a Medicines Monitoring Unit (MEMO), Department of Clinical Pharmacology and Therapeutics, Level 7, Ninewells Hospital, Dundee DD1 9SY; b Department of Medical Microbiology, Ninewells Hospital, Dundee DD1 9SY, UK
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Abstract |
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Introduction |
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Trimethoprim or trimethoprim/sulphamethoxazole are the drugs most commonly recommended as first-line treatment for uncomplicated cystitis.35 In developing countries >80% of bacteria causing urinary tract infections are now resistant to these drugs.69 In developed countries <30% of urinary isolates are resistant to trimethoprim, but rates of resistance have been increasing in these and other human pathogens.10,11 Information linking rates of prescribing of trimethoprim to the prevalence of trimethoprim resistance are inconsistent,1215 and it has been suggested that many of the community isolates may have originated from a hospital source.16
We performed a pilot study that linked individual patient data about dispensed prescribing from community pharmacies to the results of microbiology tests on samples submitted from the community.17 This showed that trimethoprim resistance was associated with previous exposure to trimethoprim, but was also associated with previous hospitalization and exposure to oestrogen. We now report the results of a much larger study that was designed to allow multivariate analysis of the relative contribution of multiple risk factors and to exclude patients with multiple urine samples, who are an important source of bias in studies of the prevalence of antibiotic resistance.18
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Patients and methods |
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Study design
The study compared exposure to antibiotics and other risk factors in a cohort of subjects who submitted urine cultures with significant growth (>104105 cfu/mL) of Gram-negative trimethoprim-resistant organisms with a cohort of subjects who submitted urine cultures with significant growth of Gram-negative trimethoprim-susceptible organisms.
The primary exposure variables, prior exposure to trimethoprim and prior exposure to any other antibiotic, were adjusted for other possible risk factors. These were available for all subjects in the analysis and included age, sex, socio-economic status, type of bacteria isolated, diabetes mellitus,20 corticosteroid21 and oestrogen21 therapy. In addition, data on prior hospitalizations were available.
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 Ninewells Hospital catchment area with a total study population of approximately 163 000 people.
Study subjects
All subjects in Tayside who submitted urine samples or dip slides for culture and susceptibility (disc susceptibility test using Stokes' method) in the study period of January 1993 to December 1995 were possible study subjects. Subjects with incident urine samples were determined by eliminating the subjects who submitted samples in the first 6 months of the study period (January 1993 to June 1993, inclusive). The first sample submitted after 30 June 1993 was considered a subject's incident sample and was used in the analysis of exposure and risk factors. Subjects were then divided into those whose urinary isolates were resistant to trimethoprim (the resistant cohort) and those whose urinary isolates were susceptible to trimethoprim (the susceptible cohort) on the basis of a disc test. Subjects with no significant growth in their urine sample were not included. Catheter samples and samples not tested for trimethoprim were also excluded from the study.
Definition of risk factors
Community exposure to dispensed drugs.
Subjects were defined as exposed to an antimicrobial drug if they were dispensed any antibiotics listed in the British National Formulary (BNF)22 in Chapters 5.1.15.1.13 in the 180 days preceding the date of submission of the urine sample. Exposure to trimethoprim was analysed separately. Exposure to an antimicrobial drug between 0 and 3 days before the submission of a urine culture was considered non-exposed, because it was unclear whether the sample was collected before consumption of antibiotics or vice versa.
Since the use of certain other drugs has been associated with an antimicrobial, data on these other drugs were extracted from the databases and used in the analysis as possible risk factors. These were: exposure to oral corticosteroids defined as a drug listed in the BNF in Chapter 6.3, but excluded inhaled corticosteroids; exposure to hormone replacement therapy (HRT) defined as a drug listed in the BNF in Chapter 6.4.1; and exposure to oral contraceptives (OCP) defined as a drug listed in the BNF in Chapter 7.3. Subjects were considered exposed to the above drug groups if a prescription was dispensed at any time in the 180 days before urine sample submission.
Hospitalizations.
Hospitalization for any reason in the 180 days before submission of urine sample was defined as a risk factor.
Socio-economic status.
The socio-economic status of subjects was determined by small area postcodes derived from census data and analysed as Carstairs deprivation categories.23 The seven unequal deprivation categories range from deprivation category 1 (most affluent) to deprivation category 7 (least affluent). Deprivation categories 6 and 7 were combined because of low numbers of subjects.
Diabetes mellitus.
