Clarithromycin and risk of Clostridium difficile-associated diarrhoea

Mark H. Wilcox

Department of Microbiology, University of Leeds and The General Infirmary, Leeds LS2 9JT, UK

Sir,

Guyot and colleagues1 reported a retrospective analysis of antibiotic and other potential risk factors in Clostridium difficile-associated diarrhoea in elderly in-patients. They claimed that clarithromycin was a significant risk factor for C. difficile-associated diarrhoea, but there are important caveats to their report. Most important was their choice of control patients. Rather than comparing risks in cases with those in asymptomatic controls, the authors selected patients for whom diarrhoeal stools had been routinely submitted to the laboratory, but which tested negative for C. difficile toxins. Hence, any risk factor identified by their approach was simply one associated with a diarrhoeal faecal specimen that was C. difficile toxin positive, and not a risk factor for antibiotic-associated diarrhoea per se. Furthermore, the decision to select control patients admitted to wards where C. difficile cases occurred was markedly weakened by not using one-to-one matching. The authors noted that cases (29 out of 64) clustered on six wards, and yet, because controls were not individually matched to cases by ward location, only 22 out of 64 control patients were from these six wards. While this difference by itself is not significant, not controlling adequately for ward location may be an important confounding variable if there is uneven (qualitative or quantitative) distribution of virulent C. difficile strain types within the two study hospitals. Cases and controls were not matched by age (other than both were >65 years); the summary age details for each group do not state whether these were mean or median values (the latter would have been preferable). Furthermore, length of stay before onset of diarrhoea was significantly longer in cases than in controls, so the former had greater potential for hospital acquisition of C. difficile.

I question the statement ‘which reflects the tendency to use clarithromycin as monotherapy in the elderly’. I sus-pect that Guyot et al. may have meant to say ‘which reflected the tendency . . .’, i.e. in the context of a study elsewhere, to which they refer. Clarithromycin monotherapy in hospitalized patients in the UK is not the norm, and the authors themselves note that combination therapy (with either cefuroxime or co-amoxiclav) is routine practice in their hospitals. Also, the authors do not expand on the influence of their observation that clarithromycin was commonly used for 10 days compared with only 3 days of cefuroxime on the association of the former with C. difficile diarrhoea. In short, what was the contribution of duration of antibiotic treatment (and multiple exposure) to the association they found? Notably, it has been shown that prolonged antibiotic duration and multiple antibiotics are risk factors for C. difficile infection.2 Guyot et al. used four references36 to provide contrast to their observation that neither cephalosporin nor ß-lactam usage was associated with their control group of elderly patients with diarrhoea. However, the studies cited were not directly comparable. Two of these3,4 did not calculate specific antibiotic associated risks, but instead reported antibiotic policy interventions. Interestingly, but not noted by Guyot et al., both the remaining studies quoted found excess C. difficile diarrhoea in patients receiving macrolides.5,6

In order to avoid drawing erroneous conclusions on antibiotics associated with C. difficile diarrhoea, cases and controls should ideally be matched, at least in respect of age, major admission diagnoses and location. Multiple antibiotic therapy, duration of treatment and duration of hospital stay are important potential confounding variables and others, such as nasogastric tubes, have been found by some to be associated with C. difficile diarrhoea. Ethically it is difficult to devise a study that will answer definitively whether or not macrolides are significantly associated with C. difficile diarrhoea, as this would involve withholding potentially effective antibiotics from some patients. A fluoroquinolone could, however, provide adequate cover for atypical pathogens. Indeed, new-generation fluoroquinolones may have a role in the empirical treatment of infection in the elderly, providing they themselves are given a clean bill of health in the setting of endemic C. difficile infection.

Notes

Tel: +44-113-233-5595; Fax: +44-113-233-5649; E-mail: markwi{at}pathology.leeds.ac.uk

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 . Bignardi, G. E. (1998). Risk factors for Clostridium difficile infection. Journal of Hospital Infection 40, 1–15.[ISI][Medline]

3 . McNulty, C., Logan, M., Donald, I. P., Ennis, D., Taylor, D., Baldwin, R. N. et al. (1997). Successful control of Clostridium difficile infection in the elderly care unit through use of a restrictive antibiotic policy. Journal of Antimicrobial Chemotherapy 40, 707–11.[Abstract]

4 . Boswell, T. C., Nye, K. J. & Smith, E. G. (1998). Increased incidence of Clostridium difficile infection. Journal of Hospital Infection 39, 78–9.[ISI][Medline]

5 . Impallomeni, M., Galletly, N. P., Wort, S. J., Starr, I. M. & Rogers, T. R. (1995). Increased risk of diarrhoea caused by Clostridium difficile infection in elderly patients receiving cefotaxime. British Medical Journal 311, 1345–6.[Free Full Text]

6 . MacGowan, A. P., Feeney, 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]