The Percentage of Antibiotic Resistance in Uncomplicated Community-Acquired Urinary Tract Infections

Findings of the RedAres Project

Background: Uncomplicated bacterial urinary tract infections (uUTIs) are commonly seen in outpatient practice. They are usually treated empirically with antibiotics. The pertinent German Clinical Practice Guideline contains recommendations on antibiotic selection, with the additional advice that the local resistance situation should be considered as well. However, up-to-date information on local resistance is often unavailable, because microbiological testing is mainly recommended for complicated UTIs. Resistance rates are often higher in recurrent uUTIs than in single episodes. In this study, we aimed to determine the resistance rates of Escherichia coli (E. coli) in patients with community-acquired uUTIs and to make these data available to the treating physicians.

Methods: In a nationwide cross-sectional study in Germany (DRKS 00019059), we determined the percentages of resistance to antibiotics recommended for uUTIs (first choice: fosfomycin, nitroxoline, mecillinam, nitrofurantoin, trimethoprim; second choice: cefpodoxime, ciprofloxacin, cotrimoxazole, levofloxacin, norfloxacin, ofloxacin) over the period 2019–2021. The data were stratified by single episodes vs. recurrent UTIs (rUTIs).

Results: Data from 2390 subjects were analyzed. E. coli was found in 75.4% of the samples with positive urine cultures (1082 out of 1435). The resistance rate of E. coli in single episodes (n = 725) was less than 15% for all antibiotics tested. In rUTIs (n = 357), resistance rates were also less than 15% for the most part; the only exceptions were trimethoprim (21.4%) and cotrimoxazole (19.3%).

Conclusion: For single episodes of uUTI, all of the antibiotics studied can be recommended, at least as far as their resistance profiles are concerned. For recurrent UTI, all but trimethoprim and cotrimoxazole can be recommended. The second-choice antibiotics examined do not have a more favorable resistance profile than the first-choice antibiotics.

Urinary tract infections (UTIs) are among the most commonly occurring community-acquired bacterial infections. Antibiotics are the recommended treatment (1, 2). In 2013, UTIs (N39.0) were diagnosed in 7.3% of all females over 12 years of age with medical insurance provided by the German health insurance fund Barmer Gmünder Ersatzkasse (GEK), while acute cystitis (N30.0) was diagnosed in 1.7% (4). In uncomplicated cystitis, the most common lower urinary tract infection, the recommended treatment, the recommended treatment is empirical administration of antibiotics without prior microbiological testing (5). Although the use of fluoroquinolones has declined, there is continuing overprescription of broad-spectrum antibiotics for the empirical treatment of UTIs (2), despite the availability of five different narrow-spectrum antibiotics (fosfomycin, nitroxoline, mecillinam, nitrofurantoin, trimethoprim) that are recommended as first-line treatment in the relevant German Clinical Practice Guideline of 2017 (5). Among their other functions, guidelines are intended to support decision-making processes in the selection of the appropriate treatment, but they are often not heeded. Moreover, the selection of antibiotic is often not based on current resistance rates or spectrum of action, despite recommendations in the guidelines. (6). With regard to resistance rates, an antibiotic is deemed appropriate for empirical use if the resistance rate of Escherichia (E.) coli to the substance concerned is below 20% (7).

For many women, the first UTI is followed by subsequent infections. In a representative population survey carried out in 2014 in the UK, 3% of women reported a history of recurrent infections (three or more infections in the previous 12 months) (8). The baseline survey of a clinical trial in women with UTIs in Germany found recurrent UTI (rUTI) rates of 17% and 23% in the two arms of the study (9). The proportion of women with rUTIs was shown to increase with age (10). Guidelines published to date make no recommendations on modified treatment options for rUTIs; however, there is evidence of different resistance rates in this group (11, 12).

Based on this knowledge, the RedAres study (REDuction of Antibiotic RESistance in the outpatient treatment of patients with uncomplicated urinary tract infections according to clinical practice guidelines) was undertaken.

