Chakrabarti RN. Animal Models of Antibiotic Associated Colitis. In: Proceedings of the First Asian Congress on Anaerobic Bacteria in Health and Disease. Eds Mehta A, Kochar N (Seth GS Medical College & K.E.M. Hospital, Bombay, India) 1987:260-266.  Back to cited text no. 19    
20.Kelly CP. Immune response to Clostridium difficile infection. Euro J Gastroenterol Hepatol 1996;8:1048-1053.  Back to cited text no. 20    
21.Kelly CP, Pothoulakis, C, LaMont JT. Clostridium difficile colitis. N Engl J Med 1994;330:257-262.  Back to cited text no. 21    
22.Eglow R, Pothoulakis C, Itzkowitz S, Israel EJ, O'Keane CJ, Gong D, Gao N, XuYL, Walker WA, La Mount JT. Diminished Clostridium difficile toxin A sensitivity in newborn rabbit ileum is associated with decreased toxin A receptor. J Clin Invest 1992;90:822-829.  Back to cited text no. 22    
23.Peterson LR, Kelly PJ, Nordbrock HA. Role of culture and toxin detection in laboratory testing for diagnosis of Clostridium difficile-associated diarrhoea. Eur J Clin Microbiol Infect Dis 1996;15:330-336.  Back to cited text no. 23    
24.Brazier JS. The diagnosis of Clostridium difficile-associated disease. J Antimicrob Chemother 1998;41:29-40.   Back to cited text no. 24  [PUBMED]  [FULLTEXT]
25.Gerding DN, Johnson S, Peterson LR, Mulligan ME, Silva J Jr. Clostridium difficile-associated diarrhoea and colitis. Infect Control Hosp Epidemiol 1995;16:459-477.  Back to cited text no. 25    
26.Murray PR, Webber CJ. Detection of Clostridium difficile cytotoxin in HEp2 and CHO cell lines. Diagn Mirobiol Infect Dis 1983;1:331-333.  Back to cited text no. 26    
27.Ayyagari A, Sharma P, Mehta VS, Agarwal KC. Prevalence of Clostridium difficile in pseudomembranous colitis and antibiotic-associated colitis in North India. J Diarrhoel Dis Res 1986;4:157-160.  Back to cited text no. 27    
28.Pothoulakis C, LaMont JT. Clostridium difficile colitis and diarrhoea. Gastroenterol Clin North Am 1993;22:623-637.  Back to cited text no. 28    
29.Boriello SP, Honour P. Simplified procedure for the routine isolation of Clostridium difficile from faeces. J Clin Pathol 1981;34:642-644.  Back to cited text no. 29    
30.Willis AT. Anaerobic bacteriology: clinical and laboratory practice. 3rd ed. (Butterworths, London) 1977:111-166.  Back to cited text no. 30    
31.Wren B, Clayton C, Tabaqchali S. Rapid identification of toxigenic Clostridium difficile by polymerase chain reaction. Lancet 1990;335:423.  Back to cited text no. 31  [PUBMED]  
32.Boondeekhun HS, Gurtler V, Odd ML, Wilson VA, Mayall BC. Detection of Clostridium difficile enterotoxin gene in clinical specimens by the polymerase chain reaction. J Med Microbiol 1993;38:384-387.  Back to cited text no. 32    
33.Stubbs SLJ, Brazier JS, O' Neill GL, Duerden BI. PCR targeted to the 16S-23S rRNA gene intergenic spacer region of Clostridium difficile and construction of a library consisting of 116 different PCR ribotypes. J Clin Microbiol 1999;37:461-463.  Back to cited text no. 33    
34.Sparks SG, Carman RJ, Sarker MR, McClane BA. Genotyping of enterotoxigenic Clostridium perfringens fecal isolates associated with antibiotic associated diarrhoea and food poisoning in north America. J Clin Microbiol 2001;39:883-888.  Back to cited text no. 34    
35.Borriello SP, Larson HE, Welch AR, Barclay F. Enterotoxigenic Clostridium perfringens: a possible cause of antibiotic associated diarrhoea. Lancet 1984;1:305-307.  Back to cited text no. 35    
36.Larson HE, Borriello SP. Infectious diarrhoea due to Clostridium perfringens. J Infect Dis 1988;157:390-391.  Back to cited text no. 36    
37.McDonaold M, Ward P, Harvey K. Antibiotic associated diarrhoea and methicillin resistant Staphylococcus aureus. Med J Aust 1982;1:462-464.  Back to cited text no. 37    
38.Minami J, Katayama S, Matsushita O, Sakamoto H, Okabe A. Enterotoxic activity of Klebsiella oxytoca cytotoxin in rabbit intestinal loops. Infect Immun 1994;62:172-177.  Back to cited text no. 38    
39.Benoit R, Dorval D, Loulergue J, Bacq Y, Oliver JM, Audurier A, Metman EH. Post antibiotic diarrhoeas: role of Klebsiella oxytoca. Gastroenterol Clin Biol 1992;16:860-864.  Back to cited text no. 39    
40.Holmberg SD, Osterholm MT, Senger KA, Cohen ML. Drug resistant Salmonella from animal fed antimicrobials. N Engl J Med 1984;311:617-622.  Back to cited text no. 40    
41.Olsen SJ, DeBess EE, McGivern TE, Marano N, Eby T, Mauvais S, Balan VK, Zirnsterin G, Cieslak PR, Angulo FJ. A nosocomial outbreak of fluoroquinolone- resistant Salmonella infection. N Engl J Med 2001;344:1572-1579.  Back to cited text no. 41    
42.Hovius SE, Rietra PJ. Salmonella colitis clincially presenting as a pseudomembranous colitis. Neth J Surg 1982;34:81-82.  Back to cited text no. 42    
43.Danna PL, Urban C, Belin E, Rahal JJ. Role of Candida in pathogenesis of antibiotic associated diarrhoea in elderly inpatients. Lancet 1991;337:511-514.  Back to cited text no. 43    
44.Gupta TP, Ehrinpreis MN. Candida-associated diarrhoea in hospitalised patients. Gastroenterology 1990;98:780-785.  Back to cited text no. 44    
45.Spencer RC. The role of antimicrobial agents in the aetiology of Clostridium difficile associated disease. J Antimicrob Chemother 1998;41:21-27.  Back to cited text no. 45    
46.Wenisch C, Parschalk B, Hasenhundl M, Hirschl AM, Graninger W. Comparison of vancomycin, teicoplanin, metronidozole and fusidic acid for the treatment of Clostridium difficile - associated diarrhoea. Clin Infect Dis 1996;22:813-818.  Back to cited text no. 46    
47.Surawicz CM, Mc Farland LV, Elmer G, Chinn J. Treatment of recurrent Clostridium difficile colitis with vancomycin and Saccharomyces boulardii. Am J Gastroenterol 1989;96:981-988.  Back to cited text no. 47    
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