a Department of Microbiology, West Middlesex University Hospital,Twickenham, TW7 5AF b Pharmacy Department, St Mary's Hospital, London W2 1NY c Department of Diagnostic Bacteriology, St Mary's Hospital, London W2 1NY, UK
Sir,
Previous studies have identified the use of second- and third-generation cephalosporins as a risk factor for Clostridium difficile-associated diarrhoea (CDAD)1,2 and intervention studies which replaced cephalosporins reduced the incidence of CDAD in the elderly.3,4 At St Mary's Hospital in 1997, 34% of patients aged over 65 years with diarrhoea, who were examined for C. difficile toxin, tested positive compared with 17% of younger patients. As part of an investigation of the reasons for this we performed a case control study on antibiotic use in elderly patients.
Data for this study were collected from February to December 1999 in elderly patients (>65 years) with diarrhoea admitted to 20 wards of St Mary's Hospital and to one university-affiliated hospital specializing in care of the elderly. All liquid stool specimens sent to the laboratory were tested by EIA (Premier Cytoclone A + B) for the presence of C. difficile toxins A and B and cultured for Salmonella, Shigella and Campylobacter spp. on selective media.
We defined a case as a patient over 65 years old producing liquid stools with C. difficile detected by EIA. We selected as controls patients aged over 65 years admitted to wards where C. difficile cases occurred, whose faeces were liquid and who tested negative for C. difficile toxins. Excluded from the control group were patients who were admitted with diarrhoea or in whose faeces other bacterial pathogens were identified. Data collected prospectively comprised patient identifiers, ward assignment at onset of diarrhoea, dates of admission and onset of diarrhoea, indication for antibiotics and antibiotics administered within 4 weeks before onset. Data were collected from drug charts and medical records on to standardized forms, then entered into EPI Info version 6 (CDC, Atlanta, GA, USA). Categorical variables were compared by chi-squared test and continuous variables by KruskalWallis test or t-test if normally distributed. A level of significance of P < 0.05 was selected.
During the 10 month study period, 64 cases and 64 controls were studied. Case and control patients were similar in age, sex and location (Table). Although cases clustered on the intensive care unit (ICU), the renal ward, the vascular ward and three geriatric wards in some months, admission to these wards was not identified as a risk factor for CDAD (Table
). Cases stayed on average 10 days longer than controls in hospital before the onset of CDAD. Prolonged hospital stay increases the risk of acquisition of C. difficile and is usually a marker for severe underlying disease.
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Clarithromycin was identified as the single significant risk factor for CDAD if given within 1 month before onset (odds ratio 5.69, P < 0.01). In contrast to previous studies, cephalosporins and ß-lactams were not associated with CDAD when compared with our control group of elderly patients with diarrhoea.14 Even if the odds ratios were calculated for the subgroup of elderly patients with RTI (n = 44), which creates a control group of patients with RTI and diarrhoea testing negative for C. difficile toxin, the use of clarithromycin was again identified as the antibiotic risk factor (odds ratio 7.5, P < 0.05).
There are some case reports that describe C. difficile-associated colitis after use of clarithromycin, for example, for otitis in an infant and following the eradication of Helicobacter pylori in an adult.5,6 Clarithromycin decreases the total count of anaerobes in the gut, so it is not surprising that it is implicated in the overgrowth of C. difficile. In other casecontrol studies, macrolides were also associated with CDAD. Impallomeni et al.2 found a significant odds ratio of 2.8 for erythromycin and MacGowan et al.1 observed that a greater use of macrolides was associated with CDAD, which was only significant if the antimicrobial use for less than 7 days before onset was evaluated. However, although clarithromycin was used in more cases who developed CDAD, the difference from their control group was not significant. Antibiotic combination therapy did not emerge as a significant risk factor for CDAD though the odds ratio amounted to 10 for the combination of co-amoxiclav plus clarithromycin. Low numbers (n < 5) impeded the statistical evaluation of combination therapy, which reflects the tendency to use clarithromycin as monotherapy in the elderly.
This study identifies prolonged hospital stay, RTI and the use of clarithromycin as risk factors for CDAD. An intervention study which reduces the use of clarithromycin in the treatment of RTI in the elderly might help to establish whether clarithromycin and RTI are independently associated with CDAD.
Notes
J Antimicrob Chemother 2000; 46: 642643
* Corresponding author. Tel: +44-208-5655858; E-mail: drguyot{at}compuserve.com
References
1 . 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, 53741.[Abstract]
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Impallomeni, M., Galletly, N. P., Wort, S. J., Starr, I. M. & Rogers, T. R. (1995). Increased risk of diarrhoea caused by Clostridium difficile in elderly patients receiving cefotaxime. British Medical Journal 311, 13456.
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, 70711.[Abstract]
4 . Boswell, T. C., Nye, K. J. & Smith, E. G. (1998). Increased incidence of Clostridium difficile infection. Journal of Hospital Infection 39, 789.[ISI][Medline]
5 . Braegger, C. P. & Nadal, D. (1994). Clarithromycin and pseudomembranous enterocolitis. Lancet 343, 2412.
6 . Archimandritis, A., Souyioultzis, S., Katsorida, M. & Tzivras, M. (1998). Clostridium difficile colitis associated with a triple regimen, containing clarithromycin and metronidazole, to eradicate Helicobacter pylori. Journal of Internal Medicine 243, 2513.[ISI][Medline]