Crdoba et al.

BMC Infectious Diseases (2017)

17:670 DOI 10.1186/s12879-017-2785-y

RESEARCHARTICLE Open Access

Prevalence of antimicrobial resistant

Escherichia coli from patients with
suspected urinary tract infection in
primary care, Denmark
1* 1 2 2 1
Gloria Crdoba , Anne Holm , Frank Hansen , Anette M. Hammerum and Lars Bjerrum

Abstract
Background: Escherichia coli is the most common pathogen causing Urinary Tract Infections (UTI). Data
from the current National Surveillance program in Denmark (DANMAP) may not accurately represent the
prevalence of resistant E. coli in primary care, because only urine samples from complicated cases may be
forwarded to the microbiological departments at hospitals for diagnostic examination. The aim of this study
was to assess the prevalence of resistant E. coli to the most commonly used antimicrobial agents in primary
care in a consecutive sample of patients from general practice.
Methods: Observational study carried out from December 2014 to December 2015. Thirty-nine general practices
from The Capital Region of Denmark included adult patients with urinary tract symptoms and suspected UTI. All urine
samples were sent to the central laboratory Statens Serum Institut (SSI). Significant bacteriuria was interpreted
according to the European Urinalysis Standards. Susceptibility testing was performed and interpreted according to
the European Committee on Antimicrobial Susceptibility Testing (EUCAST) standards.
Results: From the 39 general practices 505 patients were recruited. Completed data were obtained from 485
(96%) patients. According to the European Urinalysis Standards, 261 (54%) patients had positive bacteriuria.
The most common uropathogen in patients with uncomplicated (uUTI) and complicated (cUTI) urinary tract
infection was E. coli 105 (69%) and 76 (70%), respectively. Eighty-two (45%) of 181 E. coli isolates were
resistant to at least one of the tested antibiotics and 50 out of 82 isolates were resistant to two or more
antimicrobial agents. The highest resistance-rate was found against ampicillin 34% (95% CI 24;42) in uUTI and
36% (24;46) in cUTI. There were no differences in the distribution of resistance between uncomplicated and
complicated cases. The prevalence of resistance was similar to the one reported in DANMAP 2014.
Conclusion: In E. coli from uUTI there is high resistance rates to antimicrobial agents commonly used in
primary care. There was no difference in the distribution of resistant E. coli in suspected uUTI vs cUTI. In
Denmark, data from the National Surveillance program DANMAP can guide the decision for choice of
antibiotic in patients with suspected UTI seeking care in primary care.
Trial registration: ClinicalTrials.gov NCT02249273.
Keywords: E. coli, Antibiotic resistance, Urinary tract infections

* Correspondence: [email protected]
1
The Research Unit for General Practice and Section of General Practice,
Department of Public Health, University of Copenhagen; ster Farimagsgade
5, 1014 Copenhagen, Denmark
Full list of author information is available at the end of the article

The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Crdoba et al. BMC Infectious Diseases (2017) 17:670 Page 2 of 6

Background practices accepted to consecutively recruit patients with

Antimicrobial resistance is one of the most important the following characteristics: i.) inclusion criteria: Adult
threats to human health [1]. Multiple surveillance pro- patients (i.e. > 18 years of age) seeking care in general
grams have been launched worldwide to monitor the practice during office hours with dysuria and/or urinary
spread of resistant strains in community acquired and frequency as the main reason for consultation, and in
nosocomial infections [2, 3]. which GPs suspected a UTI; ii.) exclusion criteria: a)
Urinary tract infection (UTI) is the second most com- Currently taking antibiotics, b) Inability to provide a urine
mon bacterial infection managed in primary care [4, 5] sample, c) Inability to sign an informed consent, d)
and Escherichia coli is the most common pathogen caus- Previous participa-tion in this study.
ing UTI [6, 7]. E. coli resistant to antibiotics is on the rise,
with great variation across regions [8, 9]. Data collection
Experts recommend [10, 11] that choice of antibiotics in The day of the index consultation, all patients provided 10
patients with suspected complicated UTI should be based mL of urine, which was sent to Statens Serum Institut
on the results of a urine culture and susceptibility test, (SSI). The urine sample was preserved in boric acid and
while the choice of antibiotics in patients with suspected sent by certified post the same day of the consultation.
uncomplicated UTI should be based on up-to-date sur-
veillance data of patients from primary care. Thus, pro- Culture and susceptibility testing at the reference
spective surveillance of resistant patterns of uropathogens laboratory
isolated from all patients attending primary care is crucial At SSI, the culture was analyzed by a medical laboratory
for guiding first and second line antibiotic selection. scientist, who had no information about the clinical his-
Previous studies have suggested a systematic bias in sur- tory of the patient. A positive culture was defined as
3
veillance data because uncomplicated UTIs (uUTI) are un- growth of 10 Colony Forming Unit per milliliter
derrepresented, leading to an overestimation of resistance (CFU/mL) for E. coli according to the European Urinaly-
rates in primary care [12, 13]. This is problematic because sis Standards [14].
general practitioners (GPs) need an accurate knowledge of Aerobic urine culture was carried out with 1 L on
the prevalence of resistance to the most commonly used Blood agar plate and Blue agar plate (SSI Diagnostics;
antibiotics in primary care in order to make an appropriate Hillerd, Denmark) and 100 L on ESBL chromogenic
treatment decision (i.e. choosing the right antibiotic). culture media (Brilliance ESBL AGAR; Oxoid, UK).
In Denmark, the DANMAP programme is used for ESBL plates were examined after one day of incubation
surveillance of antimicrobial consumption and anti- and read according to the colour chart provided by the
microbial resistance in bacteria from animals, food and manufacturer. Phenotypic confirmation of ESBL produc-
humans [2]. DANMAP reports the prevalence of resist- tion was performed by the Total ESBL Confirm Kit
ance for bacteria from clinical samples analyzed at the 98,014 (Rosco Diagnostics, Taastrup, Denmark).
departments of clinical microbiology in Denmark. Part of Susceptibility testing was performed and interpreted
the urine samples analyzed at the microbiology de- according to EUCAST standards [15] on Mueller-Hinton
partments come from general practice. agar plates using Neo-Sensitabs (Sulfamethoxazole, tri-
The inferred prevalence of resistant strains in primary methoprim, ampicillin, amoxicillin-clavulanic acid, cef-
care may suffer from selection bias as GPs may predom- podoxime, ciprofloxacin, nitrofurantoin and mecillinam
inantly send urine samples to culture in patients with (Rosco Diagnostics).
complicated UTI or treatment failure.
In this paper, we report the results of a study aiming to Data analysis
assess the prevalence of resistant E. coli to the most We considered UTI as uncomplicated if the patient was a
commonly used antimicrobial agents in Denmark in pa- non-pregnant woman, under 65-year old without reported co-
tients with suspected (both complicated and uncompli- morbidity and assessed by the nurse or GP as not having an
cated) UTI seeking care at primary care level. acute complicated cystitis or suspected pyelonephritis. In
contrast, we considered UTI as complicated if the pa-tient
Methods was a man, a pregnant woman, a woman 65-year or older or
Study design with a reported co-morbidity or assessed by the nurse or GP
Prospective observational study carried out from to have complicated cystitis or pyelonephritis.
December 2014 to December 2015. The proportions of susceptible and resistant E. coli isolates
were compared between uncomplicated and complicated
Participants UTI. Proportion of resistant E. coli isolates in our study was
Five-hundred practices from The Capital Region of Denmark compared to the proportion of resistant E. coli isolates from
were randomly invited to participate. Thirty-nine primary healthcare from the National surveillance program
Crdoba et al. BMC Infectious Diseases (2017) 17:670 Page 3 of 6

