1 Department of Clinical Microbiology and Infectious Disease, Baskent University Faculty of Medicine, Ankara, Turkey; 2 Infectious Disease Clinics, Ankara Numune Education and Research Hospital, Ankara, Turkey
Received 21 April 2005; returned 11 June 2005; revised 1 August 2005; accepted 30 August 2005
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Abstract |
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Methods: The study was performed with isolates from community-acquired UTIs collected from 15 centres representing six different geographic regions of Turkey. All microbiological procedures were carried out in a central laboratory. Multivariate analysis was performed for detection of risk factors for resistance. Use of quinolones more than once within the last year, living in a rural area, having a urinary catheter, age >50 and complicated infections were included in the model as variables and logistic regression was performed.
Results: A total of 611 Gram-negative isolates were studied: 321 were isolated from uncomplicated UTI and 290 were isolated from complicated UTI. E. coli was the causative agent in 90% of the uncomplicated UTIs and in 78% of the complicated UTIs (P < 0.001). Seventeen percent of E. coli strains isolated from uncomplicated cases and 38% of E. coli strains isolated from complicated UTI were found to be resistant to ciprofloxacin. In multivariate analysis, age over 50 [odds ratio (OR): 1.6; confidence interval (CI): 1.082.47; P = 0.020], ciprofloxacin use more than once in the last year (OR: 2.8; CI: 1.385.47; P = 0.004) and the presence of complicated UTI (OR: 2.4; CI: 1.543.61; P < 0.001) were found to be associated with ciprofloxacin resistance. Detection of strains of E. coli producing extended-spectrum ß-lactamase (ESBL) enzymes was two times more common in the patients who received ciprofloxacin than those who did not (15% versus 7.4%).
Conclusions: The increasing prevalence of infections caused by antibiotic-resistant bacteria makes the empirical treatment of UTIs more difficult. One of the important factors contributing to these high resistance rates might be high antibiotic use. Urine culture and antimicrobial susceptibility testing are essential in Turkey for patients with UTI who have risk factors for resistance, such as previous ciprofloxacin use. Fluoroquinolone-sparing agents such as nitrofurantoin and fosfomycin should be evaluated as alternative therapies by further clinical efficacy and safety studies.
Keywords: uropathogen E. coli strains , antibiotic resistance , ESBL positivity
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Introduction |
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Therapeutic options in the setting of high resistance against both trimethoprim/sulfamethoxazole and quinolones need to be studied. In this study, we describe the antimicrobial susceptibility patterns of uropathogenic E. coli strains collected from 15 different centres to verify the current situation in Turkey and we also describe the risk factors for infection with ciprofloxacin-resistant uropathogenic E. coli, and particularly its association with ciprofloxacin use.
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Methods |
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Patients between 18 and 65 years of age with community-acquired UTI were included in the study. Hospital stay within the last month was the exclusion criterion. Male patients, patients who had had more than three episodes of UTI in the last year, those with upper UTI, pregnant patients, patients with urinary tract abnormalities, patients with a urinary catheter, those who had a urological operation, and those who had urolithiasis were interpreted as having complicated UTI.
Data collection
Fifteen centres in Turkey participated in the study in the period between 1 January 2004 and 31 May 2004. Urinalysis of consecutive urine samples which grew 105 cfu/mL bacteria were obtained from laboratory records. Patients who had both
105 cfu/mL bacteria and pyuria were interviewed face to face, and, if this was not possible, by telephone inquiry to complete a structured questionnaire. Among these patients, the ones who had pyuria or pollakuria or urgency were included in the study. This project was approved by the Baskent University Research Committee and was funded by Baskent University Research Foundation.
The questionnaire collected data relating to demographic characteristics (age, sex, address), symptoms (dysuria, urgency, pollakuria), criteria indicating the presence of complicated UTI underlying disease, whether there had been any hospital stay within the last month, and antibiotic usage within the last year. Forms and the identified Gram-negative uropathogens were sent to the central laboratory. Duplicate forms and isolates were excluded from further analysis.
