Antibacterial resistances in uncomplicated urinary tract infections in women: ECO·SENS II data from primary health care in Austria

Urinary tract infections (UTI) are a frequent reason for consultation of women in primary health care [1‐4]. According to epidemiological surveys an annual incidence of 11.3 million cases in the USA and 175 million cases worldwide can be estimated [5, 6]. Approximately 80% of the cases with a significant positive urine culture for pathogens an infection with Escherichia coli (E. coli) can be expected; other causative bacteria are Staphylococcus saprophytic us, Klebsiella pneumonia, Proteus mirabilis and group B streptococci [7, 8].

The natural course of these UTIs shows a low rate of spontaneous cure even after a follow up of 6 weeks [9]. Since UTIs are a frequent reason for prescribing antibiotics (AB) the decision which AB should be prescribed has to be considered prudently. Normally, when antibiotics for treating an acute UTI are prescribed in primary health care the nature of the causative bacterium can only be presumed because current resistance data from the primary health care sector are scarce [10‐12]. However, to avoid the increasing threat of antibiotic resistances the local resistance patterns, especially for UTIs where resistances to commonly used antibiotics like ampicillin and trimethoprim are increasing, have to be respected [13‐17]. Therefore, it is necessary to gain susceptibility data especially from the primary health care sector and not only from hospitals or specialized centre’s because these resistances differ from that seen in the ambulatory sector [18].

Some studies on this topic have been performed. One has been the ECO·SENS project [17]. It was an international survey to investigate the prevalence and susceptibility of uropathogens causing acute uncomplicated community-acquired UTIs in primary care in the years 1999 and 2000. Collectively, 4,734 women with symptoms of acute UTI from 252 community care centre’s in 16 European countries including Austria and, in addition, Canada were enrolled. A total of 3,278 women (69.2%) had culture proven lower UTIs with E. coli responsible for 77% of all culture proven pathogens. Six years later a similar project, ECO·SENS II was conducted to provide and follow up data on epidemiology and susceptibility of uropathogens causing UTIs in primary care in 5 European countries: United Kingdom, Sweden, Austria, Portugal and Greece. In the context of the ECO·SENS II study it is the aim of the present analysis to provide data about the antimicrobial susceptibility of E. coli and K. pneumonia causing uncomplicated UTIs in women in primary health care in Austria and to compare the corresponding data of the ECO·SENS project (1999-2000) with the ECO·SENS II project (2007-2008) data. In addition, these results were contrasted with the resistance data for E. coli in the Austrian resistance report 2008 (AURES) for the ambulatory sector [15].

The urine cultures were carried out for the purposes of this study only. Patients were required to provide a freshly voided midstream urine sample. Immediately after sampling, an Uricult dip slide was prepared and forwarded by courier to the central laboratory for microbiological testing (Laboratory for Clinical Microbiology, Central Hospital, Växjö, Sweden). No dipstick testing for leucocytes was performed in advance due to the impossibility to exclude an UTI by a negative result [17, 19]. After the arrival at the central microbiological laboratory the dip slide was incubated for 18-24 hours at 35°C followed by assessing the bacterial density of the original urine sample leading to one of four possible results:

A positive result means a Gram-negative culture and ≥ 10³ cfu/ml, a negative result means no growth or < 10³ cfu/ml, mixed means the presence of more than two species, other means the growth of Gram-positive bacteria.

Significant bacteriuria was defined as ≥ 10³ cfu/ml as there is evidence that a significant number of women with symptoms of UTI do not have bacteriuria exceeding this value [20]. Further, this value corresponds to the lower limit of the former ECO·SENS survey [17].

Qualitative assessment was done by sub-culturing for identification and testing for antibiotic susceptibility of E. coli and K. pneumonia. The isolates were tested against the following antimicrobial agents: Mecillinam, ampicillin, amoxicillin + clavulanic acid, sulphametoxazole trimethoprim, trimethoprim/sulfamethoxazole, ciprofloxacin, nalidixic acid, nitrofurantoin, gentamicin, fosfomycin/trometamol, Cephadroxil, cefotaxime and ceftazidime. The susceptibility of E. coli and K. pneumonia is expressed by inhibition zone sizes and grouped as susceptible or resistant in accordance with the results of the disk diffusion method and the corresponding breakpoint values published by the Swedish Reference Group for Antibiotics [21]. The distribution of mecillinamin MIC-values for both E. coli and K. pneumonia isolates was determined by Etest®.

In addition to the antibiotic resistance data, demographic data (age) of the patients related were documented by the GPs. The age was stratified into two clusters: The first one with patients aged 18-50 years, the second one with patients aged 51-65 years.

The resistance data for E. coli in uncomplicated UTIs in 18-65 year old women gained by this study are the most recent data for this disease in Austria at this moment [12]. Moreover, Austria participated in both surveys in the ECO·SENS 1999/2000 as well as in the ECO·SENS II 2007/2008. For this reason changes in the antibiotic resistances could be described between these two periods and interpreted with caution. The chance to conduct such a comparison was due to the number given by the centre’s (19/23), the number of patients recruited (298/327), the mean age (41.0/40.2) and the symptom score (5.4/5.5) were similar and the inclusion/exclusion criteria as well as the study procedures, the laboratory and the susceptibility testing according to the Swedish Reference Group for Antibiotics and its Subcommittee on Methodology (SRGA) [21] for the two studies were identical. Nevertheless, it has to be considered that this comparison is between two cross-sectional studies and, therefore, it has limitations which were discussed below.