Patients with diabetes mellitus were identified using DARTS, a validated register of all patients with diabetes in Tayside, Scotland.24
Data analysis
Cohort risk factors were assembled and odds ratios were calculated with 95% confidence intervals (CIs) using the statistical package SAS (version 6.12, SAS Institute Inc., Cary, NC, USA). Logistic regression fitted continuous and categorical data to find significant predictor variables associated with an increased likelihood of infection with trimethoprim-resistant bacteria.25 The logistic model was calculated in the forward direction with variables entering the model at <5% significance and exiting the model when significance was >5%.
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Results |
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Discussion |
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Hospitalized patients are much more likely to be colonized with trimethoprim-resistant bacteria than subjects in the community.27,28 Because of the close genetic homology between resistant isolates from hospital and community, it has been suggested that many of the community isolates may have originated from a hospital source.16
Within-hospital studies of the relationship between antibiotic prescribing and resistance have been hindered by difficulties in defining terms, selection biases, artefacts produced by study methods and failure to control for confounding variables.29,30 Previous studies of the relationship between trimethoprim prescribing and resistance in the community have suffered from similar methodological problems. Some studies of prescribing within whole populations12,13 have not had access to data about individual patients, and have therefore been unable to exclude patients with multiple urine samples, who are an important source of bias.18 The most recent population-based study was able to exclude multiple urine samples;26 however, the association between antibiotic prescribing and resistance may be confounded by other variables that cannot be investigated without additional data about individual patients.30 The only previous studies that did have information about prescribing and resistance within individual patients suffered from selection bias, being confined to children attending a day care centre14 or patients hospitalized with bacteraemia.15 Our study is the first multivariate analysis of potential risk factors for trimethoprim resistance using data about individual patients from an entire population. We have shown that trimethoprim resistance is strongly associated with prior exposure to trimethoprim in the community, as well as with exposure to other antibiotics. Prior exposure to hospital was significantly associated with trimethoprim resistance in a univariate analysis but not in the multivariate analysis, indicating that hospitalization was confounded by other risk factors and should not be considered independent.
In our study, 35% of patients with infections caused by trimethoprim-resistant bacteria had not been exposed to trimethoprim, other antibiotics or hospitalization in the previous 6 months, indicating that resistance can emerge or persist independently of these risk factors. Family members of subjects infected with trimethoprim-resistant bacteria have a higher risk of colonization by trimethoprim-resistant bacteria than family members of uninfected control subjects.31 Intrafamilial spread of drug resistance has also been demonstrated for Streptococcus pyogenes32 and coagulase-negative staphylococci.33 Intrafamilial spread of drug resistance could be due to transfer of genetic information between bacteria as well as cross infection of household contacts by drug-resistant bacteria.34 Trimethoprim resistance is encoded by plasmids, which are highly transferable between bacteria.35,36
Travel is an additional potential mechanism for acquisition of drug-resistant bacteria or genetic determinants of resistance.37 Stool samples were obtained from 13 individuals before, during and after travel to Mexico. None of these individuals took prophylactic antibiotics, although four of 13 took short courses of an antimicrobial agent for therapy of traveller's diarrhoea. No trimethoprim-resistant E. coli isolates were found by this method before travel, whereas 57% of the individuals had trimethoprim- and co-trimoxazole-resistant E. coli by the final week in Mexico. This increase in resistance occurred regardless of whether an individual took a short course of antimicrobial therapy. The most likely source of drug-resistant bacteria is food, which may contain strains of E. coli that are multiply drug resistant but are not enterotoxigenic.38
We have shown that infection with trimethoprimresistant bacteria is strongly associated with prior exposure to trimethoprim. However, exposure to antibiotics other than trimethoprim was also independently associated with trimethoprim resistance in our study and in a recent study from Wales.26 This suggests that a reduction in the use of trimethoprim alone may not reduce the prevalence of trimethoprim resistance. Streptomycin resistance has persisted in hospitals, despite the fact that streptomycin has been virtually unused for over 20 years, probably because streptomycin resistance is linked to other genes that have different selective pressures.39 It is also likely that decay in the prevalence of drug-resistant bacteria will occur slowly after reduction in overall use of antibiotics.40 Nonetheless, we have provided prescribers and the public with further evidence to show that exposure to antibiotics in the community does increase the prevalence of drug-resistant bacteria. This new information endorses the recommendation that every effort should be made to minimize unnecessary use of antibiotics in the community.2
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Acknowledgments |
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Notes |
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References |
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2 . Hart, M., Livermore, D. M. & Weinberg, J. R. (1998). In The Path of Least Resistance, pp. 1152. Standing Medical Advisory Committee Sub-Group on Antimicrobial Resistance. Department of Health, London.
