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EDITORIALS: Frédéric Barbut and Jean Luc Meynard Managing antibiotic associated diarrhoea BMJ 2002; 324: 1345-1346 [Full text]

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No probiotics can be recommended for the prevention of antibiotic associated diarrhoea

Mark H Wilcox   (11 June 2002)

METRONIDAZOLE PREFERRED TREATMENT FOR ANTIBIOTIC ASSOCIATED DIARRHOEA IN PREGNANCY

Scott Pegler, Dr Patricia McElhatton, Consultant Teratologist. Head of NTIS The National Teratology Information Service, Regional Drug & Therapeutics Centre, Wolfson Unit, Claremont Place, Newcastle upon Tyne, NE2 4HH   (26 July 2002)

No probiotics can be recommended for the prevention of antibiotic associated diarrhoea 11 June 2002
Mark H Wilcox, Consultant / Reader / Head of Medical Microbiology Microbiology, Leeds General Infirmary, Leeds LS1 3EX, UK Send response to journal: Re: No probiotics can be recommended for the prevention of antibiotic associated diarrhoea	I wish to highlight several contentious points both in the editorial by Barbut and Meynard (8 June 2002. BMJ 2002;324:1345-1346) and the meta- analysis by D'Souza et al. (8 June 2002. BMJ 2002;324:1361) on use of probiotics to prevent antibiotic associated diarrhoea (AAD). Barbut and Meynard claim that the risk of AAD is higher with, amongst others, a combination of aminopenicillins and clavulanate. However, the references they cite do not support this assertion, and indeed it is notable that there are very few published reports associating co-amoxiclav with C. difficile diarrhoea. This is all the more remarkable given the widespread usage of this antimicrobial combination. UK MCA data on reports of antibiotic associated colitis have not been published since 1994.1 Although these crude data were not adjusted for number of prescriptions, and thus are likely to be biased towards frequently used agents available in oral formulations, it is interesting that co-amoxiclav is not listed. When discussing the diagnosis of C. difficile diarrhoea, Barbut and Meynard omit to mention the now widespread recognition of C. difficile strains deficient in toxin A but producing toxin B.2 Thus, only the tissue culture assay or enzyme immunoassays that detect toxin B (+/- toxin A) should be used for the laboratory diagnosis of C. difficile diarrhoea. The usual dosage of oral metronidazole for the treatment of C. difficile diarrhoea is 400mg tds or 500mg tds, as opposed to 250mg tds as stated by Barbut and Meynard; 250mg tablets are not available in the UK. Also, Barbut and Meynard advocate that antiperistaltic agents should be avoided because of the risk of retention of C. difficile toxins in the gut lumen. This risk claim is largely theoretical and is not supported by study data. In a retrospective comparison of outcome following treatment with metronidazole or vancomycin in mild to moderate C. difficile diarrhoea there was no evidence of impaired response in patients receiving anti- diarrhoeal agents.3 Risks associated with the administration of live micro-organisms to patients, particularly the frail elderly with inflamed gut mucosae, have not been well examined. Cases of fungaemia (not 'bacteraemia' as stated by Barbut and Meynard) have indeed been reported in immunocompromised patients following administration of S. boulardii. It should be noted however that one such case has also been reported in an immunocompetent patient treated with a commercial preparation of S. boulardii,4 highlighting the potential virulence of this yeast in humans. Importantly, McCullough et al.5 found that S. boulardii isolates obtained from varied commercial sources differed in virulence in murine models of systemic infection, suggesting a lack of uniformity of yeast strains in such preparations. Also, commercially available S. boulardii strains had moderate virulence compared with Saccharomyces cerevisiae (baker's yeast) in these models.5 A meta-analysis of probiotic studies in general is an inappropriate tool to answer the question of whether they can usefully