Received 11 March 2002; returned 14 May 2002; revised 10 June 2002; accepted 15 July 2002
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Abstract |
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Methods: Self-completion questionnaires were used to collect clinical, demographic and exposure data from cases of campylobacter infection reported to a sentinel surveillance scheme in England and Wales. Isolates from those cases were referred to the Public Health Laboratory Service Campylobacter Reference Unit for speciation, subtyping and antimicrobial resistance testing. Cases infected with a ciprofloxacin-resistant C. jejuni were compared with cases infected with a sensitive strain using casecase analysis. Single risk variable analysis and logistic regression analysis were employed. The analysis was restricted by travel status to control for the confounding effect of foreign travel.
Results and conclusion: Over half (55%) of the campylobacter infections acquired abroad were resistant to ciprofloxacin, compared with 10% of UK-acquired strains [relative risk 5.23; 95% confidence interval (CI) 4.585.96]. For travel-associated cases, ciprofloxacin-resistant infections were independently associated with travel to Spain [odds ratio (OR) 6.87; 95% CI 3.5213.38], Portugal (OR 22.40; 95% CI 4.36114.99) or Cyprus (OR 11.74; 95% CI 1.28108.02), and the consumption of chicken (OR 4.95; 95% CI 2.1211.56) or bottled water (OR 3.70; 95% CI 1.698.10). Indigenous cases infected with a ciprofloxacin-resistant strain were more likely to report the consumption of pre-cooked cold meats (OR 2.13; 95% CI 1.443.13). The risk of acquiring a ciprofloxacin-resistant campylobacter infection was strongly associated with foreign travel. Restricting the analyses by travel status revealed different sets of risk exposures for acquiring a resistant C. jejuni strain, suggesting that different intervention strategies will be required.
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Introduction |
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Campylobacter enteritis is usually an unpleasant but self-limiting disease where treatment is often limited to fluid and electrolyte replacement.5 Where antimicrobial therapy is indicated (for patients with high fever, bloody diarrhoea or more than eight stools a day; for patients whose symptoms have not lessened or are worsening at the time of diagnosis; or patients whose symptoms have persisted for more than a week6), the treatment of choice has tended to be erythromycin.7,8
The introduction of fluoroquinolones provided a suitable therapeutic alternative to erythromycin for adults with gastrointestinal symptoms because of their activity against most enteric pathogens.9 However, the emergence of resistance to fluoroquinolones has become a major public health problem worldwide.1014
The Campylobacter Sentinel Surveillance Scheme was launched on 1 May 2000.15 The overall aim of the scheme is to generate hypotheses for campylobacter infection systematically by the integration of standardized epidemiological and typing data. Twenty-two District Health Authorities, with a population of 12.5 million people, are collaborating in the scheme, which aims to capture standardized information on
15% of all laboratory-confirmed campylobacter infections in England and Wales. The health authorities are broadly representative of England and Wales as a whole.
This study focuses on data generated during the first year of the scheme, and aims to determine factors affecting the acquisition of a ciprofloxacin-resistant Campylobacter jejuni infection.
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Materials and methods |
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The combined data set was analysed using Stata version seven (Stata Corporation). Date of onset was used to define the season in which infection took place. Spring was defined as March to May, summer as June to August, autumn as September to November and winter as December to February. Standard occupational classification was employed to determine cases socio-economic group.20 Additional categories were created for individuals who described their occupation as unemployed, pre-school child, school child, student, homemaker, retired, part time, and for those who were unable to work because of disability or long-term illness. Food exposures were coded to compare those who had eaten a particular food in the 2 weeks prior to onset (once or more than once) with those who had not. Daily water consumption was coded to differentiate no exposure from one to four, five to nine and >10 glasses of water drunk. Patient age was arranged in 10 year age groups. Individuals with missing data were omitted from the analyses using those data.
For the casecase comparison, cases with a ciprofloxacin-resistant C. jejuni infection were designated a case, whereas those infected with a sensitive strain were designated a control. In order to control for the confounding effect of foreign travel,21,22 analysis was restricted to those cases who travelled abroad in the 2 weeks before illness and those who did not. For each data set, demographic and clinical differences were assessed using Pearsons 2 test and Students t-test. Initial comparisons were undertaken using single risk variable analyses. MantelHaenszel odds ratios (ORs) were calculated for each explanatory variable. Logistic regression was then applied to obtain maximum likelihood estimates of the effect of exposures on the outcome of interest whilst controlling for potential confounders. Variables with a P value of <0.1 from the single risk variable analysis were included initially. Step-wise exclusion was used to simplify the model: variables were removed one at a time and tested for significance using the likelihood ratio (LR) test. Potential interactions (between the main effects included in the initial logistic regression model and age, sex and season) were also examined using the LR
2 test.