The project was supported by healthcare research funding from the Innovation Fund of the German Federal Joint Committee (13, 14).

The survey presented here formed part of the RedAres project. In a Germany-wide cross-sectional study, the resistance rates of E. coli and other uropathogenic bacteria to the antibiotics recommended in the Clinical Practice Guideline were surveyed—stratified into single episodes and recurrent infections—for the period 2019–2021, in order to be able to provide the resistance data to primary care physicians.

Methods

The study was conducted in five regions of Germany: Northwest (the federal states of Lower Saxony, Bremen, Hamburg, and Schleswig-Holstein), North (Mecklenburg–West Pomerania, Saxony–Anhalt, Berlin, Brandenburg), Southeast (Thuringia, Saxony, Bavaria), Southwest (Baden–Württemberg, Hesse, Saarland, Rhineland–Palatinate), and West (North Rhine–Westphalia). Women were recruited to take part in the study by primary care physicians. A total of 148 practices (12–40 per region) took part in the study. The participating physicians were asked to recruit female patients with uncomplicated UTIs (uUTIs). The inclusion criteria were as follows:

• Female
• Age ≥ 18 years
• No functional or anatomical changes, urological/renal disease, kidney stones, immunosuppression, or urinary catheter (7)

Written consent was obtained from every participant. A urine sample (midstream urine) from each participant was analyzed. The following additional factors were recorded: pregnancy, diabetes mellitus, hospitalization in the preceding 2 weeks, antibiotic intake in the preceding 2 weeks, and frequency of occurrence of UTI in the preceding 6 months (7).

Patients with preceding hospitalization or preceding antibiotic intake were excluded. If the current UTI was at least the second episode within 6 months, the UTI was classified as recurrent (rUTI) (5).

The diagnostic microbiological testing of the urine samples was performed at nine different laboratories that were regularly used by the participating physicians’ practices. Testing for pathogens and resistance was generally conducted by means of automated procedures. A positive urine culture was defined as detection of ≥ 10³ colony-forming units (CFU)/mL. The resistance of E. coli and other uropathogenic bacteria (Klebsiella pneumoniae, Enterococcus spp., Proteus mirabilis, group B streptococci/S. agalactiae, Staphylococcus saprophyticus, Citrobacter spp., Staphylococcus aureus) to all antibiotics recommended for first- or second-line treatment of uUTIs in the Clinical Practice Guideline of 2017 was investigated. The results were interpreted according to the EUCAST standards. Antibiotics not included in the automated testing procedures were tested by means of agar diffusion. This was the case for nitroxoline, nitrofurantoin, and pivmecillinam in several laboratories, and for all other antibiotics in single cases.

The laboratories transmitted the resistance results via the German national Antimicrobial Resistance Surveillance (ARS) system, a laboratory-based surveillance system at the Robert Koch Institute (RKI) (15). The laboratories that took part in the study were already a part of ARS before the study began.

Statistical methods

Data analysis was carried out using R 4.2.1 (16). The 95% confidence intervals for rates were calculated by means of the Wilson method. Based on a sample size calculation designed to determine the resistance rate of E. coli to trimethoprim with uncertainty of ± 4%, at least 700 patients needed to be included per region in order to yield a high probability of being able to evaluate 385 samples per region in which E. coli was detected.

Before the study began, its data protection quality was assessed by the Data Protection Officer at the RKI. The RKI received exclusively pseudonymized data. The study is registered with the German Registry of Clinical Trials (DRKS00019059). (The following internal review board approvals had been obtained: ethics committee of Charité – Berlin University Medicine [EA2/127/19], Greifswald University Medicine [BB 126/19], North Rhine Medical Association [2019–353], Rhineland–Palatinate State Medical Association [2019–14585], Saxony State Medical Association [EK BR 77/19], Schleswig-Holstein Medical Association [011 20 m]).

