Antimicrobial Resistance of Escherichia coli Causing Uncomplicated Urinary Tract Infections: A European Update for 2014 and Comparison with 2000 and 2008

Antimicrobial resistance (AMR) in clinically important pathogens, such as Escherichia coli, is of continuing concern [1]. Changes in resistance levels are best monitored by prospective, multi-national, surveillance programs, employing standardized procedures to collect the isolates and determine their antimicrobial susceptibility [2]. The ECO.SENS (The pan-European Escherichia coli sensitivity survey) project was the first such study to investigate the antimicrobial susceptibility of E. coli in acute uncomplicated urinary tract infections (UTIs) in women. It was first conducted between 1999 and 2000, involving 1417 isolates from 4734 women in 17 countries [3], and again in 2008 involving 903 isolates from 1697 women in 5 countries [4].

We report here an update on the antimicrobial susceptibility of isolates of similar origin from five countries which participated in either both or one of the previous surveys representing areas of Europe with varying AMR problems.

The selection of patients and procedures involved has been reported previously and are summarized only briefly here [3, 4]. Methodological differences if any are described. The study involved isolates of E. coli from non-hospitalized females aged 18 years and over, with symptoms of acute uncomplicated lower UTI, which included any or all of the following: frequency, dysuria, urgency, and suprapubic pain. In France (14 centers), Spain (3 centers), Sweden (1 center), and the United Kingdom (UK; 2 centers), all isolates were from patients in primary healthcare. In Germany (four centers), isolates were from women attending hospital clinics and the laboratory had difficulties guaranteeing the community origin of the isolates. Isolates were sent to the Department of Clinical Microbiology at the Central Hospital, Växjö, Sweden. Their antimicrobial susceptibility to mecillinam [amdinocillin (United States Adopted Name)], amoxicillin–clavulanic acid, cefadroxil (as a screen for cephalosporin resistance, particularly ESBL production), nitrofurantoin, ciprofloxacin, and trimethoprim was determined by disc diffusion using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodology and breakpoints [5, 6]. Isolates resistant to the first-generation cephalosporin, cefadroxil, were investigated for production of extended-spectrum beta-lactamase (ESBL) by double disc synergy testing using cefotaxime with and without clavulanic acid and ceftazidime with and without clavulanic acid.

Resistance rates were compared to those obtained in 2000, for all countries and to those obtained in 2008 for Sweden and the UK for all antimicrobials with the exception of amoxicillin–clavulanic acid. The methodology for determining susceptibility to amoxicillin–clavulanic acid in the current study was different from that used in the previous studies [7]. Statistical comparison was by Fisher’s exact test, 2-tailed, with P < 0.05 indicating statistical significance.

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation at the respective institutions and with the Helsinki Declaration of 1964, as revised in 2013. No patient identifiers other than sex and age were recorded and, as such, informed consent was not required for inclusion in this study.

Percentage susceptibilities to the agents tested are shown in Table 1. When compared to the results from 2000, there were instances where resistance had increased significantly in 2014, as follows: Germany showed a significant increase in resistance to cefadroxil (1.4% to 12.0%; P < 0.001), ciprofloxacin (2.2% to 20.2%; P < 0.0001), and trimethoprim (22.5% to 36.8%; P < 0.05); Spain showed a significant increase in resistance to mecillinam (1.0% to 6.5%; P < 0.01), cefadroxil (3.1% to 8.3%; P < 0.05), ciprofloxacin (14.7% to 30.8%; P < 0.001), and trimethoprim (25.1% to 37.3%; P < 0.05); Sweden showed a significant increase in resistance to ciprofloxacin (0% to 7.3%; P < 0.001) and trimethoprim (8.8% to 16.9%; P < 0.05); and the UK showed a significant increase in resistance to ciprofloxacin (0.6% to 15.3%; P < 0.0001), trimethoprim (13.3% to 46.0%; P < 0.0001), and nitrofurantoin (0% to 5.6%; P < 0.01). Spain also showed a significant decrease in resistance to nitrofurantoin (4.2% to 0%; P < 0.01).