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Results |
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Six hundred and fifty-three cases of C. jejuni infection (19%) reported travel outside the UK in the 2 weeks before the onset of illness, 2783 cases (80%) did not, and for 53 cases (2%) this information was not recorded. Cases of C. jejuni infection who reported foreign travel in the 2 weeks before the onset of symptoms were more likely to be infected with a ciprofloxacin-resistant strain (347/653; 53%) compared with those who did not (283/2783; 10%) [risk ratio (RR) 5.23; 95% confidence interval (CI) 4.585.96; P < 0.001]. This relationship was not observed with resistance to erythromycin (0.6% versus 0.7%; RR 0.81, 95% CI 0.282.36; P = 0.7).
Travel-associated C. jejuni cases
Over half (347; 53%) of the 653 travel-associated cases of C. jejuni were infected with a ciprofloxacin-resistant strain. One hundred and forty-eight (23%) were infected with a strain sensitive to all antimicrobials, and a further 158 cases (24%) were infected with a C. jejuni strain that was sensitive to ciprofloxacin but resistant to at least one other antimicrobial agent. The latter group of cases was excluded from further analysis. There was no difference between cases infected with ciprofloxacin-resistant strains and strains sensitive to all antimicrobials with regard to mean age (39.0 versus 38.0; t-test P = 0.57), gender (47% versus 49% male; 2 P = 0.37), mean length of illness (12.7 versus 13.5 days; t-test P = 0.56) or admission to hospital (both 6%;
2 P = 0.9).
Exposures associated with ciprofloxacin-resistant strains amongst travel-associated C. jejuni casessingle risk variable analysis (Table 1). Travel-associated cases who were infected with a ciprofloxacin-resistant strain of C. jejuni were more likely to have travelled to Spain or Portugal in the 2 weeks before illness than cases infected with a strain sensitive to all antimicrobials. They were also more likely to report the consumption of chicken, sausages or bottled water. They were less likely to have travelled to France or Africa, to report the consumption of baby food or mains water, and they were less likely to have had contact with animals.
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Exposures independently associated with ciprofloxacin-resistant strains amongst travel-associated C. jejuni caseslogistic regression analysis (Table 2). Cases infected with a ciprofloxacin-resistant strain of C. jejuni were more likely to have travelled to Spain, Portugal or Cyprus in the 2 weeks prior to illness than those cases infected with strains sensitive to all antimicrobials. They were more likely to report the consumption of chicken and bottled water. They were less likely to have consumed mains water, to have had contact with a pet bird or to have travelled to Africa.
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Amongst the 2783 cases who acquired their C. jejuni infection in the UK, 291 (10%) were infected with a ciprofloxacin-resistant strain and 1593 (56%) were infected with a strain sensitive to all antimicrobials. A further 952 cases were infected with a C. jejuni strain that was sensitive to ciprofloxacin but resistant to at least one other antimicrobial. These cases were excluded from further analysis. There was no difference between cases infected with ciprofloxacin-resistant strains and strains sensitive to all antimicrobials with regard to mean age (40.1 versus 37.9; t-test P = 0.12), gender (48% versus 50% male; 2 P = 0.62), mean length of illness (11.8 versus 11.2 days; t-test P = 0.66) or admission to hospital (14% versus 12%;
2 P = 0.39).
Exposures associated with ciprofloxacin-resistant strains amongst indigenous C. jejuni casessingle risk variable analysis (Table 3). Indigenous cases with a ciprofloxacin-resistant C. jejuni infection were more likely to be ill in the autumn or winter than cases infected with a strain sensitive to all antimicrobials, and were less likely to be ill in the summer. They were more likely to report the consumption of pre-cooked cold meats in the 2 weeks before illness and were less likely to have drunk water from a private supply.
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Exposures independently associated with ciprofloxacin-resistant strains amongst indigenous C. jejuni caseslogistic regression analysis (Table 4). Cases with a ciprofloxacin-resistant C. jejuni infection were more likely to report the consumption of pre-cooked cold meats in the 2 weeks prior to illness than those cases infected with strains sensitive to all antimicrobials. They were less likely to be ill in the summer or to report the consumption of water from a private supply.