Laboratory methods
Clean-catch urine samples obtained from patients were inoculated onto 5% blood agar and Eosin-Methylene Blue (EMB) agar with 0.01 mL calibrated loops by a semi-quantitative technique in each centre. Pyuria was detected either with positive dip-stick test or 510 leucocytes in the urine centrifuged at 2000 rpm for 5 min. Culture plates were incubated for 1824 h at 37°C. The isolated bacteria were identified by conventional methods in each laboratory. Identification procedures were repeated in the central laboratory to minimize the variations between the laboratories. Standard biochemical reactions were performed at the first step and BBL Crystal Enteric/NF 4.0 identification kits (Becton Dickinson) were used when needed. All isolates were stored at 70°C. Bacteria were classified according to whether they were isolated from uncomplicated or complicated UTI. Antimicrobial susceptibility testing was performed by a disc diffusion method using two panels of antibiotics; one tested against strains from uncomplicated UTI, the other tested against strains from complicated UTI. The antibiotics tested against both groups were ampicillin, amoxicillin/clavulanate, cefazolin, cefuroxime, ceftriaxone, cefixime, aztreonam, gentamicin, ciprofloxacin, ofloxacin, nalidixic acid, trimethoprim/sulfamethoxazole and sulfisoxazole. Three antibiotics tested only against strains from uncomplicated UTI were cefadroxil, nitrofurantoin and fosfomycin. Seven antibiotics tested only against complicated UTI strains were piperacillin, piperacillin/tazobactam, ticarcillin/clavulanate, cefepime, cefoperazone, ceftazidime and amikacin.
Antibacterial susceptibility testing was performed according to the NCCLS criteria in the central laboratory in order to obtain standardization.9 Quality was assured by testing E. coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853 in every batch. All zone determinations for these strains were within the ranges given by NCCLS for the antibiotics tested in this study. Extended-spectrum ß-lactamase (ESBL) determination was performed by phenotypic confirmation with C/CD (ceftazidime/ceftazidime clavulanate) discs as recommended by the NCCLS.9 In this test, a 5 mm increase in a zone diameter for disc ceftazidime/clavulanate versus ceftazidime disc alone demonstrates that the strain has ESBL enzyme.
Statistical methods
Data were analysed using Stata Statistical Software, version 8.0 (STATA Corporation, TX, USA). Proportion comparisons for categorical variables were done using 2 tests, although Fisher's exact test was used when data were sparse. Significance was set at P < 0.05 using two-sided comparisons. A multivariate model was performed for ciprofloxacin resistance. The ciprofloxacin resistance was the dependent variable in logistic regression. Age over 50, ciprofloxacin use more than once in the last year, complicated UTI, and hospitalization, were included as the variables in the model.
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Results |
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The mean age was 45 with a range of 1865 for the uncomplicated UTI patients and 48 (1865) for the complicated UTI patients. Fifteen (5%) of 321 uncomplicated UTI patients and 16 (6%) of 290 complicated UTI patients were from a rural area.
E. coli was the causative agent in 90% of the uncomplicated UTIs and 78% in complicated UTI (P < 0.001) (Table 1). E. coli strains isolated from complicated UTI were more often resistant to the commonly used antibiotics (Table 2). Nitrofurantoin and fosfomycin had the lowest resistance rates for the uncomplicated UTI strains. ESBL were detected in 5% of the E. coli strains isolated from uncomplicated UTI and 12% of the E. coli strains isolated from complicated UTI.
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In multivariate analysis, age over 50 [odds ratio (OR): 1.6; confidence interval (CI): 1.082.47; P = 0.020], ciprofloxacin use more than once in the last year (OR: 2.8; CI: 1.385.47; P = 0.004) and complicated UTI (OR: 2.4; CI: 1.543.61; P < 0.001) were found to be associated with ciprofloxacin resistance among the E. coli strains (Table 4). Both forward and backward selection methods revealed the same significant variables.
