Community-acquired antibiotic resistance in urinary isolates from adult women in Canada

SMX) is recommended as first-line empirical treatment for acute cystitis in adult women in North America, where resistance of Escherichia coli to TMP-SMX is less than 20% (1,2). TMP-SMX resistance has increased over time (3,4), with a resulting shift toward the use of other antibiotics for acute cystitis, including fluoroquinolones (5,6). There is concern that this may promote the more rapid emergence of fluoroquinoloneresistant uropathogens and reduce the effectiveness of fluoroquinolones in treating more serious infections (7,8). Trying to determine the rate of TMP-SMX resistance in community-acquired cases of acute cystitis has been problematic. Widely varying rates of resistance have been reported in different countries (9) and from different regions within the same country (4). In Canada, a study of outpatients attending tertiary care hospitals found that 19% of E coli isolates were resistant to TMP-SMX; however, the study included men and children (10). Two other community-based studies found that 8% (11) and 11% (12) of E coli isolates were resistant to TMPSMX. We conducted a national study of community-acquired


METHODS
Canadian laboratories providing microbiology services were contacted by mail in 2004.Some laboratories had participated in a previous study (12), while others were identified from Health Canada and Internet listings of commercial laboratories.A faxback form was provided to indicate interest in participation or a request for additional information.Two follow-up reminder letters were sent to nonresponders.
Each laboratory was asked to provide 100 recent urine culture and susceptibility reports positive for significant bacterial growth by their usual criteria.They were asked to limit reports to those submitted from family physicians' offices, and to exclude nursing homes, hospitalized patients and hospital outpatient departments.Only one report per patient was included.The culture report provided the patient age, sex, and city and province of residence.Where no patient address was provided, the laboratory address was used.Patient names were removed from reports.The organism, colony count and antibiotic susceptibility was determined from the reports.Organisms with intermediate susceptibility were considered susceptible.The analysis was limited to adult women 16 years of age and older.
Categorical variables were described using frequencies and compared with χ 2 testing (STATA Release 6.0, StataCorp, USA).A wide range of oral and parenteral antibiotic susceptibilities were reported.Antimicrobial resistance were determined to be 'any resistance' (resistance to at least one antibiotic reported) or 'multidrug resistance' (resistance to two or more antibiotics reported).In assessing regional differences, the analysis was limited to four antibiotic classes (ampicillin, TMP-SMX, fluoroquinolones and nitrofurantoin).Multiple logistic regression was used to control for age and other differences between regions.Ethics approval was obtained from the Mount Sinai Hospital Research Ethics Board.

