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Introduction
The worldwide prevalence of community-acquired urinary tract infections (UTIs) is not well known. However, studies show that among gram-negative bacteria, E. coli is the most prevalent uropathogen, accounting for most of community-acquired UTIs.1,2,3
UTIs treatment is one of the major contributors to antibiotic use worldwide. 4 Over the last decades, the indiscriminate use of antibiotics led to an increase in antimicrobial resistance among uropathogens, which became a worldwide concern.4
Fluoroquinolone Resistance has increased since its introduction in the treatment of UTI and its consumption is associated with increasing resistance in E. coli.5
Substantial evidence points to an increase, over the last years, in ciprofloxacin resistance in community-acquired UTIs caused by E. coli, and this increase is particularly high in developing countries.6 The goal of this study was to analyze the trends of antibiotic resistance in ciprofloxacin-resistant Escherichia coli isolated from community-acquired urinary tract infections from 2011 to 2017.
Methods
This was a time series study conducted from January 2011 to December 2017 in the city of Goiania (estimated population for 2019, 1 516 113),7 in the mid-west of Brazil, analyzing data of community-originated, positive urine cultures from persons aged 18 years or older, in which ciprofloxacin-resistant E. coli was isolated and identified. These records were from four clinical laboratories, serving both public and private patients (including health insurance), with specimen collection offices distributed in all regions (North, South, East and West) of the city of Goiania, Goiás, Brazil.
Only results from the first record of each patient were considered to avoid data duplication, unless there was reinfection three months after the first infection, with a different antimicrobial susceptibility profile. Any non-conclusive result (for any reason), which was not followed by patient returning for new specimen collection were excluded.
The urine cultures performed by the participating laboratories were obtained from midstream urine, processed, and incubated in CLED Agar at an average temperature of 35°C. Urine cultures were deemed positive when bacterial count was above 100 000 colony forming units per milliliter of urine (CFU/mL).8 Isolate identification and antimicrobial susceptibility test were performed with the VITEK2 automated system (BioMérieux).
Antimicrobials tested included nitrofurantoin, norfloxacin, nalidixic acid, ampicillin, amoxicillin/clavulanate, cefoxitin, ceftriaxone, ertapenem, piperacillin/tazobactam, meropenem, amikacin, gentamicin, and tobramycin. Results were interpreted according to guidelines from the Clinical and Laboratory Standards Institute.9 For the purposes of this study, susceptibility was classified as susceptible or resistant; intermediate susceptibility was counted as resistance.
Demographic data and susceptibility profiles were stored in a Microsoft Excel database and analyzed with the softwares SPSS 20.0 and Stata 15.0.
Descriptive analysis of demographic data and antimicrobial bacterial resistance used absolute (n) and relative (%) frequencies. Bivariate logistic regression was employed to assess the association between sex and age and risk of resistance by ciprofloxacin-resistant E. coli.
Trends in the antibiotic resistance patterns were determined using the Prais-Winsten generalized linear regression;10 then, the annual percent change (APC) and respective 95% confidence interval (CI 95%) were calculated from the β1 coefficient and standard error (SE) of the regression analysis. Upward trends were identified when regression coefficients were positive and downward trends when they were negative; regression coefficients not significantly different from zero (p-value >0.05) indicated no trend. In addition, the change at both ends of the series (2011 and 2017) was calculated (∆%) and its statistical significance was assessed with Pearson's chi-square test or Fisher's exact test. In all analyses, p-values <0.05 were considered statistically significant.
The study was conducted in accordance with the principles expressed in the Declaration of Helsinki and was approved by the Pontifical Catholic University of Goiás Research Ethics Committee (Opinion No. 348 549 and protocol No. 16242013.2.0000.0037).
Results
In this study, 20 272 positive urine culture reports were identified during the period from January 2011 to December 2017 of patients with community-acquired UTI, of which 3363 (26.1%) were ciprofloxacin-resistant E. coli infections.
The highest prevalence (40.91%) of UTIs for ciprofloxacin-resistant E. coli occurred in men, and are more likely to be infected with ciprofloxacin-resistant E. coli [2,132 (1,891-2,402)] (p = <0.001). Regarding age, the prevalence of ciprofloxacin-resistant E. coli infections was high in all age groups, but the greatest chance of being infected was in the ≥60 [2.392 (2.087-2.742)] age range (<0.001) (Table 1).
Table 1 Susceptibility pattern of ciprofloxacin resistant E. coli by sex and age in isolates from 2011 to 2017. Goiânia, Goiás, Brazil
* Univariate Logistic Regression.
An upward trend of ciprofloxacin-resistant E. coli isolated was observed between 2011 and 2017, with an APC of 5.2% (95% CI: 2.6; 7.8; p=0.001). In this period the fraction of ciprofloxacin-resistant isolates increased significantly from 19.2% to 27.9%, representing a variation of + 45.3% (∆%) (p <0.001) (Figure 1).
Fig. 1 Variation in the proportion of increased resistance of ciprofloxacin-resistant E. coli in the municipality of Goiânia, Goiás, Brazil in the period 2011-2017.
There was a significant increase in the resistance of ciprofloxacin-resistant E. coli to nitrofurantoin, 508.8% (p <0.001), and to ceftriaxone, 250.0% (p <0.001), from 2011 to 2017. For the other antibiotics, resistance either decreased or did not change significantly (Table 2).
Table 2 Change in the pattern of resistance of ciprofloxacin-resistant E. coli from 2011 to 2017
* Pearson's chi-square test; ** Fisher's exact test.
