A population study of first exposure to community antibacterials in children and the suitability of routine urine samples for study of the acquisition of drug resistance

Douglas Steinke1, Alistair Emslie-Smith2, Paul Boyle3, Hilary Kay Young4, George Macfarlane5 and Peter Davey1,*

1 MEMO, Department of Clinical Pharmacology, Ninewells Hospital, University of Dundee, Dundee DD1 9SY; 2 General Practitioner, Red Wing, Wallacetown Health Centre, Dundee; 3 Department of Geography and Geosciences, University of St Andrews, St Andrews; 4 Division of Environmental and Applied Biology, School of Life Sciences, University of Dundee; 5 Department of Molecular and Cellular Pathology, University of Dundee, Dundee, UK

Received 14 January 2002; returned 20 June 2002; revised 15 August 2002; accepted 28 August 2002


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The study objectives were to measure time from birth to first exposure to antibacterials in children and compare the characteristics of children who submit urine samples with the general population. Antibacterials were dispensed to 63% of children within 1 year of birth, increasing to 75% within 2 years after birth. Boys had earlier exposure to antibacterials than girls. Children submitting urine samples were more likely to be socio-economically deprived, have prior exposure to antibacterials and have prior hospital admission. In conclusion, urine samples are unsuitable for a prospective cohort study of the relationship between antibacterial exposure and resistance in children.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Several studies have demonstrated an association between community antibacterial prescribing and resistance, but bias and confounding may obscure real associations or create apparent associations.1 Cohort studies identify incident colonization by drug-resistant bacteria and therefore help to minimize misclassification bias and confounding.1 The aims of this study were to quantify time to first exposure to antibacterials in the first 2 years of life and compare the characteristics of children from whom urine samples are submitted with the general population.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The study used record linkage of data about dispensed antibacterial prescribing, microbiology results and hospital discharges at the Medicines Monitoring Unit (MEMO).2

Study population

The study population comprised individuals from the Tayside region of Scotland who were resident in Tayside and registered with a general practitioner between January 1993 and December 1995. Urine sample data were obtained from the Department of Medical Microbiology at Ninewells Hospital, which has a catchment population of ~163 000 people.

Study subjects

The study included two analyses, a cohort study using all children born in Tayside in 1993 and measuring exposure to antibacterials in the 2 years following birth, and a case–control study comparing children who submitted a urine sample with the general population. Cases were children from Tayside aged 0–10 years who submitted urine samples or dip slides for culture and susceptibility to the Ninewells laboratory between January 1993 and December 1995. Each case was age–sex matched to two comparators from the general population who had not submitted urine samples.

The relationship between age and prevalence of trimethoprim resistance in Gram-negative bacteria from urinary samples was measured in samples submitted from subjects aged 0–40 and resident in Tayside from 1993 to 1995.

Definition of risk factors

Exposure to dispensed drugs or hospitalization. Subjects were defined as exposed to an antibacterial drug if they were dispensed any antibacterials listed in the British National Formulary (BNF) in sections 5.1.1 to 5.1.13 before the date of submission of the urine sample. Exposure to hospital admission was ascertained from the Scottish Morbidity Record for all acute hospitals in Tayside.

Socio-economic deprivation. Socio-economic status of the subjects was determined by small area postcodes derived from census data and analysed as Carstairs deprivation categories.2 Socio-economic deprivation was defined as being in category 6 or 7.

Statistical analysis

Kaplan–Meier statistics for the cohort study and odds ratios for the case–control study were calculated with SAS version 8 (SAS Institute Inc., Cary, NC, USA).


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In the cohort born in 1993, 63% of children were exposed to antibacterials within 1 year of birth and 75% by the age of 2. Males were exposed earlier (67% in the first year versus 60% of females, P < 0.01) and children from socio-economically deprived areas were exposed to antibacterials earlier than children from less deprived areas (75% versus 60% in the first year, P < 0.001).

Children who submitted urine samples were different from the general population of children aged 0–10 years (Table 1). They were more likely to be socio-economically deprived (OR 3.77; 95% CI 3.39–4.20), to have been exposed to antibacterials (OR 1.88; CI 1.70–2.07) or to have been hospitalized (OR 1.78; 95% CI 1.62–1.97).


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Table 1.  Comparison of children aged 0–10 years who submitted urine samples with two comparators per case, matched for age (to the nearest year) and sex
 
The relationship between age and resistance in urinary isolates was complex (Figure 1). Resistance increased with age up to 6 years, then declined with age until 20 years, then increased with age. Antibacterial exposure was highest in the first 2 years of life and decreased steadily thereafter (Figure 1). Data about resistance are only presented up to age 40 but rates of resistance remained similar up to age 70–79, then increased to 33% at age 80–89 and to 44% at age 90 or over.



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Figure 1. Relationship between age, antibiotic exposure and the prevalence of trimethoprim resistance in isolates from urine samples. Note: age is in 2 year bands up to the age of 10.