3 . Anonymous. (1998). Managing urinary tract infection in women. Drug and Therapeutics Bulletin 36, 302.[Medline]
4 . Hooton, T. M., Winter, C., Tiu, F. & Stamm, W. E. (1995). Randomized comparative trial and cost analysis of 3 day antimicrobial regimens for treatment of acute cystitis in women. Journal of the American Medical Association 273, 415.[Abstract]
5 . Tice, A. D. (1999). Short-course therapy of acute cystitis: a brief review of therapeutic strategies. Journal of Antimicrobial Chemotherapy 43, Suppl. A, 8593.[ISI][Medline]
6 . Amyes, S. G. B., Tait, S., Thompson, C. J., Payne, D. J., Nandivada, L. S., Jesudason, M. V. et al. (1992). The incidence of antibiotic resistance in aerobic faecal flora in South India. Journal of Antimicrobial Chemotherapy 29, 41525.[Abstract]
7 . Bartoloni, A., Cutts, F., Leoni, S., Austin, C. C., Mantella, A., Guglielmetti, P. et al. (1998). Patterns of antimicrobial use and antimicrobial resistance among healthy children in Bolivia. Tropical Medicine and International Health 3, 11623.[Medline]
8 . Lamidanra, A. & Ndep, R. B. (1989). Trimethoprim resistance in urinary tract pathogens in two Nigerian hospitals. Journal of Antimicrobial Chemotherapy 23, 1514.[Abstract]
9 . Urassa, W., Lyamuya, E. & Mhalu, F. (1997). Recent trends on bacterial resistance to antibiotics. East African Medical Journal 74, 12933.[ISI][Medline]
10
.
Gupta, K., Scholes, D. & Stamm, W. E. (1999). Increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in women. Journal of the American Medical Association 281, 7368.
11 . Harnett, N. M. (1991). Increasing incidence of resistance among shigellae to trimethoprim. Lancet 337, 622.
12 . Huovinen, P., Renkonen, O. V., Pulkkinen, L., Sunila, R., Gronroos, P., Klossner, M. L. et al. (1985). Trimethoprim resistance of Escherichia coli in outpatients in Finland after ten years' use of plain trimethoprim. Journal of Antimicrobial Chemotherapy 16, 43541.[Abstract]
13 . Raz, R., Hefter, H., Oren, B., Kennes, Y. & Potasman, I. (1993). Antimicrobial resistance of urinary isolates in the community and its relation to antibiotic use. Israeli Journal of Medical Science 29, 2079.
14 . Reves, R. R., Fong, M., Pickering, L. K., Bartlett, A., Alverez, M. & Murray, B. (1990). Risk factors for fecal colonization with trimethoprim-resistant and multiresistant Escherichia coli among children in day-care centers in Houston, Texas. Antimicrobial Agents and Chemotherapy 34, 142934.[ISI][Medline]
15
.
Pedersen, G., Schonheyder, H. C., Steffensen, F. H. & Sorensen, H. T. (1999). Risk of resistance related to antibiotic use before admission in patients with community-acquired bacteraemia. Journal of Antimicrobial Chemotherapy 43, 11926.
16 . Kraft, C. A., Platt, D. J. & Timbury, M. C. (1985). Trimethoprim resistance in urinary coliforms from patients in the community: plasmids and R-transfer. Journal of Antimicrobial Chemotherapy 15, 3117.[Abstract]
17
.
Steinke, D. T., Seaton, R. A., Phillips, G. A., MacDonald, T. M. & Davey, P. G. (1999). Factors associated with trimethoprim-resistant bacteria isolated from urine samples. Journal of Antimicrobial Chemotherapy 43, 8413.
18 . Huovinen, P. (1985). Recording of antimicrobial resistance of urinary tract isolates effect of repeat samples on resistance levels. Journal of Antimicrobial Chemotherapy 16, 4437.[Abstract]
19 . Evans, J. M. M., McDevitt, D. G. & MacDonald, T. M. (1995). The Tayside Medicines Monitoring Unit (MEMO): a record-linkage system for pharmacovigilance. Pharmaceutical Medicine 9, 17784.
20 . Critchley, J. A. J., Chan, T. Y. K. & Cumming, A. D. (1997). Renal Diseases. In Avery's Drug Treatment, 4th edn, (Speight, T. M. & Holford, N. H. G., Eds), pp. 1067112. Adis International Limited, Auckland.
21 . Yancey, M. K. (1992). Host defenses and bacterial resistance. Orthopedic Clinics of North America 19, 41333.
22 . Joint Formulary Committee. (1997). British National Formulary. British Medical Association and Royal Pharmaceutical Society of Great Britain, London.