Resistance in 2014 was significantly greater than that recorded in 2008 in the UK with a significant increase in resistance to ciprofloxacin (0.5% to 15.3%; P < 0.0001), nitrofurantoin (0% to 5.6%; P < 0.01), and trimethoprim (14.9% to 46.0%; P < 0.0001).

Overall there were 35 (4.8%) isolates positive for ESBL production. The incidence in each country was 2.4% in France, 10.5% in Germany, 4.7% in Spain, 2.9% in Sweden, and 4.0% in the UK.

There were only minor differences in methodology between the first two surveys and that reported here. The surveys in 2000 and 2008 involved many centers in each country [3, 4]. In contrast, the latest study was truly multi-center only in France, whereas samples from the other countries came from up to four centers. No upper age limit was imposed on patients in the current study, whereas an upper age limit of 65 years was specified previously. Despite these differences, the three surveys had very important similarities. All involved women with acute uncomplicated UTIs. Urine samples in all three surveys were obtained from women in primary healthcare, with the exception of Germany in the current study, where most of the isolates were from women attending hospital clinics. Antimicrobial susceptibility was performed at the same laboratory for all three studies.

Susceptibility in the current study was determined using EUCAST breakpoints and standardized methodology [5, 6]. The methodology used in the current study was different to that used previously, as it used a different medium and inoculum as specified by EUCAST. However, the zone diameter breakpoints were the same for all antimicrobials with the exception of amoxicillin–clavulanic acid [5‐7]. The most recent guidelines for amoxicillin–clavulanic acid use a fixed concentration of clavulanic acid and apply specifically to urinary isolates [5, 6]. The new susceptibility breakpoint for isolates from UTIs is defined as an amoxicillin minimum inhibitory concentration of ≤32 mg/L. Due to these differences in methodology it is impossible and inappropriate to compare the resistance rates for this antimicrobial between on one hand 2014 and on the other 2000 and 2008. However, it is acceptable to compare the results from the three surveys for all other antimicrobials. Statistical comparison is also acceptable, although for the reasons discussed above, one should not place too much emphasis upon the degrees of statistical significance found.

Our results and the trends observed are comparable to those observed elsewhere over a similar timescale. In France, resistance to amoxicillin–clavulanic acid [8] and trimethoprim–sulfamethoxazole [8, 9] has been highlighted, and there are similar reports from Germany [10, 11], along with resistance to cephalosporins [10]. Resistance to quinolones and trimethoprim–sulfamethoxazole in Spain is well documented [12, 13]. Although antimicrobial susceptibility in E. coli isolates in Sweden is generally high, trimethoprim resistance levels have been a cause for concern [14]. Similarly, the high level of trimethoprim resistance in the UK is well documented [15].

The Antimicrobial Resistance Epidemiological Survey on Cystitis (ARESC) study in Europe and Brazil, which involved similar patients to those in our study, noted that susceptibility to E. coli of over 90% was found for mecillinam, nitrofurantoin, and fosfomycin only [16]. Although fosfomycin was not tested in our latest study, consistent and high susceptibility of E. coli in all countries was similarly noted for mecillinam and nitrofurantoin. Interestingly, investigation of 34 isolates of E. coli resistant to either mecillinam or nitrofurantoin from the first ECO.SENS study in 2000 indicated the low probability of future clonal spread of resistance to these agents [17]. Our update has confirmed no major increase in mecillinam or nitrofurantoin resistance has taken place in the last 15 years.

The continuing and increasing resistance to ciprofloxacin and trimethoprim is disturbing and impacts on the choice of therapy for women with acute uncomplicated UTIs, particularly in domiciliary practice, where treatment is usually empirical. Antimicrobial susceptibility surveys such as the ECO.SENS and ARESC are essential and provide the most appropriate information on which to base such treatment. Our data, and that of others, indicate that mecillinam, nitrofurantoin, and fosfomycin are suitable options for empirical therapy of women with acute uncomplicated UTI. These are old agents with indications limited to lower uncomplicated UTIs. Interest in the redevelopment of these old agents has awakened with the galloping resistance to other agents and with the lack of new agents [18].