prevent AAD. Different micro-organisms given in different dosages to different populations receiving different antibiotics should not be grouped together when trying to answer such questions. For example, two of the studies included were in children, and one examined an adult population with mean age 48 years (reference 33), which is much younger than typical patients with AAD caused by the prime pathogen C. difficile. It has also been shown (see above) that different preparations of apparently the same probiotic can differ markedly,5 thus emphasising the drawbacks of grouping together even one micro-organism let alone several probiotics. Furthermore, a recent large, randomised, double blind, placebo controlled trial of lactobacillus GG versus placebo found no decrease in rate of diarrhoea (29.3% vs. 29.9%) or of C. difficile infection in patients receiving the probiotic.6 This study comprised 302 patients, 50% more than the largest of the four lactobacillus studies included in the meta- analysis by D'Souza and colleagues. Finally, Barbut and Meynard rightly emphasise that the most important way to prevent AAD is to avoid antibiotic use. When it is truly necessary to use antibiotics they should be prescribed judiciously, particularly in susceptible patients managed in C. difficile endemic settings. Currently, no probiotics can be recommended for the prevention of AAD. References 1. Medicines Control Agency. Antibiotic-associated colitis. Current Problems in Pharmacovigilance 1994; 20: 7. 2. Wilcox M.H., Fawley W. Virulence of Clostridium difficile toxin A -negative strains. J Hosp Infect 2001; 48: 81. 3. Niault M, Thomas F, Prost J, Hojjat Ansari F, Kalfon P. Fungemia due to Saccharomyces species in a patient treated with enteral Saccharomyces boulardii. Clin Infect Dis 1999, 28: 930. 4. Wilcox MH, Howe R. Diarrhoea caused by Clostridium difficile: response time for treatment with metronidazole and vancomycin. J Antimicrob Chemother 1995; 36: 673-9. 5. McCullough MJ, Clemons KV, McCluster JH, Stevens DA. Species identification and virulence attributes of Saccharomyces boulardii (nom. inval.). J Clin Microbiol 1998; 36: 2613-2617. 6. Thomas MR, Litin SC, Osmon DR, Corr AP, Weaver AL, Lohse CM. Lack of effect of Lactobacillus GG on antibiotic-associated diarrhea: a randomized, placebo-controlled trial. Mayo Clin Proc 2001; 76: 883-9.
METRONIDAZOLE PREFERRED TREATMENT FOR ANTIBIOTIC ASSOCIATED DIARRHOEA IN PREGNANCY 26 July 2002
Scott Pegler, Medicines Information Pharmacist, Swansea NHS Trust Medicines Information Centre, Morriston Hospital, Swansea NHS Trust, Swansea SA6 6NL, Dr Patricia McElhatton, Consultant Teratologist. Head of NTIS The National Teratology Information Service, Regional Drug & Therapeutics Centre, Wolfson Unit, Claremont Place, Newcastle upon Tyne, NE2 4HH Send response to journal: Re: METRONIDAZOLE PREFERRED TREATMENT FOR ANTIBIOTIC ASSOCIATED DIARRHOEA IN PREGNANCY	EDITOR - In their editorial “Managing antibiotic associated diarrhoea” (1), Barbut and Meynard quote U.S guidance recommending vancomycin as the first line therapy when treating pregnant women with this condition. We wish to comment that this advice would differ from UK guidance issued by Medicines Information Centres in the UK (UKMI) and the National Teratology Information Service (NTIS). The advice of UKMI and NTIS is to recommend metronidazole rather than oral vancomycin, after a careful risk assessment of each drug. Vancomycin is poorly absorbed from the normal, intact gastrointestinal tract (2). However, the presence of an inflammatory bowel process can result in increased absorption of the oral product (3), and when used in patients with pseudomembranous colitis, vancomycin may occasionally reach concentrations in serum which are therapeutic (4). This may lead to a theoretical potential for damage to the fetal VIIIth cranial nerve. In contrast, a number of epidemiological studies involving women have shown no conclusive evidence that metronidazole causes an increased risk of malformations, stillbirths, or low birth weight