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RESEARCH: Mary Hickson, Aloysius L D'Souza, Nirmala Muthu, Thomas R Rogers, Susan Want, Chakravarthi Rajkumar, and Christopher J Bulpitt Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial BMJ 2007; 335: 80 [Abstract] [Full text]

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A prectical approach to prevent diarrhoea associated with antiobiotics and Clostridium difficile

Maria Louise O. Demesa   (3 July 2007)

milk as a placebo?

vijayashankara nanjegowda   (13 July 2007)

Results of study of probiotic yoghurt drink to prevent antibiotic-associated diarrhoea are not widely applicable

Mark H Wilcox, Jonathan A. Sandoe   (13 July 2007)

Probiotics are they the answer for Clostridium difficile associated diarrhoea?

Kordo B A Saeed, Nicholas Cortes, TatShing Yam   (13 July 2007)

Curd as prevention and treatment of Diarrhoeas: Probiotic, nourishment, electrolytes, Lactose free, taste??!!

Neeru Gupta, Kishan Kumar Jani   (14 July 2007)

Effect of PPI?

Mario B Konfortov   (16 July 2007)

Helicobacter pylori treatment, improved by probiotics.

Enrique J. Sánchez-Delgado, MD, Professor   (16 July 2007)

Why exclude high risk antibiotics?

Tom Billyard   (16 July 2007)

yakult or yazoo - What say you, seniore?

sunku h guptha   (17 July 2007)

Restricting the use of Antibiotics: A cost effective way to prevent antibiotic associated diarrhea

S Kapoor   (17 July 2007)

Probiotics and the enteric ecosystem !

MOHAMED S. NOSHI,MD,FACP   (17 July 2007)

Used of probiotic study: lack of appropriate control group

Jeorge M. Orendi   (18 July 2007)

Antibiotic associated diarrhoea and primary care

Shaun Conway   (20 July 2007)

Prescribe probiotics?

Sreekanth J Pillai   (20 July 2007)

Tobacco: potential confounder

Michael K Park   (26 July 2007)

Critical appraisal

ABRAHAM P. GEORGE, Rosemary Mccan, Peter Morgan, Ruth Philp, Sue Hunt   (27 July 2007)

A win-win intervention

Dr Beena R. Nayak, -   (27 July 2007)

Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics

NAZAR R DESSOUKI   (28 July 2007)

Author's Reply

Mary Hickson, Aloysius L D’Souza, Nirmala Muthu, Thomas R Rogers, Susan Want, Chakravarthi Rajkumar, Christopher J Bulpitt   (3 August 2007)

Local incidence of Clostridium difficile associated diarrhoea to be considered.

Jesús Rodríguez-Baño, Lorena López-Cerero, and María M. Portillo   (8 August 2007)