 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Most of the children in our cohort were exposed to antibacterials very rapidly after birth. These results are broadly similar to a recent study from Denmark in which 50% of children were exposed to one or more courses of antibacterials in each of the first 2 years of life.3 However, markedly higher rates of exposure to antibacterials were observed in a cohort from the USA: 79% by the age of 1, compared with 50% in our cohort and 93% by the age of 2, compared with 75% in our cohort.4 In both of these studies, as in our cohort, boys were exposed to antibacterials earlier than girls.3,4

We found that children from socio-economically deprived areas were exposed to antibacterials earlier than children from less deprived areas, whereas two previous studies reported that children from affluent areas were more likely to be exposed to antibacterials than children from deprived areas.5,6 However, both of these studies measured total exposure (e.g. number of prescriptions per 1000 inhabitants) rather than time to first exposure. Socio-economic deprivation is consistently associated with respiratory illness in general and particularly with acute respiratory infections, such as otitis media. Potential explanations include overcrowding,7 higher passive exposure to smoking8 and lower levels of breast-feeding.9 The fact that socio-economic class does influence exposure to antibacterials is a further reason for believing that epidemiological studies of resistance in urinary isolates may be biased or confounded, because in our study children who submitted urine samples were significantly more likely to be deprived than the general population.

There are limited data in the literature concerning the relationship between age and antibacterial resistance. Studies of the faecal microflora show high rates of resistance in children under the age of 10 but we have only identified one study that analysed resistance in 0–1 year olds.10 This showed that resistance was lower in <1 year olds than in 1–5 year olds, but was higher in 1–5 year olds than in 6–17 year olds. These data suggest that the complex relationship between age and resistance in urinary isolates from our patients (Figure 1) is likely to reflect changes in the faecal microflora. However, our results also show that children who submit urine samples differ from the general population (Table 1) and it would be preferable to undertake further studies on the faecal microflora of a more representative sample of the general population. It is plausible that the relationship between age and resistance in cross-sectional studies reflects changes in individuals over time. If so, this is probably due to intensive exposure to antibacterials in the first 2 years of life with a subsequent decline in resistance due to lower use of antibacterials by older children. This possibility could only be confirmed by a longitudinal study.


    Acknowledgements
 
The study was funded by a grant from TayRen: the Tayside Primary Care Research Network, and MEMO is part of the MRC Health Services Research Collaboration; the views expressed in this article are not necessarily those of the MRC HSRC.


    Footnotes
 
* Corresponding author. Tel: +44-1382-644144; Fax: +44-1382-642637; E-mail: peter{at}memo.dundee.ac.uk Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Steinke, D. & Davey, P. G. (2001). The association between antibiotic resistance and community prescribing: a critical review of bias and confounding in published studies. Clinical Infectious Diseases 33, S193–205.[ISI][Medline]

2 . Steinke, D. T., Seaton, R. A., Phillips, G., MacDonald, T. M. & Davey, P. G. (2001). Prior trimethoprim use and trimethoprim-resistant urinary tract infection: a nested case–control study with multivariate analysis for other risk factors. Journal of Antimicrobial Chemotherapy 47, 781–7.[Abstract/Free Full Text]

3 . Thrane, N., Olesen, C., Md, J. T., Sondergaard, C., Schonheyder, H. C. & Sorensen, H. T. (2001). Influence of day care attendance on the use of systemic antibiotics in 0- to 2-year-old children. Pediatrics 107, E76.[Medline]

4 . Bergus, G. R., Levy, S. M., Kirchner, H. L., Warren, J. J. & Levy, B. T. (2001). A prospective study of antibiotic use and associated infections in young children. Paediatric and Perinatal Epidemiology 15, 61–7.[ISI][Medline]

5 . Henricson, K., Melander, E., Molstad, S., Ranstam, J., Hanson, B. S., Rametsteiner, G. et al. (1998). Intra-urban variation of antibiotic utilization in children: influence of socio-economic factors. European Journal of Clinical Pharmacology 54, 653–7.[ISI][Medline]

6 . Hofmann, J., Cetron, M., Farley, M. M., Baughman, W. S., Facklam, R. R., Elliot, A. J. et al. (1995). The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta. New England Journal of Medicine 333, 481–6.[Abstract/Free Full Text]

7 . Rees Jones, I., Urwin, G., Feldman, R. A. & Banatvala, N. (1997). Social deprivation and bacterial meningitis in North East Thames region: three year study using small area statistics. British Medical Journal 314, 794–5.[Free Full Text]

8 . Spitzer, W. O., Lawrence, T., Dales, R., Hill, G., Archer, M. C., Clark, P. et al. (1990). Links between passive smoking and disease: a best-evidence synthesis. Clinical Investigative Medicine 13, 17–42.

9 . Howie, P. W., Forsyth, J. S., Ogston, S. A., Clark, A. & Florey, C. D. (1990). Protective effect of breast feeding against infection. British Medical Journal 300, 11–6.[ISI][Medline]

10 . Degener, J. E., Smit, A. C., Michel, M. F., Valkenburg, H. A. & Muller, L. (1983). Faecal carriage of aerobic Gram-negative bacilli and drug resistance of Escherichia coli in different age-groups in Dutch urban communities. Journal of Medical Microbiology 16, 139–45.[Abstract]