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Discussion |
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Foreign travel remains an important risk factor for antimicrobial resistance,21,22 and travel to Spain, Portugal or Cyprus was independently associated with the acquisition of a ciprofloxacin-resistant strain. These findings have two implications. The first is that general practitioners need to ensure that they obtain accurate travel histories since, if antimicrobial treatment is necessary, ciprofloxacin would not now appear to be the treatment of choice in travellers returning from these countries. The second is that travellers to these destinations who might buy ciprofloxacin over the counter, such as at commercial travel clinic, for the treatment of travellers diarrhoea cannot be guaranteed that such treatment will work.
Foreign travel is a marker both for activities undertaken whilst abroad, and for differences in the incidence of resistance between countries. Restricting our analyses by travel status revealed different sets of risk exposures for acquiring a resistant C. jejuni strain at home and abroad, suggesting that different intervention strategies might be required.
The apparent association between the consumption of chicken and the acquisition of a ciprofloxacin-resistant C. jejuni infection amongst foreign travellers might point to the use of enrofloxacin in veterinary medicine and animal husbandry. Enrofloxacin has been used extensively in the broiler industry in the first week of life to reduce vaccination problems or in the third or fourth week of life to combat respiratory problems due to Escherichia coli.14 Its introduction into veterinary medicine in the Netherlands in 1987 was followed by the emergence of ciprofloxacin-resistant campylobacters in poultry products (14%) and man (11%) by 1989,13 and similar patterns have been observed in Spain24 and the USA.22 Rapid development and persistence of ciprofloxacin resistance in C. jejuni, with MICs increasing from 0.25 to 32 mg/L within the 5 day treatment time, has been shown following fluoroquinolone (sarafloxacin or enrofloxacin) treatment of broiler chickens.25 Enrofloxacin (and sarafloxacin) belongs to the same class of antimicrobials as ciprofloxacin, and selection of resistance to one drug leads to cross-resistance to the other.26 The lack of a similar association amongst home-acquired cases of C. jejuni infection might reflect the more stringent controls on the veterinary use of antimicrobials that exist in the UK compared with some other countries.27 Since the majority of poultry consumed in the UK is home produced28 the opportunity for human exposure to resistant campylobacters might be reduced.
The association between bottled water and the acquisition of a ciprofloxacin-resistant C. jejuni infection amongst travel-associated cases is striking. No interactions between this variable and age group, gender, season or any other variables included in the initial logistic regression model were observed. This, in conjunction with the relatively narrow CI surrounding the estimate of the OR, suggests that the effect is real. Current advice to overseas travellers states that bottled water (preferably carbonated with gas) in sealed containers should be used if the individual is in any doubt about the local water quality.29 We did not ask specific questions about the type of water drunk (sparkling or still) or whether it was consumed with or without ice, and therefore this hypothesis merits further investigation to assess whether this advice might require refinement.
An alternative explanation of the above finding is that the consumption of bottled water reduces the risk of acquiring a sensitive strain of C. jejuni. Those who routinely drink bottled water would be expected to have lower levels of exposure to pathogens found in mains water, and sensitive strains of C. jejuni were more commonly isolated from individuals who reported the consumption of mains water while abroad compared with those who did not.
Drinking mains water abroad or water from a private supply in England and Wales appeared to favour infection with sensitive C. jejuni strains, implying that many environmental campylobacters have not yet acquired resistance. In a study of 96 C. jejuni isolates from farm animals and the environment in the north west of England, most isolates exhibited a higher level of resistance than a National Collection of Type Cultures (NCTC) strain, but none had the high MICs of ciprofloxacin and erythromycin typically associated with clinical resistance.30 This reinforces the need for an agreed susceptibility testing method in order to make meaningful comparisons between microbiological results and their clinical significance. Furthermore, the question of the proportion of campylobacter infection attributable to water consumption, regardless of antimicrobial susceptibility, needs further study.
The consumption of pre-cooked cold meats amongst home-acquired cases of C. jejuni infection was independently associated with the acquisition of a ciprofloxacin-resistant strain. Cold cooked meats have been implicated in a recent epidemiological study of campylobacter infection in the USA.31 The researchers found that cases were more likely to report the recent consumption of chicken luncheon meat and ham than controls. However, there is no evidence in the literature to support the association between the consumption of cooked meats and a ciprofloxacin-resistant C. jejuni infection yet. As we did not ask specific questions about the types of meat consumed, or their country of origin, then this hypothesis warrants further investigation.