A prectical approach to prevent diarrhoea associated with antiobiotics and Clostridium difficile 3 July 2007
Maria Louise O. Demesa, Resident Medical Physician Paranaque City , Philippines 1700 Send response to journal: Re: A prectical approach to prevent diarrhoea associated with antiobiotics and Clostridium difficile	The article is well appreciated and the authors are commendable.It tackles an easy and practical way of the prevention of diarrhoea caused by antibiotic and Clostridium Difficile.It is also timely because of increasing statistics of patients with C. diff. Recent data published by the Health Protection Agency (HPA), 2007) showed that each year in England more than 50,000 inpatients aged 65 years and over had C. diff infections. C. diff cases rose by 5.5% in 2006 compared with 2005.However,a study stated that use of proton pump inhibitors (PPI) and other drugs that suppress gastric acid production may be driving the incidence C. diff infection (Dial et al, 2005)thus exclusion of patients with peptic ulcer disease or on gastric supressing drugs may be included in the exclusion. The study in conclusion, is very beneficial and informative. Competing interests: None declared
milk as a placebo? 13 July 2007
vijayashankara nanjegowda, senior specialist, paediatrics sohar,sultanate of oman, 311 Send response to journal: Re: milk as a placebo?	Dear Sir, The study on probiotics in the prevention of antibiotic induced diarrohea has used milk drink as a placebo to compare the outcome results.The milk in any form can itself cause diarrhoea partcularly in elderly individuals who would be having varying degrees of lactase deficiency. This could have influenced the results of this study. Competing interests: None declared
Results of study of probiotic yoghurt drink to prevent antibiotic-associated diarrhoea are not widely applicable 13 July 2007
Mark H Wilcox, Clinical Director of Pathology, Director of Infection Control Microbiology & Infection Control, Leeds Teaching Hospitals & University of Leeds, LS1 3EX, Jonathan A. Sandoe Send response to journal: Re: Results of study of probiotic yoghurt drink to prevent antibiotic-associated diarrhoea are not widely applicable	Probiotic use is a highly controversial issue, not least because of the intense public and media interest in the health claims associated with a diverse set of products. Hickson et al.1 use three references to support the benefit of probiotics in antibiotic-associated diarrhoea (AAD), including a meta-analysis in 2002 by some of the authors.2 This was subsequently challenged, specifically because a meta-analysis of probiotic studies in general is an inappropriate tool to answer the question of whether they can usefully prevent AAD.3 Studies of probiotics clearly need to be assessed for specific micro-organisms given to well defined populations. Interestingly, a meta-analysis published in 2005 concluded that studies conducted to date provide insufficient evidence for the routine clinical use of probiotics to prevent or treat C. difficile- associated diarrhoea.4 We agree that better designed and larger studies are needed to address this issue. To this end, Hickson and colleagues’ study is potentially an important contribution to the debate about probiotic use to prevent AAD.1 We caution about the extrapolation of Hickson and colleagues’ results. We are particularly concerned with their conclusion that a probiotic yoghurt drink, given during and after antibiotic treatment, ‘has the potential to decrease morbidity, healthcare costs, and mortality if used routinely in patients aged over 50’.1 The magnitude of protective effects by the probiotic yoghurt against AAD and C. difficile infection (CDI) reported by Hickson and colleagues were stark. However, important issues about the study design and conclusions were not considered or given sufficient weighting in the discussion. In particular, the highly selective inclusion and exclusion criteria are crucial in result interpretation. It took over two years to recruit 135 patients out of 1760 screened individuals, and only 113 of these were followed for evidence of diarrhoea. Put simply, how can data pertaining to less than 7% of a potential target population be extrapolated to routine use? Length of hospital stay is a risk factor for infective AAD.5 Crucially, Hickson and colleagues examined patients with median lengths of hospital stay before and after randomisation of 1 day and 8-9 days, respectively. Thus, the study patients had a relatively short duration of hospital stay (just over one week). A recent large study in Leeds found that the mean length of hospital stay prior to the onset of diarrhoeal symptoms due to infective AAD was 29.2 + 4.1 days.5 Thus, Hickson and colleagues may have examined atypical elderly in-patients, with respect to risk of CDI, because of their relatively short duration of hospital stay. Furthermore, relatively short stay patients are likely to have fewer co- morbidities and be less frail than typical CDI cases.6 Excluding recipients on the basis of antibiotic use/history as defined in this study means that the most vulnerable patients, with the most to gain from an effective prophylaxis regimen, were not examined. Antibiotic polypharamcy is a risk factor for CDI.7 However, the majority of study subjects received only one antibiotic, which in our experience is unusual in elderly in-patients. Why was an age threshold of 50 years used? Was protection against AAD seen in probiotic recipients in distinct age groups, especially in those (>75 years) at greatest risk of CDI? A quarter of the study subjects received prophylactic antibiotics peri- operatively; these should not have been included with patients being treated for infection, or at least should have been analysed separated. Most surgical antibiotic prophylaxis is short duration (up to 24 hours). Despite the fact that antibiotic duration is also a risk factor for CDI, no such data are provided in study subjects.8 Patients receiving ‘high risk antibiotics (clindamycin, cephalosporins, aminopenicillins) or more than two courses of other antibiotics in the past four weeks’ were excluded from the study. Aminopenicillins are defined (incorrectly) in the footnote of Table 1 as ‘amoxicillin, benzylpenicillin, co-amoxiclav, flucloxacillin’, and are claimed to be high risk antibiotics for CDI. In fact, penicillin and flucloxacillin are not aminopenicillins and are generally considered as low or moderate risk agents for the development of CDI, consistent with their narrow spectra of activity. Exclusion of patients from the study who had received recent penicillin or flucloxacillin part-explains the extremely high rate of failure to recruit (92% of screened patients). Furthermore, a result of the confusion surrounding the definition of high risk antibiotics is that it is unclear how many study patients genuinely received ‘high risk’ antibiotics. The only groups about which there is a current consensus of high CDI risk are second/third generation cephalosprins and clindamycin.8,9 The data concerning diarrhoea development should be presented according to receipt of high risk antibiotics. Also, the logistic regression analysis should have included the (correctly defined) level of antibiotic risk for antibiotic associated diarrhoea as a covariate. This would help clarify whether probiotics could protect against AAD associated with high and low risk agents. Subject randomisation to probiotic or placebo was stratified for each of the three study hospitals, but not within each hospital. CDI risk