23 . McLoone, P. (1994). Carstairs Codes for Scottish Postcode Sectors from the 1991 Census. Public Health Research Unit, University of Glasgow, Glasgow.
24 . Morris, A. D., Boyle, D., McAlpine, R., Emslie-Smith, A., Jung, R. T., Newton, R. W. et al. (1997). The Diabetes Audit and Research in Tayside Scotland (DARTS) Study: electronic record linkage to create a diabetes register. British Medial Journal 315, 5248.
25 . Hosmer, D. W. & Lemeshow, S. (1989). Applied Logistic Regression. John Wiley & Sons, New York.
26
.
Magee, J. T., Pritchard, E. L., Fitzgerald, K. A., Dunstan, F. D. J. & Howard, A. J. (1990). Antibiotic prescribing and antibiotic resistance in community practice: retrospective study, 19968. British Medical Journal 319, 123940.
27 . Leistevuo, T., Toivonen, P., Osterblad, M., Kuistila, M., Kahra, A., Lehtonen, A. et al. (1996). Problem of antimicrobial resistance of fecal aerobic Gram-negative bacilli in the elderly. Antimicrobial Agents and Chemotherapy 40, 2399403.[Abstract]
28 . Young, H. K. & Hillyear, J. K. (1994). Trimethoprim resistance in urinary pathogens in northern Scotland; epidemic spread of a resistance plasmid encoding the type Ib trimethoprim-resistant dihydrofolate reductase. Journal of Medical Microbiology 41, 3438.[Abstract]
29 . McGowan, J. E. (1983). Antimicrobial resistance in hospital organisms and its relation to antibiotic use. Reviews of Infectious Diseases 5, 103348.[ISI][Medline]
30
.
Carmeli, Y., Samore, M. H. & Huskins, W. C. (1999). The association between antecedent vacomycin treatment and hospital- acquired vancomycin-resistant Enterococci: a meta-analysis. Archives of Internal Medicine 159, 24618.
31 . Rydberg, J. & Cederber, A. (1986). Intrafamilial spreading of Escherichia coli resistant to trimethoprim. Scandinavian Journal of Infectious Diseases 18, 45760.[ISI][Medline]
32 . Gamba, M. A., Martinelli, M., Schaad, H. J., Steuli, R. A., DiPersio, J., Matter, L. et al. (1997). Familial transmission of serious disease-producing group A Streptococcus clone: case reports and review. Clinical Infectious Diseases 24, 111821.[ISI][Medline]
33 . Miller, Y. W., Eady, E. A., Lacey, R. W., Cove, J. H., Joanes, D. N. & Cunliffe, W. J. (1996). Sequential antibiotic therapy for acne promotes the carriage of resistant Staphylococci on the skin of contacts. Journal of Antimicrobial Chemotherapy 38, 82937.[Abstract]
34 . Saunder, N. J., Hood, D. W. & Moxon, E. R. (1999). Bacterial evolution: bacteria play pass the gene. Current Biology 9, R180 R183.[ISI][Medline]
35 . Harnett, N. (1992). Transferable high-level trimethoprim resistance among isolates of Escherichia coli from urinary tract infections in Ontario, Canada. Epidemiology of Infection 109, 47381.
36 . Nijsten, R., London, N., van den Bogaard, A. & Stobberingh, E. (1995). In-vivo tansfer of resistance plasmids in rat, human or pig-derived intestinal flora using a rat model. Journal of Antimicrobial Chemotherapy 36, 97585.[Abstract]
37 . Murray, B. E., Mathewson, J. J., DuPont, H. L., Ericsson, C. D. & Reves, R. R. (1990). Emergence of resistant fecal Escherichia coli in travellers not taking prophylactic antimicrobial agents. Antimicrobial Agents and Chemotherapy 34, 5158.[ISI][Medline]
38 . Wood, L. V., Morgan, D. R. & DuPont, H. L. (1983). Antimicrobial resistance of Gram-negative bacteria isolated from foods in Mexico. Journal of Infectious Diseases 148, 766.[ISI][Medline]
39 . Chiew, Y. F., Yeo, S. F., Hall, L. M. C. & Livermore, D. M. (1998). Can susceptibility to an antimicrobial be restored by halting its use? The case of streptomycin versus Enterobacteriaceae. Journal of Antimicrobial Chemotherapy 41, 24751.[Abstract]
40 . Austin, D. J., Kristinsson, K. G. & Anderson, R. M. (1999). The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance. Proceedings for the National Academy of Sciences, USA 96, 11526.
Received 22 November 1999; returned 23 March 2000; revised 7 June 2000; accepted 19 March 2001