The study showed that 47% of women complaining of symptoms of an uncomplicated UTI had significant bacteriuria caused by E. coli which is 73.4% of all grown bacteria; a percentage very similar to the results found in the ECO·SENS study nine years before and the ARESC study from 2006 [16, 17].

Concerning the resistance patterns of E. coli the study showed that mean resistance rates of ampicillin (28.8%), sulphametoxazole (14.4%), trimethoprim (15.8%) and trimethoprim/sulphametoxazole (14.4%) remained high or even increased (ampicillin) between the years 1999/2000 and 2007/2008. Lower mean resistance levels were found for nalidixic acid (9.6%), amoxicillin/clavulanic acid (8.9%), ciprofloxacin (4.1%) and Cephadroxil (4.1%), with a change (except Cephadroxil) in resistance rates between the two ECO·SENS studies. Resistance rates of mecillinam (0%), nitrofurantoin (0.7%), fosfomycin (0.7%), gentamycin (1.4%), cefotaxime (2.7%) and ceftazidime (2.7%) remained very low. Based on the literature we could confirm the persisting very low resistance rate for mecillinam [8].

Fortunately, the resistance of E. coli to nitrofurantoin and fosfomycin were both less than 1% since these two antibiotics are recommended in the S3-guideline for the treatment of uncomplicated UTI as first-line drugs [22] but how is the prescribing behavior of GPs and what do local guidelines recommend? For instance the Austrian ABSGROUP recommend pivmecillinam, amoxicillin/clavulanic acid and sultamicillin as first-line drugs [23]. For amoxillin/clavulanic acid the resistance rate in the ECO·SENSE II study for Austria was 8.9% which is not yet alarming but a negative trend. Therefore, our study can promote further surveillance of antibiotic resistance, especially, in the primary health care sector not only to check the currentness of guidelines but also the make the GPs think about their own prescribing behavior, not only in Austria.

Only 2 (1.4%) ESBL producing isolates of E. coli and no ESBL producing strain of K. pneumonia were found which is comparable to a study from France with low level of ESBL (1.2%) in uncomplicated UTIs in outpatients [24].

The quite high and compared to the results of the ECO·SENS study increased resistance rates of amoxicillin/clavulanic acid, ciprofloxacin and nalidixic acid should be respected when choosing an appropriate antibiotic for uncomplicated UTIs. The use of ampicillin, sulphamethoxazole, trimethoprim and trimethoprim/sulphametoxazole in uncomplicated UTIs in women should be questioned as suggested by the even higher resistance results of the ARESC-study (48.3% for ampicillin and 29.0% for trimethoprim/sulphametoxazole) [16].

The increase in fluorochinolon resistance is not yet alarming but deserves further careful observation taking into consideration the increasing use of this antibiotic in uncomplicated UTIs [25, 26].

The comparison of the resistance rates of this study with the corresponding rates of the Austrian Resistance Report 2008 (AURES) shows much higher resistance rates for aminopenicillin, fluorochinolon and trimethoprim/sulphametoxazole as well as a higher rates to mecillinam in the AURES 2008 [15]. The reason for the higher resistance rates described in the AURES 2008 may result from the different data collection methodology. In the AURES the resistance data for all E. coli specimens sent to one of the reference laboratories are described. In a routine primary health care setting, samples from the primary care sector are sent predominantly to a laboratory if a complicated UTI occurred. Therefore, these data do not fit as reference data for local or national guidelines. However, in a lot of countries data collected like these are the only available which should be questioned. To obtain comprehensive resistance data for uncomplicated UTIs that have to find their way into the guidelines, clearly structured studies have to be performed on a regular base.

The missing resistance testing of uropathogens like other Enterobacteriaceae and Staphylococcus saprophytic us as well as the low numbers of K. pneumonia isolates and the exclusion of mixed cultures can be considered as limitation of this study. Further limitations were the patients and GPs inclusion process which was consecutive and voluntary. It could be speculated that the GPs that were already sensible concerning the topic antibiotic resistance and prudent antibiotic prescription participated in this study only. Moreover, the comparison of the results of two cross-sectional studies has to be questioned due to the lack of knowledge concerning further demographic data of the participating patients and the non-exact matching of the participating GP offices.

The resistance data found are an important contribution to the therapeutic safety and quality in General Practice in Austria.

Since there is a growing concern about an increase in antibiotic resistance also in the ambulatory sector due to frequent and sometimes uncritical prescriptions of antibiotics the results of this study could help to estimate the scope of the problem by increasing the knowledge about antibiotic resistance pattern before a possible therapy is prescribed. The knowledge of changes in antibiotic resistance over time is the next essential step for choosing the appropriate antibiotic [27]. The findings of this study should result in a regular surveillance system for bacteria and resistances emerging in the ambulatory sector designed after the model of the EARS-Net (formerly EARSS, European Antimicrobial Resistance Surveillance System) [28] for women and for men. It is not enough to sample and test all specimens coming to a laboratory from the ambulatory sector by chance to obtain comprehensive resistance data for the primary health care sector for special diseases. Structured studies have to be performed on a regular base. In addition to a surveillance system, more UTI preventive interventions should be promoted [29].