varies markedly within a hospital,10 as does exposure to C. difficile. In turn, environmental burden of C. difficile may correlate with CDI incidence.11 Thus, controlling for exposure to C. difficile is important to ensure that the true risk of developing CDI is equivalent for treatment groups. This may occur with a randomised study design, but is not certain, especially for the relatively small number of subjects recruited per hospital in this case. Were the CDI rates in those wards where probiotic versus control recipients were managed similar? It is stated in the Methods that ‘a baseline stool sample was collected to screen for asymptomatic C. difficile carriage’. The Results only refer to ‘one patient in each group was positive for C. difficile toxin at baseline’. Was culture for C. difficile actually performed? This would have provided information on prevalent C. difficile ribotypes, the true baseline carriage rate (toxin status is not equivalent to asymptomatic C. difficile carriage) and any relationship between carriage and risk of AAD or CDI. Furthermore, C. difficile culture of symptomatic subjects would have been valuable to confirm the results of toxin testing. This is particularly important here as the commercial kit assay for C. difficile toxin used in this study (Meridian) has been associated with a high false positive rate. Indeed, the positive predictive value of the kit toxin result was only 51% in a recent comparative study of detection methods for C. difficile toxin.12 In summary, the findings by Hickson and colleagues of apparent protection by a probiotic yoghurt drink against ADD and CDI cannot reasonably be extrapolated to typical elderly in-patients treated with antibiotics in the hospital setting and at high risk of these complications. The relevance of the data to units with endemic C. difficile infection, particularly caused by virulent strains such as C. difficile ribotype 027 is unknown. We have already received enquires based on this study about the potential prophylactic use of probiotic yoghurt drink. We welcome the attempt to answer questions about the effectiveness of probiotics to prevent AAD, but we believe that the conclusions as presented are prone to misinterpretation. Inappropriate antimicrobial prescribing remains a problem in hospitalised patients. Ensuring appropriate antibiotic usage should be the emphasis rather than blanket prophylactic measures, which perversely may encourage poor prescribing. References 1. Hickson M, D'Souza AL, Muthu N, Rogers TR, Want S, Rajkumar C, Bulpitt CJ. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ 2007; 0(2007):bmj.39231.599815.55v1, 29 Jun 2007. 2. D'Souza AL, Rajkumar C, Cooke J, Bulpitt CJ. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis. BMJ 2002;324:1361. 3. Wilcox MH. No probiotics can be recommended for the prevention of antibiotic associated diarrhoea. eBMJ 11 June 2002. http://bmj.com/cgi/eletters/324/7350/1345#22931. 4. Dendukuri N, Costa V, McGregor M, Brophy JM. Probiotic therapy for the prevention and treatment of Clostridium difficile-associated diarrhea: a systematic review. CMAJ 2005;173:167-70. 5. Asha N, Tomkins D, Wilcox MH. Comparative Analysis of Prevalence, Risk Factors, and Molecular Epidemiology of Antibiotic-Associated Diarrhea Due to Clostridium difficile, Clostridium perfringens, and Staphylococcus aureus. J Clin Microbiol 2006;44:2785-91. 6. Kyne L, Merry C, O'Connell B, Kelly A, Keane C, O'Neill D. Factors associated with prolonged symptoms and severe disease due to Clostridium difficile. Age Ageing 1999;28:107-13. 7. Bignardi GE. Risk factors for Clostridium difficile infection. J Hosp Infect 1998;40:1-15. 8. Wistrom J, Norrby SR, Myhre EB, Eriksson S, Granström G, Lagergren L, Englund G, Nord CE, Svenungsson B. Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study. J Antimicrob Chemother 2001;47:43-50. 9. Davey P, Brown E, Fenelon L, Finch R, Gould I, Hartman G, Holmes A, Ramsay C, Taylor E, Wilcox M, Wiffen P. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.:CD003543. DOI: 10.1002/14651858.CD003543.pub2. 10. Karlstrom O, Fryklund B, Tullus K, Burman LG. A prospective nationwide study of Clostridium difficile-associated diarrhea in Sweden. The Swedish C. difficile Study Group. Clin Infect Dis 1998;26:141-5. 11. Fawley WN, Wilcox MH. Molecular typing of endemic Clostridium difficile infection. Epidemiol Infect 2001;126:343-50. 12. van den Berg RJ, Vaessen N, Endtz HP, Schulin T, van der Vorm ER, Kuijper EJ. Evaluation of real-time PCR and conventional diagnostic methods for the detection of Clostridium difficile-associated diarrhoea in a prospective multicentre study. J Med Microbiol 2007;56:36-42. Competing interests: MHW has received honoraria for consultancy work, financial support to attend meetings and research funding from Astra-Zeneca, Bayer, Genzyme, Pfizer, Vicuron and Wyeth. JAS has received honoraria for consultancy work and financial support to attend meetings from Novartis and Wyeth.
Probiotics are they the answer for Clostridium difficile associated diarrhoea? 13 July 2007
Kordo B A Saeed, Specialist Registrar in Microbiology Southampton General Hospital, Microbiology Dept, Tremona Road, SO16 6YD, Nicholas Cortes, TatShing Yam Send response to journal: Re: Probiotics are they the answer for Clostridium difficile associated diarrhoea?	Article appraised Mary Hickson, Aloysius L D'Souza, Nirmala Muthu, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ published online 29 June 2007; doi:10.1136/bmj.39231.599815.55 The authors conclusions were: Consumption of a probiotic drink containing Lactobacillus casei, L bulgaricus and Streptococcus thermophillus can reduce the incidence of antibiotic associated diarrhoea and Clostridium difficile associated diarrhoea (CDAD). This will reduce morbidity, mortality and healthcare costs if used routinely in patients aged over 50. Commentary On the face of it, the results from Hickson et al. would seem to provide persuasive evidence that consumption of these probiotic drinks will reduce the incidence of antibiotic associated diarrhoea and CDAD. The trial has used clear definition of diarrhoea, a randomised double blind design and data analysis showing numbers needed to treat and cost benefit. However, before implementing a change in clinical practice a number of issues warrant further consideration. In addition to the study weaknesses outlined by the authors themselves in their conclusion, in our opinion a number of other issues limit the generalisablity of this data to many hospital in-patients. Firstly, the study criteria resulted in a large number of patients being excluded from the analysis. For example, excluded patients included those with “bowel pathology that could result in diarrhoea”, those receiving “more than two courses of other antibiotics in the past four weeks “and also those receiving “high risk antibiotics” (defined as clindamycin, cephalosporins and aminopenicillins). As a result of these exclusion criteria we consider the actual study population quite unrepresentative of a typical elderly care medicine in-patient population. In our experience these groups of patients often have multiple co- morbidities and receive multiple courses of antibiotics, including agents considered “high-risk” by Hickson et al. Thus the data produced, including numbers needed to treat and cost to prevent cases of antibiotic associated diarrhoea and CDAD apply only to this specific study population and cannot be generalised to the wider hospital population. We therefore feel the authors cannot