a National Institute of Public Health and the Environment, PO Box 1, 3720 BA Bilthoven and Public Health Laboratories at b Enschede, c Tilburg, d Rotterdam, e Goes and f Nijmegen, The Netherlands
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Abstract |
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Introduction |
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In this article we report on the development of resistance to fluoroquinolones in E. coli isolates from UTI in The Netherlands. Data from a sentinel surveillance programme, which collected data on resistance from five laboratories from 1989 to 1998, were combined with data on prescription of fluoroquinolones in the community in order to investigate whether patterns of resistance correlate with trends in the prescription of these antibiotics.
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Materials and methods |
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During the study period, 198998, five regional public health laboratories in The Netherlands (Rotterdam, Nijmegen, Goes, Tilburg and Enschede) forwarded all routine data on the occurrence of E. coli, including antibiotic susceptibility data, to the National Institute of Public Health and the Environment. These laboratories cover approximately 14% of the Dutch population (15.4 million inhabitants in 1994). They tested >75% of the E. coli isolates for resistance to amoxycillin, trimethoprim, nitrofurantoin and norfloxacin. Only E. coli isolates from urine were included. Repeat isolates of E. coli from the same patient taken within 2 months were ignored. Detailed information on the number of prescriptions and defined daily doses (DDDs) prescribed in the community (including nursing homes and outpatient clinics; excluding inpatient clinics) was obtained for fluoroquinolones, nitrofuran derivatives, trimethoprim and co-trimoxazole (sulphamethoxazole and trimethoprim) from the Drug Information Project of the Supervising Board for Health Care Insurance in The Netherlands, Amstelveen (199297). Information on the incidence of UTI was obtained from a sentinel GP surveillance system in the east of The Netherlands (Nijmegen and surroundings).
The incidence of UTI was used to investigate whether there was a link between the number of prescriptions and the incidence of resistance on the basis of groups stratified by age and gender. Data from a sentinel GP surveillance system indicated that the incidence of UTI was lower in younger age groups than in older age groups, resulting in a relatively low prescription rate of antibiotics for treatment of UTI. So, in order to link prescription to resistance directly, the number of prescriptions (DDD/1000 medically insured) was divided by the incidence (UTI/1000 person-years), giving the number of prescriptions per case of UTI (DDD/case UTI).
Laboratory methods
Susceptibility test results were interpreted with reference to breakpoints published by the Dutch Committee on Susceptibility Testing Guidelines.8 The breakpoints for resistance were: 64 mg/L for amoxycillin and nitrofurantoin, and
16 mg/L for trimethoprim and norfloxacin. Sensitivity testing methods were not standardized.
Statistical methods
Analyses were performed with SAS software, version 6.12 (SAS Institute, Cary, NC, USA). The percentage of norfloxacin-resistant E. coli was univariately compared for independent variables, such as year of isolation, age of patient, source of isolate (laboratory), origin of the patient (general practice, nursing home, inpatient or outpatient clinic). Using multivariate, logistic regression, the relative risks for the dependent variable, resistance to norfloxacin, were estimated for the independent variables.
Because of cross-resistance between norfloxacin and other fluoroquinolones used for therapy of UTI, such as ciprofloxacin and ofloxacin, it is justifiable to compare norfloxacin resistance (as a marker for fluoroquinolone resistance) with the total prescription of fluoroquinolones. Separate strata for year of isolation, gender and age were used to study the associations between resistance to norfloxacin (excluding samples from inpatient clinics) and prescription of fluoroquinolones, nitrofuran derivatives and trimethoprim with or without sulphamethoxazole.
Linear regression curves were fitted using prescription rate as the independent variable and resistance as the dependent variable. The prescription rate, measured in DDD, was adjusted for the incidence of urinary tract infection in the different age groups (averaged for 6 years (199297) for every age group), resulting in DDD/case UTI.
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Results |
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A total of 91 669 E. coli isolates were available for analysis; of these, 2232 were resistant to norfloxacin, 23 226 to trimethoprim, 4726 to nitrofurantoin and 31 903 to amoxycillin. Resistance to trimethoprim and norfloxacin had increased steadily over the study period, whereas resistance to amoxycillin and nitrofurantoin had remained constant (Table I). The increase in norfloxacin resistance was associated with an increase in multiresistance, defined as resistance to norfloxacin and to at least two of the other three antibiotics (Table I
).
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Multivariate analysis showed that the increase in norfloxacin resistance over time was independent of other risk factors, such as age, gender, laboratory and origin of the patient. The effects of age, gender and patient's origin on norfloxacin resistance were not influenced by the location of the laboratories (Table II). However, the effect of age on resistance was strongly determined by gender; in male patients, resistance to norfloxacin was already high in younger age groups, in contrast to the corresponding age groups in female patients (Table II
).