Results

Altogether, 3233 females were recruited to take part in the study (205–799 per region) (Table 1). The Northwest region was excluded from analysis due to the low number of participants. Further exclusion criteria were: absence of consent, failure to meet the inclusion criteria, and incomplete transmission of data (Figure).

Figure

Flow chart

Table 1

Numbers of participating laboratories and physicians’ practices, number of study participants

A total of 2390 participants were included for analysis. There was a positive urine culture in 1435 participants. The age distribution of the latter was 18–98 years (median 57, varying per region from 56 to 58.5 years).

In 11.7% of cases, two pathogens or more were detected in the urine culture. E. coli was confirmed in 75.4% (1082) of all positive urine cultures. In 67% of these cases (725 probands) it was a single episode, while 33% (3657 probands) had rUTIs. Pregnancy was reported by 0.3% of the study participants, diabetes mellitus by 13.8%.

Other commonly encountered pathogens were Klebsiella pneumoniae (5.5%), Enterococcus spp. (5.2%), Proteus mirabilis (4.6%), and group B streptococci/S. agalactiae (4.8%) (Table 2).

Table 2

Distribution of pathogens

Resistance rates of E. coli

Germany-wide

For single episodes, the rates of resistance of E. coli to fosfomycin, nitrofurantoin, and nitroxoline were 0.8%, 0.1%, and 0.6%, respectively (Table 3). Higher resistance rates were seen to pivmecillinam (5.9%) and trimethoprim (14.1%). The resistance rates against the second-line antibiotics we investigated varied between 4.0% for cefpodoxime and 11.5% for cotrimoxazole.

Table 3

Escherichia coli resistance rates

There were minor differences between resistance rates to first-line antibiotics for rUTIs and single episodes; however, resistance tended to be slightly higher for rUTIs. These differences were more pronounced for the second-line antibiotics. The resistance rates against trimethoprim and cotrimoxazole were higher than for single episodes, at 21.4% and 19.3% respectively.

Regions

In the individual regions the differences in resistance rates between single episodes and rUTIs tended to be minor (

Table 4

Resistance rates of Escherichia coli stratified by region

Table 4). Only in the Northeast region were the rates of resistance to trimethoprim and cotrimoxazole considerably higher for rUTIs than for non-recurrent uUTIs.

Resistance rates of uropathogenic bacteria

For single episodes nationwide, the lowest resistance rate of other uropathogenic bacteria was to nitrofurantoin at 4.5%.The highest resistance rates were to trimethoprim (14.5%), ofloxacin (13.8%), and cotrimoxazole (12.1%) (eTable 1). For rUTIs, the lowest resistance rate was to nitrofurantoin (5.7%) and the highest rates were to trimethoprim (22.0%) and cotrimoxazole (20.1%). The resistance rates for all uropathogenic bacteria together tended to be higher than for E. coli alone.

eTable 1

Resistance rates of uropathogenic bacteria

Stratification by region showed higher resistance rates in the Southeast than elsewhere, particularly against the first-line antibiotics. Large differences were evident between the regions with regard to the rates of resistance to pivmecillinam.

Discussion

This study investigated the resistance rates of E. coli and other uropathogenic bacteria to first-line and second-line antibiotics recommended in the relevant Clinical Practice Guideline for use in community-acquired uUTIs, in four of five regions of Germany. Despite the exclusion of the fifth region (Northwest), this was the largest sample yet studied with regard to resistance rates among women with uUTIs in Germany. Regarding the empirical use of antibiotics for uUTIs, the Clinical Practice Guideline recommends that prescription should be guided by the current resistance rates in the region concerned; however, no valid large-scale data have previously been available.