justifiably conclude from their data that if probiotics is used “routinely” in over 50s we will see reduced morbidity and mortality due to CDAD. Secondly, the authors classify antibiotics as low, medium or high risk but it is not clear whether this refers to risk for antibiotic associated diarrhoea or CDAD. Flucloxacillin and benzylpenicillin are classified incorrectly as aminopenicillins and regarded as high risk antibiotics, whereas ciprofloxacin is classified as a medium as opposed to a high risk antibiotic. In addition to that, the authors presented discordant data as there is little or in fact no detailed information regarding doses or duration of antibiotics in each study arm, and no information is provided about the distribution of low, medium and high risk antibiotics in each group. Additionally, readers do not know if, due to the staff awareness of the trial, there was any change in infection control practices. However one could argue this may affect both arms equally assuming the distribution of patients in the treatment vs placebo arm was the same at all three study centres. The effects of differing CDAD rates at the three study centres may also have influenced rates of CDAD found in the study and control group. A major disadvantage the placebo group suffers is the lactose contained in the milkshake as this can trigger development of secondary lactose intolerance. On the other hand, the treatment group has an advantage as some Lactobacillus strains, if they survive the gastric acid, appear to induce expression of micro-opioid and cannabinoid receptors in intestinal epithelial cells and mediate analgesic functions in the gut in a manner similar to the effects of morphine, 1 and therefore in theory they may get slow gastrointestinal motility or perhaps even result in constipations. Reducing CDAD is an important target in the NHS so there will be a lot of interest in implementing these study findings and there may be external pressures on the trusts to target at risk patients. A systematic review that focused on studies in which C. difficile was specifically sought concluded that there was insufficient evidence for routine clinical use of probiotics to prevent or treat CDAD. 2 In our view, the study by Hickson et al shows some promising results but ultimately suffers from various design limitations meaning there is insufficient evidence on the basis of this data to justify implementation of routine use of probiotics for all patients over age of 50 who receive an antibiotic. Large, well- conducted studies are needed before probiotics can be introduced to formularies and investigators involved in trials specifically investigating the relationship between probiotics and CDAD are urged to review critically aspects of their study design to avoid some of the problems outlined in this overview. References: 1. Rousseaux, C, Thuru, X, Gelot, A, et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med 2007; 13:35. 2. Dendukuri, N, Costa, V, McGregor, M, Brophy, JM. Probiotic therapy for the prevention and treatment of Clostridium difficile- associated diarrhea: a systematic review. CMAJ 2005; 173:167. Competing interests: None declared
Curd as prevention and treatment of Diarrhoeas: Probiotic, nourishment, electrolytes, Lactose free, taste??!! 14 July 2007
Neeru Gupta, Assistant Director General Indian Council of Medical Research, Ansari Nagar, Delhi-110029., Kishan Kumar Jani Send response to journal: Re: Curd as prevention and treatment of Diarrhoeas: Probiotic, nourishment, electrolytes, Lactose free, taste??!!	The milk protein, casein, that contains all the essential amino acids required by man's body gets coagulated when curd is added to milk. The lactic acid bacteria present in it cause coagulation of casein and thus convert it into curd. Lactobacilli are probiotic micro-organisms that are part of the oral, intestinal and urogenital commensal flora. The beneficial effect of these bacterial strains, especially the eradication of or protection against pathogenic bacteria and yeasts, was shown by several studies. The preventive and therapeutic effect of lactobacilli applies to diarrhoea and urogenital infections in particular. Lactobacilli also seem to have a protective influence on the development and treatment of atopic disease1. Probiotics have multiple mechanisms of action, including prevention of pathogenic bacterial growth, binding to or penetration of pathogens to mucosal surfaces, stimulation of mucosal barrier function, or altering immunoregulation (decreasing proinflammatory and promoting protective molecules). Although multiple probiotic species block epithelial adhesion and invasion by microbial pathogens in vitro, their proven utility in clinical infections is limited to accelerating recovery from acute infectious diarrhea and preventing antibiotic- associated diarrhea2. There are studies that tested the feasibility of culturing the various lactobacilli (which serve as probiotics) in curd and cheese viz Lactobacillus delbrueckii subsp. lactis UO 004, Lactobacillus fermentum strain ME-3 and Lactococcus lactis bacteria of the strain TV2 (isolated from a self-soured curd) similar to the bacteria of the strain STE05 (Russian National Collection of Industrial Microorganisms)3,4,5. Man has been using curd for a long time. There is some evidence of efficacy in the prevention of community- acquired and nosocomial diarrhea6. More solid evidence of efficacy is found in the treatment of sporadic, infectious diarrhea, where several probiotics, and especially Lactobacillus GG, have been found capable of reducing by approximately 1 day the duration of diarrhea, shorten the initial phase of watery stools, and reducing hospital stay in developed countries. The effect is best documented in viral diarrheas6. However, in a randomized, double-blind, placebo-controlled clinical trial, infants and young children presenting with diarrhea in Bangladesh, fed on Lactobacillus paracasei ST11 showed clinically significant benefit in the management of children with nonrotavirus-induced diarrhea, but ineffectiveness in those with rotavirus diarrhea7. Although there are valid conceptual premises for probiotics to be helpful in inflammatory bowel diseases, only 1 trial has been published in children, showing Lactobacillus GG not to be superior to placebo in maintaining remission of Crohn disease6. As concluded in the study by Mary Hickson et al(8) probiotics may also prevent antibiotic-associated diarrhea (AAD) possibly via restoration of the gut microflora altered by antibiotics. Antibiotics are prescribed frequently in children and AAD is common in this population. Johnston et , in their Cochrane Database systemic review, concluded that probiotics show promise for the prevention of pediatric AAD but it is premature to routinely recommend probiotics for the prevention of pediatric AAD9. Probiotic strains of lactobacilli are increasingly being used in clinical practice because of their many health benefits. Infections associated with probiotic strains of lactobacilli are extremely rare. However, Land et al, described 2 patients who received probiotic lactobacilli and subsequently developed bacteremia and sepsis attributable to Lactobacillus species. Molecular DNA fingerprinting analysis showed that the Lactobacillus strain isolated from blood samples was indistinguishable from the probiotic strain ingested by the patients. This report indicated, for the first time, that invasive disease can be associated with probiotic lactobacilli. They, however, concluded this report should not