In the 2011-2017 time series, gentamicin displayed a downward trend in resistance, whereas for the other antibiotics there was no significant trend (Table 3).
Discussion
This study presents data on the antimicrobial resistance trends of ciprofloxacin-resistant E. coli isolated from community-acquired UTIs in a metropolis located in central Brazil.
UTIs is a disease with high prevalence, mainly caused by enteropathogens, that affects individuals of all age groups and sexes.1 Females display higher prevalence of bacteriuria, as found in this study (90.12%) and described in Madrid, Spain. (85%).3 These results show that females contracted more UTI than male. This occurs mainly in premenopausal women.11
Although the prevalence of UTIs is higher in females, this study showed that the exposure effect was 2.132 higher for males to contract ciprofloxacin-resistant E. coli UTIs than for females. Usually males are more susceptible to infectious diseases, and bacteria isolated from UTIs in males are more resistant to antimicrobials,1 requiring longer treatment to eradicate the bacteria than in females, when treated with the same first-line antimicrobials.12
The increased incidence of UTIs in older men may be related to benign prostate hyperplasia, loss of prostate fluid and neurogenic bladder conditions, men’s behavior towards their health and repeated use of antimicrobials.13,14,15
Community-acquired UTIs pathogens have displayed high resistance to fluoroquinolones, especially in developing countries.6 Our data indicate that the ciprofloxacin resistance increased from 19.2% to 27.9% (p <0.001), contrasting with United States of America data, where the resistance rate increased from 3.6% to 11.8% between 2003 and 2012.16 These results discourage the use of oral fluoroquinolone in the empirical treatment of community-acquired UTIs when the local resistance rate is >10%.17
Nitrofurantoin is the drug of choice for UTI treatment according to international guidelines,17 and resistance to this drug is usually very low;2 however, other studies have shown high resistance rates like this one.18,19 The wide variation in resistance rates may be due to local prescribing practices. In places with high prevalence of resistance to nitrofurantoin, its use should be guided by antibiogram, and, in empirical therapy, indication should consider local data on resistance, which should be periodically reviewed.
Considering the importance of this antimicrobial for the treatment of uncomplicated UTIs, it is important that other studies demonstrate the determinants of increased resistance to nitrofurantoin in E. coli.
Norfloxacin is another widely prescribed UTIs drug, in both the hospital and community settings. However, our results showed a resistance rate of 59.5%, higher than the recommended 20% limit for its use in empirical treatment of community-acquired UTI,17 indicating that norfloxacin may not be an available option for empirical UTI treatment and its use should be judicious.
The resistance to nalidixic acid identified in this study suggests that E. coli has already acquired at least a first-step quinolone resistance and its use in the susceptibility test is useful as a predictor of fluoroquinolone resistance.20,21).
This study shows that, among β-lactams, the prevalence of resistance was high for amoxicillin/clavulanate (27.1%) and low for ampicillin (0.8%); however, the use of these drugs in monotherapy should be avoided. They are less effective than other available agents17,22 and therefore are not recommended for the empirical treatment of UTI.
The increase in resistance to ceftriaxone and the high prevalence of resistance (13.5%) identified, is similar to that described in another country (20.5%).23 This resistance may be associated with more than one mechanism, including the production of extended spectrum β-lactamase (ESBL).24 Bacteria harboring quinolone-resistance plasmids often co-harbor genes encoding ESBL production, which increases the challenge in using these antibiotics, creating major public health management problems. In the in India 50% of fluoroquinolone resistant E. coli, also produce ESBL.25).
Tobramycin is also used to treat community-acquired UTIs, but resistance rates are increasing, which may be associated with other classes of antimicrobials.26
Aminoglycosides resistance is associated with several resistance genes, including those that express beta-lactamase.26 It is difficult to propose an empirical therapy when infections are caused by E. coli with multiple resistance mechanisms, as therapeutic failure may occur.
Although the study has shown significant increase in the resistance rate for nitrofurantoin (+508.8, p <0.001) and ceftriaxone (+250.0, p <0.001), it also showed no resistance trend for the antimicrobials considered in this study against ciprofloxacin-resistant E. coli, with the exception of gentamicin, which displayed a downward trend.
The analysis of the trend of resistance growth was stable for the studied antimicrobials, except for gentamicin, which showed a decline. This trend coincides with the Ministry of Health's ban on the sale of antimicrobials without a prescription,27) which resulted in a decrease in the use of antibiotics.28 Thus, the restriction of sales of antimicrobials may have contributed to the trend of decreasing resistance to gentamicin, but studies are needed to corroborate this conclusion.
The limitations of this study are related to the lack of data such as clinical manifestations (reason for requesting the exam, clinical picture), associated comorbidities, history of previous infections, recent exposure to antibiotics in the last 30 days, hospitalization or hospitalization for a long time, and use of permanent urinary catheter. However, the results presented here are important to guide empirical therapy in community-acquired UTIs.
Conclusion: This study demonstrated no resistance trend of ciprofloxacin-resistant E. coli to all antimicrobials tested except for gentamicin, which displayed a downward trend.
The change in resistance pattern of ciprofloxacin resistant E. coli was statistically significant for the following antimicrobials: nitrofurantoin, norfloxacin, cefoxitin, ceftriaxone, amikacin, gentamicin and tobramycin.
There was an increase in the proportion of ciprofloxacin resistant E. coli from 2011 to 2017, with oscillation between years. These findings are important in directing the choice of antimicrobials for empirical treatment of community-acquired UTI. Therefore, selection of empirical antibiotics should be based on data from different time periods and regions.
Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