For most antibiotics the resistance rates of E. coli were higher in rUTIs than in single episodes. The differences were minor for the antibiotics recommended as first-line agents, with the exception of trimethoprim. The resistance rates against the second-line antibiotics varied more widely. The marked differences in the resistance rates to trimethoprim and cotrimoxazole between single episodes and rUTIs had already been indicated in previous studies (11, 12). The resistance rates of E. coli to trimethoprim and cotrimoxazole in our study were similar to existing ARS data on routine diagnostic investigation of UTIs in the community (eTable 2). The ARS data primarily reflect the state of resistance with regard to complicated UTIs. rUTIs tended to reflect the resistance rates of complicated UTIs more than uncomplicated UTIs (12, 17). Accordingly, trimethoprim and cotrimoxazole should not be used empirically as first-line antibiotics in the treatment of rUTIs.

eTable 2

Resistance rates of E. coli in ARS 2020

Overall, the second-line antibiotics we investigated showed no advantage over the first-line agents with regard to resistance. This contradicts the frequently-used argument that one should primarily use second-line antibiotics due to their superior efficacy (18).

The resistance rates of nitroxoline, pivmecillinam, and fosfomycin were of particular interest. After being unlicensed for a long period of time, nitroxoline was again recommended for use in Germany in 2021. Yet it is one of the less frequently prescribed antibiotics for uUTIs (2, 19). E. coli showed hardly any resistance to nitroxoline. At the time of our study there were no recent data for comparison, especially with regard to uUTIs. In a study performed by Wagenlehner et al. in 2022, all E. coli isolates from women with the diagnosis of acute cystitis were sensitive to nitroxoline (20).

A low resistance rate of 4.5% (E. coli) was also found for pivmecillinam, which was first approved for use in Germany in 2016. Stratified by region, the resistance rates were consistently under 5% except in the West region, where the rate was 11.0%. In studies from other countries the reported rates are mostly under 5.0%, but in Poland the rate is 10% (17). Assessment of pivmecillinam must consider the intrinsic resistance of Staphylococcus saprophyticus; this plays only a minor role, however, as the resistance rate is 2.4% nationwide (Table 2).

In the case of fosfomycin the resistance rate of E. coli was below 2% both in single episodes and in rUTIs. The highest resistance rate in an individual region was 2.2%. Fosfomycin is among the most frequently administered antibiotics to treat community-acquired UTIs, yet is characterized by low resistance rates (2, 17, 19). A study published in 2019 revealed that the use of fosfomycin is unlikely to promote selection of a particular clone or the spread of transmissible resistance genes, because the fosfomycin-resistant isolates that were investigated did not display multiple resistance and carried no plasmidic fosfomycin resistance genes (21). To date, there is no sign of development of high resistance to fosfomycin, which might have been expected given its widespread use (22).

Nitrofurantoin was shown to have the lowest resistance rates out of all investigated antibiotics. This was evident primarily for E. coli, both in single episodes and in rUTIs, but also for the other uropathogenic bacteria. The low rates of resistance to fosfomycin, pivmecillinam, and nitrofurantoin support the recommendations of international guidelines (23).

The resistance rates for the individual pathogens are not shown due to the low numbers of samples. Considering that it is clinical practice in Germany to prescribe empirical antibiotic treatment without knowledge of the individual pathogen, the average resistance rates of all the typical uropathogenic bacteria together to each antibiotic have been presented. The patient’s history and clinical signs do not suffice to predict the probability of specific pathogens. The representation of an overall resistance rate of the typical pathogens is therefore convenient for prescribers, in order to determine the overall efficacy of a prescribed antibiotic, independent of the causative pathogen. Despite the occasionally higher resistance rates of all uropathogenic bacteria than of E. coli, all of the recommended antibiotics—except trimethoprim and cotrimoxazole—are suitable for use both in single episodes and in rUTIs.

In 2015 the resistance rates in uUTIs were investigated in the SARHA study (24). The RedAres project survey had a larger sample and additionally focused on rUTIs and on all uropathogenic bacteria. The antibiotics investigated differ to some extent because of the different recommendations in place at that time. For example, no data on mecillinam and nitroxoline were available in 2015. The resistance rates exhibited by E. coli in the SARHA study do not differ greatly from the survey presented here. An increase can be seen in the rates of resistance against ciprofloxacin (2015: 4.5% [2.5; 7.4]) (12).