discourage the appropriate use of Lactobacillus or other probiotic agents but should serve as a reminder that these agents can cause invasive disease in certain populations10. Apart from the use of Lactobacilli as probiotics in various diarrhea, the curd can serve as a diet with protein. And since the lactogen is converted into lactic acid, in the case of lactogen intolerance after gastroenteritis this serves as lactogen free diet. It also contains all the vitamins. Milk (also curd) has minerals too. Potassium is 138 and sodium 58 mg/100ml of milk. The composition of minerals can be altered by dilution of curd (for decreasing potassium) and addition of salt (for increasing sodium). Thus, it can make a wholesome drink with taste too. Though evidence of lactobacilli to serve as probiotic in various diarrheas, including Antibiotic associated diarrhea, is not substantial as yet (but not even ignorable) still large scale studies should be planned, for instance in school-going children, to investigate the preventive as well as therapeutic effect of curd consumption in occurrence of diarrheas. References: 1. Merk K, Borelli C, Schaller M, Korting HC. [Use of Lactobacillus as a probiotic factor to treat urogenital and intestinal infections as well as to prevent and treat allergic diseases] [Article in German] : J Dtsch Dermatol Ges. 2004 ;2(9):752-7. 2. Sartor RB. Probiotic therapy of intestinal inflammation and infections. Curr Opin Gastroenterol. 2005 Jan;21(1):44-50. 3. Fernández MF, Delgado T, Boris S, Rodríguez A, Barbés C. A washed- curd goat's cheese as a vehicle for delivery of a potential probiotic bacterium: Lactobacillus delbrueckii subsp. lactis UO 004. J Food Prot. 2005 ;68(12):2665-71. 4. Songisepp E, Kullisaar T, Hütt P, Elias P, Brilene T, Zilmer M, Mikelsaar A new probiotic cheese with antioxidative and antimicrobial activity. J Dairy Sci. 2004 ;87(7):2017-23. 5. Trenina MA, Lysenko AM, Akhverdian VZ, Mchedlishvili EB [Study of intraspecific variations of the bacterium Lactococcus lactis in adaptation to high acidity of the medium] [Article in Russian] Mikrobiologiia. 2006;75(1):118-26. 6. Guandalini S. Probiotics for children: use in diarrhea. J Clin Gastroenterol. 2006 ;40(3):244-8. 7. Sarker SA, Sultana S, Fuchs GJ, Alam NH, Azim T, Brüssow H, Hammarström L. Lactobacillus paracasei strain ST11 has no effect on rotavirus but ameliorates the outcome of nonrotavirus diarrhea in children from Bangladesh. : Pediatrics. 2005;116(2):221-8. 8. Mary Hickson, Aloysius L D'Souza, Nirmala Muthu, Thomas R Rogers, Susan Want, Chakravarthi Rajkumar, and Christopher J Bulpitt .Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ 2007; 335: 80 9. Johnston BC, Supina AL, Ospina M, Vohra S.Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev. 2007;(2):CD004827. 10. Land MH, Rouster-Stevens K, Woods CR, Cannon ML, Cnota J, Shetty AK. Lactobacillus sepsis associated with probiotic therapy. Pediatrics. 2005;115(1):178-81. Competing interests: None declared
Effect of PPI? 16 July 2007
Mario B Konfortov, GP Registrar Burn Brae Medical Group NE46 2ED Send response to journal: Re: Effect of PPI?	Dear Sirs, The article by Hickson et al certainly comes at a time when consumer interest in health foods and more specifically, probiotics is at an all time high (£4.5m spent nationally per week in 2006 1.) coupled with an abundance of related research articles (a search of PubMed on 15 Jul 07 yielding 3790 others). While the authors have certainly tried to introduce true scietific method in an area chiefly governed by sales tactics and mass advertising, it is good to see their admission regarding problems with correct randomisation. Perhaps the solution to the dilemma with the differing bottle sizes and shapes could have been solved by the manufacturer providing appropriately labelled acive culture and sterilised samples. Perhaps a more important omission in this writers opinion however, is the seeming lack of any data regarding proton pump inhibitor (PPI) treatment. Since the target population had a mean age of 74, one could safely assume a very significant proportion of those would infact be on antisecretory treatment. Given the physiological gastic pH, and its likely bactericidal effect on the cultures tested, it would have been more than useful to include outcome data for the patients on concurrent PPI treatment. 1. Collins C. http://www.yakult.co.uk/UserFiles/File/Abstract%20booklet%20final.pdf Competing interests: Like the taste of the drink being studied
Helicobacter pylori treatment, improved by probiotics. 16 July 2007
Enrique J. Sánchez-Delgado, MD, Professor, Director of Medical Education. Internist and Clinical Pharmacologist Hospital Metropolitano Vivian Pellas, Managua, Nicaragua Send response to journal: Re: Helicobacter pylori treatment, improved by probiotics.	Helicobacter pylori treatment, improved by probiotics. Mary Hickson et al, in this issue of BMJ, demonstrate the effective use of probiotics to prevent diarrhoea associated with antibiotics, with a NNT of 5 (1). We have used that action of probiotics to improve the tolerance of the treatment of gastritis and ulcers associated to Helicobacter pylori. Since 2003 we started to add the probiotics Saccharomyces boulardii (200 mg bid) to the standard triple therapies consisting of a proton pump inhibitor (PPI), clarithromycin and amoxicillin (2). Sixty four adults have been treated with this modified regime. All but one reported good or excellent tolerance to the antibiotic combination. One reported moderately disturbing diarrhoea but completed the treatment without problems. A few reported diarrhoea or abdominal discomfort, tolerable enough to complete the treatment. No one discontinued. In the meantime there are reports of the effectiveness of this approach in patients with Helicobacter pylori infection, which not only reduces side effects of anti-H pylori treatment (NNT 6), but probiotics supplementation also improves the eradication rates, with a NNT of 11. (3). After two decades of the Nobel Prize 2005 winner discovery of Marshall and Warren (4), the treatment of Helicobacter pylori can still improve with the use of probiotics. Enrique Sánchez-Delgado, MD Director of Medical Education Hospital Metropolitano Vivian Pellas, Managua, Nicaragua. 1. Hickson M, D'Souza AL, Muthu N, Rogers TR, Want S, Rajkumar C, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ 2007 335: 80 2. Rodgers C, van Zanten SV. A meta-analysis of the success rate of Helicobacter pylori therapy in Canada. Can J Gastroenterol. 2007 May;21(5):295-300. 3. Tong JL, Ran ZH, Shen J, et al. Meta-analysis: the effect of supplementation with probiotics on eradication rates and adverse events during Helicobacter pylori eradication therapy. Aliment Pharmacol Ther 2007;25:155–68. 4. Marshall BJ, Warren JR. Unidentified curved bacillus on gastric epithelium in active chronic gastritis. Lancet 1983;1:1273-5. Competing interests: None declared
Why exclude high risk antibiotics? 16 July 2007
Tom Billyard, Foundation Year 2 doctor University Hospitals Coventry and Warwickshire, Coventry, CV2 2DX Send response to journal: Re: Why exclude high risk antibiotics?	I was astounded to read in the study method that the authors had excluded 'high-risk' antibiotics (as well as some misclassified low-risk antibiotics). To do so is akin to performing a trial of an agent that claims to prevent type 2 diabetes, but excluding obese patients. Cephalosporins in particular are rapidly losing their usefulness as frontline antimicrobial agents because of their potential to cause Clostridium difficile associated diarrhoea (CDAD). The loss of these highly effective agents cannot be a good thing. Any therapy that has the potential to reduce the incidence of CDAD should be investigated with enthusiasm, but it should be done in a meaningful way. To exclude the very people in whom it is particularly important to prevent CDAD, ie those on high risk antibiotics, makes this trial of academic value only. Competing interests: None declared