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Discussion |
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This study shows that E. coli is still the most common pathogen of both uncomplicated and complicated UTI, but that there are various other causative microorganisms in the complicated group (Table 1). The resistance rates of antibiotics against complicated UTI E. coli strains are generally higher than uncomplicated UTI E. coli strains (Table 2). These results are in agreement with previous studies.4,11 Trimethoprim/sulfamethoxazole is the recommended treatment of choice for uncomplicated UTI in IDSA guidelines. However, in our study, 36% of the uncomplicated strains and 42% of the complicated strains were resistant to trimethoprim/sulfamethoxazole. Our trimethoprim/sulfamethoxazole resistance rates were higher than in previous American (16.1%) and European (14.1%) studies for uncomplicated UTI strains.7,12 Although the causes of high trimethoprim/sulfamethoxazole resistance were not studied, Steinke and co-workers demonstrated that trimethoprim resistance was independently associated with exposure to trimethoprim and to other antibiotics.10 On the other hand, irrational antibiotic prescribing for UTI was documented in 47.3% of patients in a study from Turkey.13
Among the studied antibiotics, resistance to ciprofloxacin is of great concern because fluoroquinolones are reasonable empirical agents for both uncomplicated and complicated UTI in areas where resistance to trimethoprim/sulfamethoxazole is over 20% and they have become more commonly prescribed as first-line antibiotic therapy in the last few years.6,14 Resistance rates for ciprofloxacin against uncomplicated UTI strains was reported as 014.7% in the ECO·SENS Project, 2.5% in the USA and 1.2% in outpatients in Canada.7,12,15 Recently, Alos and co-workers reported 8.5% and 19.5% resistance rates for the uncomplicated and complicated UTI strains, respectively.11 Our rates were found to be much higher: 17% for the uncomplicated UTI strains, and 38% for the complicated UTI strains. This may be due to high use of ciprofloxacin, since it is considered the drug of choice in UTI, because of high trimethoprim/sulfamethoxazole resistance. The misuse of quinolones (along with other antibiotics) has been documented by Canbaz and co-workers from Turkey.13
In univariate analysis, receiving an antibiotic regimen other than ciprofloxacin seems to be unrelated to ciprofloxacin resistance (Table 3). Multivariate analysis indicated that age over 50, ciprofloxacin use and complicated UTI were independent risk factors contributing to ciprofloxacin resistance (Table 4). The association between ciprofloxacin use and the emergence of resistance has been reported previously.6,8,11,16,17 The relationship between antimicrobial consumption and resistance seems to be not surprising. Although Kahlmeter and co-workers could not demonstrate this relationship for some antibiotics such as ampicillin and trimethoprim/sulfamethoxazole, they showed a statistically significant relationship for ciprofloxacin and concluded that the relationship between consumption and resistance is multifactorial and often confounded by other variables.16 Complicated UTI (including male gender), urinary tract abnormalities, urinary catheterization and older age were found to be associated with high ciprofloxacin resistance rates in previous studies.8,11,17
Although tests for the production of ESBL are not performed routinely for urinary isolates in our centre, we performed phenotypic confirmation tests according to the NCCLS criteria for this study population and demonstrated that ciprofloxacin resistance is seen more commonly in ESBL-positive uropathogenic E. coli isolates (P < 0.001). A similar relationship has been documented for E. coli but not for Klebsiella pneumoniae strains isolated from community-acquired UTI.18
Although the risk factors for acquiring infection by ESBL-producing bacteria have been investigated for nosocomial infections, such risk factors have not been studied for community-acquired infections. In our study, ESBL production was two times more common in patients who received ciprofloxacin than those who did not (15% versus 7.4%). Risk factors for ESBL production in isolates from non-hospitalized patients were also found to be associated with ciprofloxacin use in a recent study.19 High resistance rates for ß-lactams, trimethoprim/sulfamethoxazole and ciprofloxacin restrict empirical antibiotic use in the outpatient settings. For this reason, nitrofurantoin and fosfomycin may be reasonable alternatives for the treatment of uncomplicated UTI based on the in vitro data. Resistance rates for the study population were 4% and 0.3% for nitrofurantoin and fosfomycin, respectively. In our study, nitrofurantoin resistance was found to be higher than previously published data but fosfomycin resistance was similar.7,11,12,14 Nitrofurantoin is recommended for treating or preventing only uncomplicated cystitis and resistance to E. coli has been reported to be very low even after 50 years of use.20 Fosfomycin is also limited to the treatment of uncomplicated cystitis along with the advantage of only one dose.21 Both bacteriological and clinical cure rates were found to be high in the limited clinical studies comparing fosfomycin, nitrofurantoin and trimethoprim.22,23 Although in vitro data seem to encourage the prescription of fosfomycin and nitrofurantoin, further clinical studies evaluating the clinical efficacy and safety profiles of these two drugs are warranted.
In conclusion, trimethoprim/sulfamethoxazole does not seem to be appropriate for the empirical treatment of community-acquired UTI in Turkey, because of its very high rate of resistance. Ciprofloxacin should also be used cautiously both for uncomplicated and complicated UTI because of emerging resistance. High antibiotic use may encourage high resistance rates. Urine culture and antimicrobial susceptibility testing seem to be essential in Turkey for the uncomplicated UTI patients who have risk factors for resistance, such as previous ciprofloxacin use. Fluoroquinolone-sparing agents such as nitrofurantoin and fosfomycin should be evaluated as alternative therapies by further clinical efficacy and safety studies.
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Footnotes |
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Acknowledgements |
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References |
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