Department of Medicine/Division of Allergy and Infectious Diseases, 1959 NE Pacific St., Box 356523, University of Washington, Seattle, WA 98195, USA
Received 21 September 2004; returned 6 November 2004; revised 14 April 2005; accepted 20 April 2005
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Abstract |
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Methods: Pre-menopausal women presenting with acute uncomplicated cystitis were randomized to treatment with 3 days of ciprofloxacin, 7 days of nitrofurantoin, or a single dose of fosfomycin. Women were followed for 1 month for evaluation of clinical and microbiological responses as well as for isolation of resistant rectal E. coli.
Results: Sixty-two women (25 ciprofloxacin, 17 nitrofurantoin, 20 fosfomycin) were enrolled and eligible for analysis. All three regimens were well tolerated and resulted in >90% clinical and bacteriological cure. The prevalence of rectal E. coli was markedly decreased by ciprofloxacin and fosfomycin, but not by nitrofurantoin. One woman treated with ciprofloxacin had emergence of two ciprofloxacin-resistant rectal E. coli strains within 10 days of completing therapy. No emergence of resistance was observed in the other two treatment groups.
Conclusions: This study demonstrates that fluoroquinolone-resistant E. coli remain infrequent in the rectal flora of women with uncomplicated cystitis in Seattle. However, a 3 day course of a fluoroquinolone for treatment of uncomplicated cystitis was followed by isolation of fluoroquinolone-resistant rectal E. coli in one patient.
Keywords: urinary tract infections , drug resistance , E. coli
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Introduction |
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Patients and methods |
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Women aged 1845 years presenting to the university healthcare centre with symptoms of acute uncomplicated cystitis were offered the opportunity to participate. Subjects were also recruited through advertisements at the University of Washington campus. Additional inclusion criteria included being non-pregnant, in good general health, and having pyuria as measured by a haemocytometer counting chamber and a urine culture with 102 cfu/mL of a uropathogen. Women who were pregnant, lactating, not regularly taking contraceptives, or who had a history of chronic conditions such as diabetes, known anatomical abnormalities of the urinary tract, allergy to any of the three study drugs, or recent (<2 weeks) exposure to an oral or parenteral antimicrobial were not eligible for the study.
Study procedures
Study participants were randomized to treatment with ciprofloxacin 250 mg twice daily for 3 days, nitrofurantoin 100 mg twice daily for 7 days, or fosfomycin 3 g single dose, and were followed prospectively for 1 month. Urine and rectal cultures were performed at baseline and at 13, 1014 and 2830 days after therapy. Written informed consent was obtained from all participants, and study procedures were approved by the University of Washington Human Subjects Review Committee.
Laboratory methods
Culture and identification of urine specimens were performed using standard laboratory methods.2 The KirbyBauer disc method was used to determine antimicrobial susceptibilities of uropathogens and rectal isolates.2 Rectal swabs were collected using a portacult transport medium and transferred to the laboratory and inoculated within 24 h of collection. The swabs were plated directly onto 5% Sheep Blood agar and MacConkey agar and then streaked for isolation using a sterile loop. Flat lactose-fermenting colonies that were indole-positive were identified as E. coli. To test for selection of resistant E. coli in the rectal flora during therapy, each morphologically different colony type of E. coli on sheep's blood agar was isolated from each patient at each visit and stocked individually at 70°C in glycerol/trypticase soy broth. At the completion of the study, the E. coli strains were taken out of the freezer, reisolated, and tested for susceptibility using NCCLS guidelines to the study drug with which the patient was treated. Strain identity was assessed using XbaI digests in pulsed-field gel electrophoresis.3 Haemolysin production and papG genotypes were determined using previously described methodology.4,5
Statistical methods
The prevalence of rectal E. coli was calculated by dividing the number of women with any rectal E. coli isolated by the total number of women sampled for rectal E. coli at each visit. The difference in prevalence between treatment groups was tested using the 2 test. A binomial 95% confidence interval was calculated for the point estimate of the percentage of women with resistant strains detected in the ciprofloxacin treatment arm.
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Results |
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Causative agents and response to therapy
The majority of UTIs were caused by E. coli alone (77%) or in combination with another uropathogen (enterococci, Staphylococcus saprophyticus, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter sp.) (15%). The remaining UTIs were caused by enterococci, Klebsiella sp., Staphylococcus saprophyticus and Citrobacter sp. (12% each). Overall, clinical and bacterial cure was achieved in >90% of women in each treatment group.
Isolation of resistant E. coli
Rectal colonization with E. coli was present in 94% of women at the enrolment visit. There was a significant reduction in the prevalence of rectal E. coli after treatment with ciprofloxacin and fosfomycin, but not after treatment with nitrofurantoin (P < 0.001) (Figure 1). Two ciprofloxacin-resistant rectal E. coli strains were isolated from a single patient in the ciprofloxacin treatment group 10 days after completing therapy (study day 14). The patient had a history of a UTI in the preceding 68 weeks, but no other UTIs in her lifetime and no antibiotic usage for at least 2 weeks prior to enrolment. She was sexually active with one male partner and reported no changes in sexual partners or birth control method during the study period. She did not require additional antibiotic therapy during the study period.
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Discussion |
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Although fluoroquinolone-resistant E. coli remain infrequent as a cause of uncomplicated UTI in the USA, they are being seen with increasing frequency in such patients in Spain, for example.1 Concomitantly, fluoroquinolone-resistant E. coli have been shown to be highly prevalent in food animals given fluoroquinolone-containing feeds in Spain and elsewhere.10 Given the widespread use of fluoroquinolones in both humans and animals, it is probable that fluoroquinolone-resistant E. coli are increasingly likely to be present in colonic flora. Under the selective pressure provided by even a short 3 day treatment regimen for acute cystitis, resistant strains may predominate at least transiently. To cause UTI, fluoroquinolone-resistant E. coli would need to persist in the rectal flora and eventually colonize the vaginal introitus. Strains possessing urovirulence determinants would be more likely to eventually cause UTI.
Importantly, the ciprofloxacin-resistant strains in this study were not highly uropathogenic as evidenced by lack of P-fimbriae and ß-haemolysis, and did not result in a symptomatic UTI during the follow-up period. They were also genetically different from the susceptible strains that were isolated before therapy and post-therapy. This suggests that exposure to ciprofloxacin either resulted in selection of resistant E. coli strains which were present in quantities too low to be identified prior to drug exposure or in the acquisition of resistant E. coli strains after drug exposure. Studies of patients with complicated UTI have also found that fluoroquinolone-resistant E. coli which are isolated during or shortly after fluoroquinolone exposure are genetically different from susceptible E. coli isolated prior to drug exposure.8,9 Of note, none of the 37 women in the other two treatment regimens in the study (a single dose of fosfomycin or 7 days of nitrofurantoin) demonstrated emergence of intestinal E. coli strains resistant to the treatment drug or to ciprofloxacin. Although we report this occurrence in only one case out of 25 women who were randomized to ciprofloxacin, the findings indicate that selection for fluoroquinolone resistance can occur even with short course therapy of acute cystitis. With increasing use of fluoroquinolones for outpatient UTI in women, this low rate of selection pressure could translate into significantly increased population-based rates of fluoroquinolone resistance and adversely impact treatment options.
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Acknowledgements |
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References |
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