yakult or yazoo - What say you, seniore? 17 July 2007
sunku h guptha, cosultant physician edith cavell hospital, peterborough PE3 9GZ Send response to journal: Re: yakult or yazoo - What say you, seniore?	Dear Editor Before we start serving yakult as a matter of routine to any older adult within sniffing distance of an antibitoic, we should ask ourselves - are we sure this older adult requires an antibiotic?. The study by Hickson and colleagues unfortunately diverts the issues of irrational prescribing of antibiotics and poor hygeine standards which are much more relevant to incidence of C.Difficile diarrhoea and instead tries to offer a panacea for all iatrogenic ills. I am not sure from reading the paper whether these standards were measured. It is a multicentre study and I would imagine a wide variation between hospitals involved in terms of infection control measures. We need to know if any of the C.Diff patients were a part of cluster and we certainly should be told what antibiotics were prescribed in those patients who were excluded from analysis. Nevertheless Hickson and colleagues should be congratulated for conducting a randomised controlled trial in a difficult area. Competing interests: None declared
Restricting the use of Antibiotics: A cost effective way to prevent antibiotic associated diarrhea 17 July 2007
S Kapoor, Res. Physician University of Illinois at Chicago, Chicago, IL Send response to journal: Re: Restricting the use of Antibiotics: A cost effective way to prevent antibiotic associated diarrhea	The article by Hickson is highly interesting and provides definitive evidence that regular use of probiotic drinks can decrease the rate of antibiotic associated diarrhea (1). Another approach that requires mention in this age of rampant and unjustified antimicrobial use is a more judicious use of antibiotics. The past few decades have seen a rapid increase in the use of antibiotics even for conditions where they are not warranted. In fact studies show that antibiotics are not clinically indicated in more than half the cases they are prescribed (2). Not surprisingly this massive misuse has resulted in an increased incidence of antibiotic associated diarrhea over the past few years, especially secondary to Clostridium difficile. One approach to thwart this misuse is formulary restriction of antibiotics. For instance, in a recent study the formulary restriction of clindamycin alone resulted in a decrease in C difficile infections by 75 % (3). Another strategy that has been shown to be highly effective is mandatory prior approval of antibiotics by infectious disease specialists. This approach has been shown to reduce the incidence of C difficile diarrhea by as much as 71% (4). Last but not the least education of physicians and other prescribing providers to restrict the use of antibiotics is of utmost importance (5). Clearly a multidisciplinary antibiotic management program encompassing all these features is highly cost effective as it decreases the use of antibiotics as well as decreases the necessity to treat diarrhea and thus can go a long way in decreasing the incidence of antibiotic associated diarrhea. 1. Hickson M, D'Souza AL, Muthu N, Rogers TR, Want S, Rajkumar C, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ 2007; Jun 29; 2007;335:80 2. Gonzales R, Malone DC, Maselli JH, Sande MA. Excessive antibiotic use for acute respiratory infections in the United States. Clin Infect Dis 2001; Sep 15;33(6):757-62. 3. Pear SM, Williamson TH, Bettin KM, Gerding DN, Galgiani JN. Decrease in nosocomial Clostridium difficile-associated diarrhea by restricting clindamycin use. Ann Intern Med 1994; Feb 15;120(4):272-7. 4. Climo MW, Israel DS, Wong ES, Williams D, Coudron P, Markowitz SM. Hospital-wide restriction of clindamycin: effect on the incidence of Clostridium difficile-associated diarrhea and cost. Ann Intern Med 1998; Jun 15;128(12 Pt 1):989-95. 5. John JF,Jr, Fishman NO. Programmatic role of the infectious diseases physician in controlling antimicrobial costs in the hospital. Clin Infect Dis 1997; Mar;24(3):471-85. Competing interests: None declared
Probiotics and the enteric ecosystem ! 17 July 2007
MOHAMED S. NOSHI,MD,FACP, Senior consultant internal medicine Sheikh Khalifa Medical city ( Cleveland clinic management) ABU DHABI PO BOX 51900 Send response to journal: Re: Probiotics and the enteric ecosystem !	The study of Mary Hichson et al agains adds to our literature that emphasizes the importance of keeping our enteric ecosystem in a healthy balance. The study of Nicola de Bartoli et al at University of Pisa, recently published at American Journal of gastroenterology has documented the role of Probiotics and lactoferrin for a much better rate of eradication of H.Polori infection.* Broad spectrum antibiotics in particular, as well as clindamycin have a much higher rate of antibiotics associated diarrhea, due to interfering with the balance of bacteria in the gut though selectively eradicating the gut friendly bacteria,tipping off the balance in favour of pathological, diarrhra inducing bacteria. Within the past few years there has been severe highly virulent strains of colstridium difficile colitis in north american hospitals( USA and canada)., so virulent that it does not respond to proper measures of stopping antibiotics and administration of proper treatment including metronidazole, oral vancomycin, rifampin, and cholestyramine. Further studies using the concept of probiotics to minimize the rates of clostridium difficile infection is highly recommended. * Am J.Gastroenterology 2007;102:951-956 Competing interests: None declared
Used of probiotic study: lack of appropriate control group 18 July 2007
Jeorge M. Orendi, Consultant Medical Microbiologist University Hospital of North Staffordshire, Stoke-on-Trent, ST4 7PX, UK Send response to journal: Re: Used of probiotic study: lack of appropriate control group	Sir, The placebo group in the study of Hickson-M et al. received a longlife, sterile milkshake (Yazoo, Campina, Netherlands), 97 ml twice daily, within 48 hours of starting an antibiotic and continued until one week after stopping the antibiotic. They received the milkshake twice a day for at least a week. Such a treatment with a longlife, sterile milkshake is not part of routine hospital nutrition. This placebo group experienced a high rate of diarrhoea (34%) and C. difficile toxin-associated diarrhoea (17%). I assume the longlife, sterile milkshake contained a significant amount of sugar and other nutrients used by growing bacteria, and would thus represent a fertile medium for bacterial overgrowth, perhaps increasing the risk of antibiotic-associated diarrhoea and C. difficile-associated diarrhoea in combination with an antibiotic. Thus, although I agree that the treatment group had a significant lower rate of diarrhoea and C. difficile-associated diarrhoea than the placebo group in this highly selected group of patients, this may not be because of the protective effect of the probiotic product, but because of a deleterious effect of the placebo treatment. Since this can not be ruled out, the conclusions of the paper are not warranted. Competing interests: None declared
