What is an appropriate control group to identify risk factors for Clostridium difficile-associated diarrhoea?

Andrea Guyota,* and Steve P. Barrettb

a Department of Microbiology, West Middlesex University Hospital, Twickenham, Isleworth TW7 6AF; b Department of Microbiology, Charing Cross Hospital, London W6 8RF, UK

Sir,

In our case–control study1 we identified length of hospital stay (>28 days), respiratory tract infection (RTI) and use of clarithromycin as risk factors for Clostridium difficile-associated diarrhoea (CDAD). Since C. difficile is resistant to macrolides, its overgrowth may be favoured by clarithromycin.

Wilcox2 criticized the choice of control patients with diarrhoea and suggested asymptomatic patients would have been better. Our study is not unique in using a diarrhoea control group. Nelson et al.3 performed a case– control study for CDAD using two different control groups: an asymptomatic ward-matched group and a diarrhoea group. Both control groups gave similar results, identifying cephalosporins and antimicrobial combinations as significant risk factors for CDAD.

MacGowan et al.4 used a control group of patients with lower respiratory tract infections and found that a greater use of cephalosporins and macrolides was significantly associated with CDAD. However, clarithromycin usage could not be identified as a significant risk factor, although its usage was higher in the case group than in the control group. So far in the past all three different control groups came to the same result, pointing to the cephalosporins as risk factors for CDAD. The ideal control group would be healthy carriers of C. difficile to identify risk factors for the induction of diarrhoea. Between 10% and 20% of elderly patients admitted to hospital are healthy carriers of C. difficile.5 The pathophysiology of CDAD is complex and not fully understood.

Wilcox2 also suggests that controls should have been matched by ward in case there were differences in virulence of prevalent strains of C. difficile. However, as he points out, we did not find the breakdown of admissions by ward to be a risk factor (P < 0.05), unlike the use of clarithromycin. For reasons of space we omitted age ranges, along with details of diagnosis other than RTI and other noncontributory details. However, they were similar, with the median age of the case group at 75.5 years (64–93 years) and of the control group at 75.0 years (64–95 years); the means (± s.d.) were 77.5 (7) and 77.7 (8.2) years, respectively.

Unique in our study was the extensive usage of clarithromycin for the treatment of RTI in the elderly. We accept that clarithromycin monotherapy is not a usual recommendation. Our own antibiotic policy stipulates cefuroxime plus clarithromycin and then switch to oral co-amoxiclav plus clarithromycin. However, a review of the questionnaire forms demonstrated that in the elderly clarithromycin was used as monotherapy. In the last few years clinicians have become aware of the risk of cephalosporin usage for CDAD in the elderly and try to avoid and to replace them. Presently, macrolides are a popular alternative covering most infective agents of bacterial and atypical pneumonia.

Our study cannot distinguish whether RTI and clarithromycin are independent risk factors. It may be possible that a factor other than antimicrobial use in RTI predisposes to CDAD. The best control group would be healthy carriers to control for the risk factor for induction of CDAD.

Notes

* Corresponding author: Tel: +44-20-8565-5858; Fax: +44-20-8565-2535; E-mail: drguyot{at}compuserve.com Back

References

1 . Guyot, A., Rawlins, M. D. & Barrett, S. P. (2000). Clarithromycin appears to be linked with Clostridium difficile-associated diarrhoea in the elderly. Journal of Antimicrobial Chemotherapy 46, 642–3.[Free Full Text]

2 . Wilcox, M. (2001). Clarithromycin and risk of Clostridium difficile-associated diarrhoea. Journal of Antimicrobial Chemotherapy 47, 358–9.[Free Full Text]

3 . Nelson, D. E., Auerbach, S. B., Baltch, A. L., Desjardin, E., Beck-Sague, C., Jarvis, W. R. et al. (1994). Epidemic Clostridium difficile-associated diarrhoea: role of second and third generation cephalosporins. Infection Control and Hospital Epidemiology 15, 88–94.[ISI][Medline]

4 . MacGowan, A. P., Freeney, R., Brown, I., McCulloch, S. Y., Reeves, D. S. & Lovering, A. M. (1997). Health care resource utilization and antimicrobial use in elderly patients with community-acquired lower respiratory tract infection who develop Clostridium difficile-associated diarrhoea. Journal of Antimicrobial Chemotherapy 39, 537–41.[Abstract]

5 . Gerding, D. N., Johnson, S., Peterson, L. R., Mulligan, M. E. & Silva, J. (1995). SHEA position paper: Clostridium difficile-associated diarrhoea and colitis. Infection Control and Hospital Epidemiology 16, 459–77.[ISI][Medline]