Departments of 1 Microbiology and 2 Medicine, University Hospital Lewisham, London SE13 6LH, UK
Received 23 August 2002; returned 15 October 2002; revised 28 November 2002; accepted 4 December 2002
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Abstract |
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Keywords: levofloxacin, Clostridium difficile-associated diarrhoea (CDAD)
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Introduction |
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Levofloxacin is a fluoroquinolone antibiotic that has been shown to be comparable to cephalosporins and amoxicillin in clinical efficacy in the management of community-acquired LRTI.7 The antibacterial spectrum, pharmacokinetics and convenience of administration have also contributed to levofloxacin being recommended in the various guidelines for the management of community-acquired LRTI.6,8 The adverse event profile of levofloxacin is generally similar to those of other fluoroquinolones and thus is less likely to cause CDAD than cephalosporins and probably other ß-lactams.9
The aim of the study is to compare the incidence of CDAD following treatment of community-acquired LRTI in hospitalized patients with levofloxacin, or a ß-lactam-based therapy as recommended by the BTS (cephalosporins or amoxicillin with or without erythromycin).6
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Materials and methods |
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All the admitting physicians were arbitrarily allocated to one of the two groups (Group A or Group B). Group A physicians initially treated all the patients with levofloxacin (500 mg, 12 hourly) and Group B physicians treated with ß-lactams (cefuroxime 750 mg, 8 hourly or amoxicillin 500 mg, 8 hourly) with or without erythromycin (250 mg, 6 hourly). From November 2001, Group A physicians were asked to use ß-lactams and Group B physicians were asked to use levofloxacin to remove any bias resulting from practices of admitting physicians. This method of randomization was chosen because of difficulties in implementing individual randomization in a busy Accident and Emergency (A/E) department. The patients were also randomly admitted to any of the wards usually depending on the availability of empty beds. The hospital does not have dedicated wards for the various admitting physicians.
Patients were identified by daily perusal of records in A/E and pharmacy departments. These patients were followed up regularly (twice weekly) until discharge from the hospital. The following information was recorded for all patients: demographic details and information regarding admitting diagnosis, duration of hospital stay, previous antibiotic therapy (within the past 30 days) and current antibiotic therapy (drug, route and duration). Since the primary outcome of this study was incidence of CDAD, we did not record the outcome in terms of clinical or microbiological criteria on the basis that all the antibiotics used in this trial had been previously licensed for treatment of LRTI.
Faeces specimens of patients who developed diarrhoea (defined as three or more loose stools per day) were tested for C. difficile toxin (CDT) A using a commercially available kit (Oxoid, Basingstoke, UK). Some of the patients were tested repeatedly if the symptoms persisted and earlier tests were negative.
Those with diarrhoea with the presence of CDT were defined as having CDAD.
General practitioners in the community were asked to inform the authors if any of the patients developed diarrhoea within 1 month following discharge from the hospital.
The data were stored and analysed using Epi-Info 6, a public domain software.10 Patients treated with levofloxacin (levofloxacin group) were compared with those treated with ß-lactam-based therapy (ß-lactam group), cefuroxime-based therapy (cefuroxime group) and amoxicillin (amoxicillin group).
Statistical analysis was carried out using the Students t-test or MantelHaenzel 2 test with the significance level set at P < 0.05.
Before the commencement of the study, approval was obtained from the local ethics committee.
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Results |
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Age and sex distribution of the levofloxacin and ß-lactam groups was similar. There was no significant difference between the two groups in the number of patients who had previous antibiotic therapy. Similarly there was no significant difference in the average duration of previous antibiotic therapy. There was a lower incidence of CDAD (P <0.01) in the levofloxacin group. There was also a shorter duration of hospital stay in the levofloxacin group (P < 0.01) compared with the ß-lactam group (Table 1). There was, however, no significant difference in the duration of hospital stay after exclusion of patients with CDAD.
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The age and sex distribution of the levofloxacin and cefuroxime groups was similar. In the cefuroxime group, more patients had received previous antibiotic therapy (P < 0.02) but there was no significant difference between the two groups in the duration of previous antibiotic therapy. The patients in the cefuroxime group were significantly more likely to develop CDAD (P < 0.0001). History of previous antibiotic therapy was not a confounding factor. Similarly, although 108/229 (46%) patients in the cefuroxime group were also treated with erythromycin, stratified analysis failed to show any confounding effect on the incidence of CDAD in this group. Patients in the cefuroxime group had a significantly longer duration of hospital stay compared with those in the levofloxacin group (P < 0.0000001). The duration of antibiotic treatment for current infection was significantly longer in the cefuroxime group compared with the levofloxacin group (Table 2).
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Patients were admitted randomly to over 20 different wards in the hospital. There was no significant difference in rates of admission to various wards among the groups. Although some wards had a higher incidence of CDAD, there was no significant difference in the incidence between the groups admitted to these wards.
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Discussion |
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In a separate but related study, a colleague estimated the proportion of C. difficile A/B+ strains in our hospital. The study showed that by testing for only CDT A toxin in the faeces, we may have underestimated the true incidence of CDAD by missing 8% of cases due to C. difficile A/B+ strains. On the basis that all the groups would have been equally affected, this underestimation is unlikely to have resulted in a change in the overall findings of this study.11
The same study failed to detect C. difficile in the environment of wards that traditionally had a high incidence of CDAD. This suggests that our hospital environment was unlikely to be an important source of infection.
The results show that the patients in the levofloxacin and ß-lactam groups were generally well matched to study the incidence of CDAD. It was difficult to reliably compare the co-morbidity between the two groups because of the wide variety of co-morbid conditions encountered in elderly patients; however, we are confident that the design of the trial is unlikely to result in a preponderance of co-morbidity in either group.
Our findings show that levofloxacin was significantly less likely to be associated with CDAD than ß-lactam-based therapy. Patients in the ß-lactam group had a significantly longer duration of hospital stay. Adjusted analysis by excluding patients with CDAD showed that the longer duration of stay was as a result of patients with CDAD. Patients with CDAD had a significantly longer hospital stay compared with those without CDAD. Furthermore, the onset of CDAD either coincided with or occurred soon after completion of antibiotic therapy. It is therefore likely that CDAD is the cause of rather than the result of prolonged hospital stay.
Our study indicates that patients treated with cefuroxime were at a significantly greater risk of developing CDAD compared with the levofloxacin group. Use of cefuroxime was also associated with a significantly longer duration of hospital stay.
There was no significant difference between levofloxacin and amoxicillin groups in the incidence of CDAD and duration of hospital stay. This was despite the fact that patients in the amoxicillin group were relatively younger and fewer patients had previous antibiotic therapy.
Finally, although previous antibiotic therapy appears to be an important risk factor for CDAD in all groups of patients, it was not a confounding factor when comparing the incidence of CDAD between the groups.
In conclusion, this study confirms that levofloxacin is significantly less likely to be associated with CDAD than ß-lactam-based therapy or cefuroxime-based therapy. This feature together with its clinical efficacy and ease of administration makes levofloxacin an important alternative to ß-lactam-based therapy in the management of LRTI.
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Acknowledgements |
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Footnotes |
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References |
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