Managing antibiotic associated diarrhoea
BMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7350.1345 (Published 08 June 2002) Cite this as: BMJ 2002;324:1345
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
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.
Competing interests: No competing interests
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.
Competing interests: No competing interests