RESULTS
Of the 43 laboratories contacted, 21 (48.8%)provided urine culture reports for 2199 women from across Canada (Table 1).All cultures were obtained in 2004.The majority of reports were from Ontario, Nova Scotia and British Columbia.No reports were received from Alberta.Because of the small numbers of isolates from some provinces, adjacent provinces were grouped together into regions to examine regional variations in resistance.Quebec was excluded from the regional analysis because too few reports were received.Community-based laboratories provided all of the reports from Ontario, while hospital laboratories provided all of the reports from the eastern provinces.The mean age of women was 55.2 years (range 16 to 100 years), with most women older than 50 years of age.
The Resistance increased with age, and there was a trend toward higher levels of antibiotic resistance in the western provinces (P=0.045).Multidrug resistance was highest in British Columbia (170 of 451 [37.7%]) compared with the rest of Canada (465 of 1667 isolates [27.9%];P<0.001).After adjusting for differences in patient age and organism distribution among the regions, antibiotic resistance remained higher in British Columbia (adjusted OR 1.30, 95% CI 1.03 to 1.63) than in other regions, as did multidrug resistance (adjusted OR 1.60, 95% CI 1.28 to 1.99).
Regional variations in E coli antibiotic resistance were found for TMP-SMX and fluoroquinolones (Table 2).TMP-SMX resistance reached the 20% threshold (suggested by the Infectious Diseases Society of America for consideration of alternative first-line agents for empirical treatment [1]) in British Columbia, and approached this level in Ontario.TMP-SMX-resistant E coli were also more common in women 50 to 64 years of age (52 of 291 [ Regional variations in fluoroquinolone resistance were also seen, with significantly higher levels of resistance in British Columbia (P<0.001).Fluoroquinolone resistance increased with age, with 22 of 712 (3.1%) E coli isolates resistant to fluoroquinolones in women 16 to 49 years of age, 20 of 283 (7.1%) isolates in women 50 to 64 years of age, and 65 of 562 (11.6%) isolates in women 65 years of age and older (P<0.001).Resistance ranged from a low of 1.1% (three of 267) in women 16 to 49 years of age in eastern provinces to a high of 24.3% (36 of 148) in women 65 years of age and older from British Columbia (P<0.001;Fisher's exact test).Results were similar when the analysis was repeated using ciprofloxacin instead of all fluoroquinolones.After controlling for age, fluoroquinolone resistance remained higher in British Columbia than elsewhere in Canada (adjusted OR 3.88, 95% CI 2.57 to 5.84).
Although culture reports came from 18 different communities in British Columbia, 80% came from two communities.The rate of fluoroquinolone-resistant E coli was lower in the two communities (38 of 278 [13.7%]) than in the remaining 16 communities combined (16 of 63 [25.4%];P=0.02), indicating that the high rate of fluoroquinolone resistance in British Columbia was not due to a few communities with high resistance levels.To exclude the possibility that nursing home residents had been included, the analysis was repeated excluding women 65 years of age and older.Fluoroquinolone-resistant E coli was also higher in women younger than 65 years of age in British Columbia (18 of 193 [9.3%]) than in the western provinces (three of 138 [2.2%]), Ontario (15 of 273 [5.5%]) and the eastern provinces (four of 346 [1.1%]; P<0.001).
To assess whether E coli resistance rates were increasing, the results were compared with a previous study (Table 3) (12).Women 50 to 64 years of age and those 65 years of age and older were combined due to small numbers in the earlier study.There were no significant differences by age or region in TMP-SMX-resistant E coli between the two time periods, although there was a trend toward increased TMP-SMX resistance overall.There was a significant increase in fluoroquinolone-resistant E coli overall and by region.