Antimicrobial prescribing in human medicine has probably contributed the most to the development of resistant bacteria.27 A limitation of our study is that our questionnaire did not include a question on current or recent treatment with antimicrobials. It is possible, therefore, that uncontrolled confounding might have occurred. However, our experience with self-completion questionnaires is that questions on treatment are often poorly answered, so the addition of this data would be of little benefit.
The exclusion of those cases infected with a C. jejuni strain that was sensitive to ciprofloxacin but resistant to at least one other unrelated antimicrobial merits further discussion. Since ciprofloxacin resistance is chromosomal11 the exclusion of these cases might be considered a waste of valuable data. However, it was deemed to be necessary to account for uncontrolled confounding.
The relationship between particular C. jejuni subtypes and ciprofloxacin resistance is beyond the scope of this paper. Investigations into the relationships between resistance, exposures and subtypes would have been prohibitively complicated because of the potential for chance interactions between exposure and subtype variables. A study investigating the relationships between resistance and Campylobacter subtype, based on the laboratory data collected through the surveillance scheme, is currently underway.
Casecase analysis proved a useful tool for generating hypotheses for acquisition of a ciprofloxacin-resistant C. jejuni infection. Restricting the analysis by foreign travel identified different potential risks both at home and abroad, leading to the possibility of risk reduction by targeted prevention. Similar analyses, based on other resistance markers, are planned, and these might add to our knowledge of sources or vehicles of antimicrobial-resistant infections. Determining the contributions of human and veterinary clinical practice, animal husbandry and environmental sources (including food) requires complementary public health surveillance activities across the entire spectrum.
Supplementary data
Supplementary data for this paper are available at www. jac.oupjournals.org.
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Acknowledgements |
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This paper was presented in part at the International Conference on Emerging Infectious Diseases, Atlanta, GA, USA, 2002.
The writing committee (and their contributions): Iain A. Gillespie (running the surveillance scheme/undertaking analyses/drafting the paper), Sarah J. OBrien (designing and establishing the surveillance scheme/drafting the paper), Jennifer A. Frost (designing and establishing the surveillance scheme/drafting the paper), Keith R. Neal (drafting the paper), David Tompkins (drafting the paper), John M. Cowden (drafting the paper), James Q. Nash (Director, Ashford Public Health Laboratory) (initiating this piece of work/drafting the paper), Goutam K. Adak (Consultant Epidemiologist, PHLS CDSC) (drafting the paper).
The Campylobacter Sentinel Surveillance Scheme Steering Committee: Mr A. Charlett (Head, PHLS Statistics Unit); Dr J. M. Cowden (Consultant Epidemiologist, Scottish Centre for Infection and Environmental Health); Mrs J. A. Frost (Head, Campylobacter Reference Unit, PHLS LEP); Mr I. A. Gillespie (Clinical Scientist, Gastrointestinal Diseases Division, PHLS CDSC), Ms J. Millward (Principal Environmental Health Officer, Birmingham City Council), Dr K. R. Neal (Senior Lecturer, Department of Epidemiology and Public Health, University of Nottingham), Dr S. J. OBrien (Head, Gastrointestinal Diseases Division, PHLS CDSC), Dr M. J. Painter (Consultant in Communicable Disease Control, Manchester Health Authority), Professor Q. Syed (Regional Epidemiologist, CDSC North West); Dr D. Tompkins (Director, Leeds Public Health Laboratory).
The Campylobacter Sentinel Surveillance Scheme Collaborators: public health, environmental health and laboratory staff who serve the populations of the following health authorities: Birmingham, Bradford, Bro Taf, Bury and Rochdale, Dyfed Powys, East Kent, Barnet, Enfield and Haringey, Herefordshire, Leeds, Leicestershire, Manchester, North Cumbria, North Essex, North West Lancashire, Nottingham, Salford and Trafford, South and West Devon, South Lancashire, Southampton and South West Hampshire, Stockport, West Pennine, Wigan and Bolton. In association with: PHLS LEP, Campylobacter Reference Unit; PHLS CDSC, Gastrointestinal Diseases Division and Regional Services Division; PHLS Statistics Unit.
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Footnotes |
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The Campylobacter Sentinel Surveillance Scheme Collaborators are listed in the Acknowledgements.
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