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Data from the Drug Information Project of the Supervising Board for Health Care Insurance in The Netherlands (GIP/CVZ), Amstelveen, indicated that the prescription of fluoroquinolones had doubled from 1990 onwards (Table III). In contrast, the prescription of nitrofuran derivatives (mainly nitrofurantoin), and trimethoprim with or without sulphamethoxazole had decreased in this period (Table III
).
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Linear regression of the association between prescription rate in DDD/case UTI for fluoroquinolones, nitrofuran derivatives and trimethoprim/co-trimoxazole and resistance to norfloxacin revealed a significant association only between norfloxacin resistance and the prescription of fluoroquinolones (P < 0.002). Prescription of nitrofuran derivatives (P > 0.1) and trimethoprim with or without sulphamethoxazole (P > 0.3) was not significantly associated with norfloxacin resistance. Figure 2 depicts the relationship between norfloxacin resistance and fluoroquinolone usage.
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Discussion |
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Univariate and multivariate analyses indicated a consistent increase in norfloxacin resistance over time; this increase was not associated with age, gender, laboratory or origin of the patient (see Table II). Many of the norfloxacin-resistant strains were also resistant to two of the three other antibiotics tested (amoxycillin, trimethoprim and nitrofurantoin). We did not observe a significant increase in the strains resistant only to norfloxacin. This could indicate that, until now, norfloxacin has been prescribed only as a second-choice medication for patients in whom treatment with the antibiotics of first choice (trimethoprim or nitrofurantoin) has failed. However, we cannot exclude the possibility that this multiple resistance developed from selection of genetically linked resistance genes.
The incidence of resistance differed among laboratories, perhaps owing to different testing methods. However, the trend towards increasing resistance was demonstrated in every participating laboratory (Figure 1a). A multivariate logistic regression model did not reveal significant interaction between laboratory and year of sample collection (Table II
), indicating that the trend to increased norfloxacin resistance was not a result of, for instance, changes in laboratory methods.
Data from the multivariate model (Table II) also indicated that gender strongly influenced the effect of age on fluoroquinolone resistance, probably on account of the different nature of UTI in males and females. In female patients uncomplicated cystitis is most common, wherease in male patients complicated UTIs are more common.11,12 Males with UTI may receive prolonged therapy with fluoroquinolones, which may explain the relatively high resistance to fluoroquinolones in isolates from young male patients. Our model did not demonstrate a strong interaction between effects of origin and age on resistance to norfloxacin. This may indicate that age and origin independently affect the risk of resistance to norfloxacin. It is, however, difficult to estimate the exact contributions of age, gender and origin on norfloxacin resistance, because the method by which isolates are selected differs between general practice, nursing homes and outpatient and inpatient clinics. The increased resistance in older age groups (mainly female) might result from increased cumulative lifetime exposure in the older patients,13 or to a more complicated nature of the UTI more obviously warranting prescription of fluoroquinolones, or to the recent increase in fluoroquinolone prescription, especially for older patients.
Currently there are no indications that fluoroquinolones are prescribed regularly for respiratory infections in The Netherlands. Thus, this group of antibiotics is still most often used for the therapy of UTI. Prescription of fluoroquinolones nearly doubled from 1990 to 1997. In contrast, prescription of nitrofuran derivatives (mainly nitrofurantoin) and trimethoprim/co-trimoxazole decreased over the study period. This indicates that not only GPs, but also physicians in nursing homes and outpatient clinics, are prescribing fluoroquinolones for UTI increasingly frequently. However, it is not clear whether they prescribe these antibiotics as first-, second- or third-choice for UTI.
A comparison of the trend in norfloxacin resistance and the rates of prescription for fluoroquinolones, nitrofuran derivatives and trimethoprim/co-trimoxazole indicated a significant relationship only between norfloxacin resistance and fluoroquinolone prescription. This suggests that increased prescription of fluoroquinolones may be the driving selection force leading to increased norfloxacin (fluoroquinolone) resistance in E. coli in the community. A recent casecontrol study showed that increased resistance to trimethoprim in Gram-negative bacteria isolated from urine samples14 is associated primarily with the increased use of this antibiotic and not with the use of other antibiotics. In two other hospital casecontrol studies, resistance to fluoroquinolones in Gram-negative bacteria from nosocomial infections15 or in E. coli isolated from bacteraemia16 was strongly associated with prescription of this group of antibiotics. In these studies, too, associations with the use of other antibiotics were not significant.1416 Thus, our study indicates that resistance to norfloxacin in the community is only associated with the prescription of fluoroquinolones, and not with that of other antibiotics.
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Acknowledgments |
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Notes |
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References |
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Received 20 October 1999; returned 20 January 2000; revised 18 February 2000; accepted 27 March 2000