Antibiotic associated diarrhoea and primary care 20 July 2007
Shaun Conway, GP principal Hingham, Norfolk, NR9 4JB Send response to journal: Re: Antibiotic associated diarrhoea and primary care	Hickson’s study has problems with generalisability. It’s applicability to other elderly hospital patients is poor due to it’s low recruitment rate of 8% and specifically the exclusion of patients receiving high risk antibiotics1. Moreover it is a hospital based study and as such cannot inform the behaviour of primary care physicians. In England in 2003/4 over 30 million courses of antibiotics were prescribed in general practice2. When are we going to get a primary care based study of whether probiotics can prevent antibiotic associated diarrhoea? I must take issue with the strap line on the front page of the BMJ asking if probiotic lactobacilli can prevent iatrogenic diarrhoea. Firstly Hickson used a probiotic drink containing three bacterial species; we cannot know whether the effect was attributable to just one of the three bacteria (in which case the Strep. thermophilus might have been the therapeutic agent) or whether it was a synergistic effect between all three. Secondly you introduce the term “iatrogenic” (not used by either Hickson or MacFarland3); this is sloppy language. Many infections are accompanied by diarrhoea and the use of “associated” in the context of antibiotics and diarrhoea is preferable as it avoids an assertion of causality. 1. Hickson M, D'Souza AL, Muthu N, Rogers TR, Want S, Rajkumar C, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ 2007 doi: 10.1136/bmj.39231.599815.55 2. http://www.ppa.org.uk//news/pact-102004.htm 3. McFarland LV. Diarrhoea associated with antibiotic use. BMJ 2007;335:54-55 (14 July), doi:10.1136/bmj.39255.829120.47 Competing interests: None declared
Prescribe probiotics? 20 July 2007
Sreekanth J Pillai, Senior House Officer, Geriatric Medicine Royal Free Hospital, London, NW3 2QG Send response to journal: Re: Prescribe probiotics?	With increasing evidence for the use of concomitant probiotics with broad spectrum antibiotics, it is worth considering practical aspects of such therapy. Royal Free Hospital in London has recently been in the public eye with one of the lowest mortality rates and also one of the lowest rates of Clostridium difficile infection among teaching hospitals in the country. The Geriatric unit within the hospital has been using a narrow spectrum antibiotic policy with commendable efficacy and results demonstrate reduced rates of Clostridia associated diarrhoea. It may be prudent and quite cost effective to consider regular probiotics on patients requiring broad spectrum antibiotics especially third generation cephalosporins or extended spectrum penicillins. At present however, in actual practice, recommendation of probiotic use remains dependant on the availabilty of a relative or friend bringing the supply from outside. I believe as we gather further evidence in this field it may be judicious to consider probiotics to be supplied widely throughout the NHS and may be consider using "prescription probiotics". Competing interests: None declared
Tobacco: potential confounder 26 July 2007
Michael K Park, Assistant Professor University of Colorado, Rose Family Medicine Residency Send response to journal: Re: Tobacco: potential confounder	I applaud the authors on an important and generally well constructed study. However, I disagree with the statement that "there were no clinically important differences between the two groups at baseline". The probiotic group had a considerably larger number of smokers (19, 28%) than the control group (11, 17%). Given the well-documented albeit poorly-understood relationship between smoking and decreased symptoms in ulcerative colitis, tobacco use is a potential confounder. I'm not aware of any studies demonstrating a link between smoking and decreased rates of AAC or CDI but based on the proposed mechanisms of nicotine in UC (decreased intestinal motility and inflammation as well as protective mucogenesis), smoking may have decreased rates of diarrhea in the study population as well. This study addresses a question with significant implications on quality and cost of care. Our understanding of the potentially beneficial role of probiotics would be enhanced if tobacco and PPI use (as insightfully noted above) were better accounted for and a control other than a lactose-based drink utilized in a larger study. Competing interests: None declared
Critical appraisal 27 July 2007
ABRAHAM P. GEORGE, Specialist Registrar Public Health Greater Manchester Health Protection Unit, Rosemary Mccan, Peter Morgan, Ruth Philp, Sue Hunt Send response to journal: Re: Critical appraisal	We commend the authors for undertaking this well designed trial. We have a number of comments: · We were unclear about the inclusion and exclusion criteria and why only certain wards were used to recruit patients. We assume that patients who had been on high-risk antibiotics were excluded because prudent antibiotic prescribing alone would reduce their risk. We are not sure whether this was the authors’ intention. · The authors mentioned an equal proportion of loss to follow up in both groups during the study, which would have not biased the study results. However, no mention was made as to the characteristics of these people, in terms of antibiotic risk group, duration of antibiotic regime, ward, etc. · No statistical test was used to definitely rule out any significant differences between the baseline characteristics of both study groups. · In the flow chart, the authors classified proportion of participants in each group who had consumed more or less than 50% of probiotic prescribed. However, there is no data given on the range of consumption in both groups and whether consumption was higher early in the intervention or later. It would be interesting to know whether the timing and dosage of the probiotic affects the outcome. · Some ethnic groups consume a high amount of yogurt in their diet, which may have affected the results. There was no attempt to measure this. · If data on date of onset and duration of diarrhoea episode were available, survival analysis could have been used. · Inclusion of a sensitivity analysis would have made the economic evaluation of probiotics more robust. Competing interests: None declared
A win-win intervention 27 July 2007
Dr Beena R. Nayak, Project Associate Indian Institute of Management, Ahmedabad-15, - Send response to journal: Re: A win-win intervention	The use of Probiotics is precedented by the use of species Lactobacillus since more than two decades. Initially, it was called a placebo, then over the period of wisdom dawning upon the medical world it was called an empirical adjunct to antibiotics. Actually more than three decades ago, it was already known that competitive inhibition of pathogens could be done by the use of curd or yogurt ice-cream. This was why doctors began to prescribe yogurt ice-creams in U.S.A. in the 1980s to supplement antibiotics in the young. And then, thousands of years ago, the physician Charaka prescribed a formulation based on yogurt in diarrhoeal conditions inspired by Ayurveda, the ancient health sciences of India. Probiotics and the next gen thereof, is a Win-Win intervention helping the commensals of the gut, helping immunity of the patient to fight the bad guys in the gut and recently India's largest dairy co-operative started a marketing campaign based on Probiotic drinks and ice-cream - good for your health, good for our health!So far, in all the research reported no adverse effects have been found!it is easy to have as Probiotic curd can be grown at home in a simple way. It represents THE WIN WIN SOLUTION for India where there are still more cases of diarrhea then HIV, Malaria and TB put together AND even patients suffering from viral diarrhea would benefit from Probiotics!Last but not the least it is affordable for all! Hurrah!! Competing interests: None declared
Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics 28 July 2007
NAZAR R DESSOUKI, CONSULTANT SURGEON ST BERNARDS HOSPITAL GIBRALTAR Send response to journal: Re: Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics	Considerable research is focused on modifying the intestinal flora with probiotic bacteria to attenuate inflammatory activity and prevent relapses in ulcerative colitis, Crohn’s disease, and pouchitis. Although both Lactobacillus species and Bifidobacterium species are frequently used, the optimum use of probiotics in IBD requires greater understanding of their effects on the immune system. Competing interests: None declared
Author's Reply 3 August 2007
Mary Hickson, Research Dietitian Department of Nutrition and Dietetics, Charing Cross Hospital, London W6 8RF, Aloysius L D’Souza, Nirmala Muthu, Thomas R Rogers, Susan Want, Chakravarthi Rajkumar, Christopher J Bulpitt Send response to journal: Re: Author's Reply	Dear Editor, We would like to respond to the editorial and 3 letters regarding this study on probiotics in the prevention of antibiotic induced diarrhea. McFarland’s editorial (1) stated that a description of the time of onset of diarrhoea would be helpful. This analysis was done and was posted as extra information with the original online article. Most importantly diarrhoea usually occurred after the course of antibiotics had been completed. The main criticism made about this study is that it is not reasonable to extrapolate our results to a larger hospital population of older people who are receiving antibiotics. Wilcox & Sandoe (2) and McFarland (1) highlight the high number of excluded patients making the study group unrepresentative. Our study aimed to provide strong unequivocal evidence that a readily available probiotic drink was effective in reducing the incidence of diarrhoea. To successfully do this we had to ensure factors that may influence the occurrence of diarrhoea were controlled for. Thus, it was imperative that patients who may get diarrhoea for other reasons or from prior antibiotic use were excluded. This accounts for 55% of the exclusions. Billyand (3) appeared to believe that we had excluded subjects on ‘high-risk’ antibiotics. This was true only if these antibiotics were prescribed in the previous 4 weeks. Table 1 (online version) clearly indicates that 62-70% of patients received high-risk antibiotics. Konfortov (4) discussed the possibility of proton pump inhibitors confounding the results. This information is also discussed in the on-line extra information. The hypothesis that proton pump inhibitors increase the risk of C.difficile associated diarrhoea is controversial. There are no data to suggest that proton pump inhibitors alter the native flora of the lower bowel, affect mucosal immune factors or C.difficile-host interaction, which are important in the development of diarrhoea. Reports of an association between proton pump inhibitors and C.difficile associated diarrhea (5;6) have not been confirmed by a more robust study.(7) 1.McFarland, L. V (2007). Diarrhoea associated with antibiotic use. BMJ 335: 54-55 2.Wilcox, M. H, Sandoe, J. A (2007). Data are not widely applicable. BMJ 335: 171-171 3.Billyard, T. (2007). No high risk antibiotics? BMJ 335: 171-171 4.Konfortov, M. B (2007). No proton pump inhibitors? BMJ 335: 171-171 5.Dial S, Alrasadi K, Manoukian C, Huang A, Menzies D. (2004) Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ 171:33-38 6.Dial S, Delaney JA, Barkun AN, Suissa S. (2005) Use of gastric acid -suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA 294:2989-2995 7.Loo VG, Poirier L, Miller MA, Oughton M, Libman MD, Michaud S et al. (2005) A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 353:2442-2449 Competing interests: None declared
Local incidence of Clostridium difficile associated diarrhoea to be considered. 8 August 2007
Jesús Rodríguez-Baño, Associate Professor Hospital Universitario Virgen Macarena, Avda. Dr. Fedriani, 3. 41009 Seville, Spain, Lorena López-Cerero, and María M. Portillo Send response to journal: Re: Local incidence of Clostridium difficile associated diarrhoea to be considered.	Hickson et al conclude that consumption of a probiotic Lactobacillus preparation drink can reduce the incidence of antibiotic associated diarrhoea (AAD) and Clostridium difficile associated diarrhoea (CDAD), with an estimated absolute risk reduction of 22% and 17%, and state that this has the potential to decrease morbidity, healthcare cost, and mortality if used routinely in patiens aged over 50 [1]. The incidence of AAD and CDAD in the placebo group were 34% and 17%. However, there are substantial differences in the incidence of AAD and CADC among different hospitals that challenge the extrapolation of these results. In the context of a randomised controlled therapeutic trial for CDAD, we implemented an active program for the detection of AAD and CDAD cases in a tertiary 950-bed Spanish hospital from November 2005 throughout June 2007. Infection control nurses and/or infectious diseases doctors visited all hospital wards 5 days a week to identify patients with AAD (more than 2 liquid stools a day for more than 2 days with no other obvious cause), and a stool sample from all these patients was sent to the microbiology laboratory for the detection of toxins A, B or both (X/PECT Clostridium difficile Toxin A/B, Remel, Santa Fe, USA). If the initial sample was negative, new samples were studied whenever diarrhoea persisted. Reports of all bowel endoscopic procedures and surgery were also routinely reviewed. During the study period, 530 samples from 427 patients were analysed, and 30 samples from 25 patients (5.8%) were positive for C. difficile toxin; 15 of them were aged over 50. All patients were treated and cured (4 had recurrences that responded to subsequent therapy) and one died as a consequence of his underlying disease. Our infection control program includes individual room isolation, contact precautions, and thorough daily cleaning of rooms and bathrooms of all patients with CDAD. There were 57,838 admissions during the study period; thus, the incidence of CDAD was 0.43 per 1,000 admissions. Based on the Pharmacy and infection control surveillance data, the estimated number of patients who received antimicrobials during the period was 14,459. Thus, the estimated incidence of antibiotic associated diarrhoea was 2.95% and of CDAD among patients who received antimicrobials, 0.17%. When thinking about implementing a preventive measure in a population, the incidence of the event to be prevented in that population needs to be considered. We think that probiotic Lactobacillus preparation should not be routinely used in hospitals with low incidence of CDAD. References. 1. Hickson M, D'Souza AL, Muthu N, Rogers TR, Want S, Rajkumar C, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ 2007;335:80-3. (14 July). Competing interests: JRB has received honorariums for consultancy work from Pfizer, Merck, Wyeth and Novartis. LLC and MMP have no competing interests.