Our study was carried out during the COVID-19 pandemic, which represented a challenge for all involved. Ultimately, 24% of the primary care practices that had originally agreed to take part were unable to do so. Recruitment of study participants also proved to be challenging. For this reason, the study in the Northwest region had to be discontinued. An intention-to-treat analysis of resistance rates for the 78 uUTIs with detection of E. coli that were received in this region revealed no essential deviations from the overall findings, except for a much higher rate of resistance of E. coli against ofloxacin (eTable 3).

eTable 3

Resistance rates of E. coli: comparison between study and intention-to-treat analysis

Limitations

The participating physicians were asked to include patients who met the predefined criteria. An incentive was paid to the participating physician for each recruited participant. The questionnaire was answered solely by treating physicians, and thus neither the responses nor correct implementation of the inclusion criteria could be independently verified within the scope of the study.

Conclusion

In terms of resistance, all of the antibiotics recommended in the German Clinical Practice Guideline are suitable for use in calculated treatment for single episodes of uUTI. Trimethoprim and cotrimoxazole are rendered unsuitable due to high resistance rates. Despite the favorable situation in regard to resistance, recurrence of UTI should always prompt microbiological testing.

Acknowledgments

We are grateful to the following laboratories: Labor 28 Berlin, MVZ Labor Passau, Medizinisches Labor Ostsachsen, Bioscientia Labor Ingelheim, IMD Labor Greifswald, Labor Stein Mönchengladbach, MVZ Labor Münster, LADR Laborzentrum Nord Flintbek, and Labor Limbach Heidelberg, and to all of the physicians’ offices that took part. Our thanks are also extended to the RedAres project partners: Alexandra Greser, Christiane Wagner, Prof. Christoph Heintze, Prof. Jutta Bleidorn, Prof. Andy R. Maun, Prof. Peter Heuschmann, Olga Miljukjov, Dr. Angela Schuster, Dr. Wolfgang Schneider-Rathert, Mandy Böhme, and Paula Tigges.

Funding

The RedAres project was financed by the innovation fund of the Federal Joint Committee’s Innovation Committee.

Conflict of interest statement

GS has received payments for acting as an instructor at training courses from various medical associations, from the German Federation of Primary Care Physicians (Hausärzteverband), and from the Institute for the Advanced Training of Primary Care Physicians (Institut für hausärztliche Fortbildung). He is a member of the German Society of General and Family Medicine (Deutsche Gesellschaft für Allgemeinmedizin und Familienmedizin, DEGAM) and of the Institute for the Advanced Training of Primary Care Physicians, Bremen.

IG leads the RedAres project consortium. She has received payments for acting as an instructor on the topic of the use of antibiotics in primary care at training courses for physicians (the “Tag der Allgemeinmedizin” in Göttingen and the “Fortbildungswoche der Praktischen Medizin” on Langeoog). She is a member of the Robert Koch Institute’s Commission on Anti-Infectives, Resistance and Therapy.

TE has received payments for acting as an instructor at Antibiotic Stewardship Initiative training courses.

The remaining authors declare that no conflict of interest exists.

Manuscript received on 12 May 2023, revised version accepted on 5 December 2023.

Translated from the original German by David Roseveare.

Corresponding author
Dr. med. Anja Klingeberg
Robert Koch-Institut, Abteilung für Infektionsepidemiologie,
Nosokomiale Infektionen, Surveillance von Antibiotikaresistenz und -verbrauch

Seestr. 10, 13353 Berlin, Germany

Cite this as:
Klingeberg A, Willrich N, Schneider M, Schmiemann G, Gágyor I, Richter D, Noll I, Eckmanns T: The percentage of antibiotic resistance in uncomplicated community-acquired urinary tract infections—findings of the RedAres project. Dtsch Arztebl Int 2023; 120: 175–81. DOI: 10.3238/arztebl.m2023.0267

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