DISCUSSION
The Infectious Diseases Society of America has recommended TMP-SMX for the first-line empirical antibiotic treatment of acute cystitis, unless the level of TMP-SMX-resistant E coli in an area exceeds 20% (1).While the clinical relevance of this threshold has been questioned ( 8), treatment failure is more common in women with TMP-SMX-resistant E coli (13).The present study found that 15% of E coli isolates from adult women with community-acquired urinary tract infections in Canada are currently resistant to TMP-SMX.As a result, no changes in prescribing recommendations for Canadian physicians are needed at present.There were some areas of the country and some age groups where E coli TMP-SMX resistance was higher.The level of TMP-SMX-resistant E coli in British Columbia was 20%.This was not due to differences between British Columbia and other regions in terms of population age.TMP-SMX-resistant E coli was also common in women 65 years of age and older.The levels of TMP-SMX in these two groups are at, or are approaching, the threshold suggested by the Infectious Diseases Society of America for considering alternatives to TMP-SMX in the empirical treatment of acute cystitis.Ongoing monitoring will be needed to determine whether resistance levels increase further in these groups.
However, it is unclear whether TMP-SMX resistance in Canada has increased in community-acquired urinary tract infections in adult women.A study by Zhanel et al (10) found that 19% of E coli isolates were TMP-SMX-resistant, but the sample included men and children.Separate results for adult women by age groups were not reported.A 1997 study of urinary tract isolates from family physicians' offices in southern Ontario found that 8.2% of E coli were TMP-SMX-resistant, but the age and sex of the population was not described (11).A comparison of the current study with our previous study of adult women (12) found some increase in TMP-SMX resistance, although the change was not statistically significant.In addition, there were differences in how cultures were obtained in the two studies.In our previous study (12), urine cultures were obtained from clinically diagnosed cases of acute uncomplicated cystitis, whereas the current study used pooled urine cultures submitted to laboratories without clinical information.A study of all urinary tract infections in women seen in general practice found that 27% had complicating factors (14).The occurrence of TMP-SMX-resistant E coli was two to three times more likely in these women.A study based in New Zealand (15) also found lower levels of TMP-SMX resistance in clinically assessed cases of uncomplicated urinary tract infection compared with pooled community laboratory specimens.Thus, the suggestion of higher TMP-SMX resistance in the present study may also have been due to the use of pooled cultures.
The increase in the rate of fluoroquinolone-resistant E coli between the two time periods was significant.The level of fluoroquinolone-resistant E coli was 7%.This is higher than the levels of 1% to 1.8% reported in previous Canadian studies (10)(11)(12).We found that 10% of E coli isolates were fluoroquinolone-resistant in women older than 65 years of age, and this level was found to be 16% in British Columbia.While we were not able to rule out that some nursing home patients were included in the sample, fluoroquinolone resistance was higher in British Columbia even in younger women.
Reasons for the high level of fluoroquinolone resistance in British Columbia were not identified.However, prescriptions for fluoroquinolone antibiotics in British Columbia increased by 44% between 1996 and 2000 (16).Because prior fluoroquinolone exposure is a risk factor for fluoroquinolone resistance (17), changes in prescription practices in British Columbia in community-acquired urinary tract infections may have contributed to the higher level of resistance.If confirmed, prescribing restrictions may be needed to prevent further increases in fluoroquinolone-resistant E coli.
Resistance of E coli to nitrofurantoin has remained low over the years (8) and was also uncommon in the current study.However, physicians prescribe antibiotics empirically in acute cystitis before knowing the causative organism.We found that 9% of all isolates were resistant to nitrofurantoin overall.Greater use of this antibiotic has been suggested to limit fluoroquinolone use (8), but additional research has been recommended to address questions about overall effectiveness and safety (1,2,8).Other alternatives include beta-lactam antibiotics, although they are generally considered to be less effective (2,8).
The major limitation of the present study was the use of pooled laboratory specimens.However, this method has also been used in other studies that have provided estimates of antibiotic resistance levels in E coli (4,10,11).Although the use of pooled laboratory specimens may overestimate resistance levels (15), this provides greater confidence in the conclusion that the level of TMP-SMX-resistant E coli in acute cystitis seen by family physicians in Canada is significantly less than 20%.

CONCLUSIONS
TMP-SMX continues to be an appropriate first-line empirical antibiotic treatment for acute uncomplicated cystitis in adult women in Canada, as resistance levels remain below 20%.The level of fluoroquinolone-resistant E coli in communityacquired urinary tract infections should be monitored, and the apparent high levels of fluoroquinolone resistance in British Columbia should be confirmed to determine whether prescribing restrictions are warranted.Future studies should use urine cultures from clinically confirmed cases of acute uncomplicated cystitis to avoid overestimating resistance rates.

TABLE 1
17.9%]) and in those 65 years of age and older (103 of 572 [18.0%]) when compared with younger women (90 of 750 [12.0%];P=0.004).Adjusting for age differences among regions did not affect the results.TMP-SMX resistance remained higher in British Columbia (adjusted OR 1.94, 95% CI 1.34 to 2.81) and Ontario (adjusted OR 1.61, 95% CI 1.10 to 2.35) than in the eastern provinces.Can J Infect Dis Med Microbiol Vol 17 No 6 November/December 2006 338 Antibiotic resistance in urine isolates from adult women across Canada with community-acquired urinary tract infections

TABLE 2
Regional variations in Escherichia coli antibiotic resistance in community-acquired urinary tract infections in Canada