infants (5-17). The accumulated data on more than 1500 births involving prenatal exposure to metronidazole suggests no increase in congenital anomalies (7-17). In addition, a retrospective cohort study involving nearly 1400 exposed pregnancies did not detect either an increase in infants with any of several categories of congenital anomaly, or low birth weight infants (6). Analysis of data from the Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980-1991 found no association with congenital anomalies among 266 pregnancies treated with oral metronidazole during the first trimester (14). A recent prospective controlled study of 228 women exposed to metronidazole in pregnancy, 86% of whom were exposed in the first trimester, confirmed these findings (16). The long-term postnatal effects of intrauterine exposure to metronidazole, if any, have yet to be determined. However, data from a 20 year ongoing study gives no indication of an increased incidence of malignancies after metronidazole treatment (18). Thus, in view of the wide experience of metronidazole in preganacy, and the theoretical risks and less experience of using vancomycin in preganacy, the advice of UKMI and NTIS is to use metronidazole 400mg tds, in preference to oral vancomycin, in the dosing schedule (continuous or pulsed therapy) that had been recommended locally with Microbiology, and for the shortest duration that clears the infection. Scott Pegler Medicines Information Pharmacist Morriston Hospital Swansea NHS Trust Swansea SA6 6NL Dr Patricia McElhatton Consultant Teratologist Head of NTIS The National Teratology Information Service Regional Drug and Therapeutics Centre Wolfson Unit, Claremont Place Newcastle upon Tyne NE2 4HH References 1. Barbut F & Maynard JL. Managing antibiotic associated diarrhoea. BMJ 2002;324:1345-6. 2. Association of the British Pharmaceutical Industry. Medicines Compendium 2002. Summary of Product Characteristics. Vancocin Matrigel Capsules. Eli Lilly and Company Limited. 3. Wilhelm MP & Estes L: Vancomycin. Mayo Clin Proc 1999;74:928- 935. 4. Hutchison TA & Shahan DR (Eds): DRUGDEX® System. Vancomycin. MICROMEDEX, Greenwood Village, Colorado (Vol. 112 expiry 6/2002) 5. Schardein JL. Chemically Induced Birth Defects 3rd edition, 2000. New York: Marcel Dekker. pp 443-4 6. Piper JM, Mitchell EF, Ray WA. Prenatal use of metronidazole and birth defects: no association. Obstet Gynecol 1993;82:348-52. 7. Berget A, Weber T: Metronidazole and pregnancy. Ugeskr Laeger 1972;134:2085-9. 8. Morgan I: Metronidazole treatment in pregnancy. Int J Gynaecol Obstet 1978;15: 501-2. 9. Robinson SC, Mirchandani G: Trichemonas vaginalis. V. Further observations on metronidazole (including infant follow-up). Am J Obstet Gynecol 1965;93:502-5, 10. Scott-Gray M: Metronidazole in obstetric practice. J Obstet Gynaecol Br Commonw 1964;71:82-5. 11. Sands RX: Pregnancy, trichomoniasis, and metronidazole. Am J Obstet Gynecol 1966 94:350-3, 12. Burtin P, Taddio A, Ariburnu O, Einarson TR, Koren G. Safety of metronidazole in pregnancy: a meta-analysis. Am J Obstet Gynecol 1995;172:525-9. 13. Caro-Paton T, Carvajal A, Martin-de-Diego I et al: Is metronidazole teratogenic? A meta-analysis. Br J Clin Pharmacol 1997;44: 179-82. 14. Czeizel AE, Rockenbauer M: A population based case-control teratologic study of oral metronidazole treatment during pregnancy. Br J Obstet Gynaecol 1998;105: 322-7. 15. Morales WJ, Schorr S, Albritton J. Effect of metronidazole in patients with preterm birth in preceding pregnancy and bacterial vaginosis: a placebo-controlled, double-blind study. Am J Obstet Gynecol 1994;171:345-9. 16. Diav-Citrin O, Gotteiner T, Shechtman S et al. Pregnancy outcome following gestational exposure to metronidazole: a prospective controlled cohort study. Teratology 2001: 63;186-92. 17. Garbis H, Reuvers M, Rost van Tonningen M. Anti-infective agents. In: Drugs During Pregnancy and Lactation. Ed. Schaefer C. Elsevier 2001; pp 58-84 18. Beard CM, Noller KI, O Fallon WM et al. Cancer after exposure to metronidazole. Mayo Clin Proc 1988: 63; 147-53.