DANMAP 2014. Significance of the differences between

the independent samples were performed by using the
Pearsons Chi-Square test (alpha 5%; CI 95%) and Fisher
exact test when appropriate. Descriptive analyses were
performed using SAS software, Version 9.3 of the SAS
System for Windows 7. Copyright (c) 20022010 by SAS
Institute Inc., Cary, NC, USA.

Results
Baseline characteristics
From the 39 practices, 505 patients were recruited. There
was completed information for 485 (96%) of the patients,
from which 261 (54%) had positive bacteriuria. Of the
261 cases, 152 (58%) were classified as uncomplicated
UTI and 109 as complicated UTI. The most common
uropathogen in uncomplicated and complicated cases was
E. coli 105 (69%) and 76 (70%), respectively - Fig. 1.

Antimicrobial resistance for E. coli isolates

Eighty-two (45%) of the 181 E. coli isolates were
Fig. 2 Distribution of susceptible and resistant E. coli
resistant to at least one of the tested antimicrobial agents. isolates in uncomplicated and complicated cases
Fifty (28%) of the 181 E. coli isolates were resistant to
more than one antimicrobial agent. The distribution of
resist-ance for the tested antimicrobial agents was not from E. coli from cUTI. Resistance to third generation
signifi-cantly different for the uncomplicated and cephalosporins and clavulanate (i.e. ESBL-resistance test)
complicated cases - Fig. 2 and Additional file 1: Table S1. was found in 6% (95% CI 1;10) of E. coli from uUTI and
The highest resistance rates were found for ampicillin: 34% (95% 3% (95% CI 0;9) of E.coli from cUTI. None of the tested
CI 24;42) of the E. coli from uncomplicated cases and 36% (95% CI E. coli isolates were resistant to nitrofurantoin Table 1
24;46) of the E. coli from complicated cases. It was followed by and Additional file 1: Table S2.
sulfamethoxazole: 31%, (95% CI 21;39) of the E. coli from The differences between the resistance rates of E. coli
uncomplicated cases and 24% (95% CI 14;33) of the E. coli from isolates from the study population and DANMAP 2014 were
complicated cases. Resist-ance to pivmecillinam (first line antibiotic lower than 10% across all antibiotics, for which com-parison
in Denmark) was 1% (95% CI 0;5) in E. coli from uUTI and 9% was available. No single difference was statistically
(95% CI 2;15) significant. Table 2 and Additional file 1: Table S2.

Discussion
Summary of main finding
This study shows that in uncomplicated cases there was
high resistance to antibiotics commonly used in primary
Table 1 Resistance rates among E. coli isolates from patients

seeking care in primary care

Uncomplicated Complicated
n = 105 n = 76

Ampicillin 34% (24;42) 36% (24;46)

Sulfamethoxazole 31% (21;39) 24% (14;33)
Trimethoprim 23% (14;30) 17% (8;25)
Pivmecillinam 1% (0;5) 9% (2;15)
Ciprofloxacin 8% (2;12) 8%(1;14)

Nitrofurantoin 0 0
a 6% (1;10) 3% (0;9)
3rd gen. Cephalosporins + clavulanate
a
Fig. 1 Flow chart of the study population ESBL status tested with combinations of the third generation cephalosporins
(Cefotaxime, Ceftazidime) and clavulanate
Crdoba et al. BMC Infectious Diseases (2017) 17:670 Page 4 of 6

Table 2 Comparison of resistance rates for E. coli between Another limitation was that we relied on GPs judgment as part of
the National Surveillance program DANMAP and our study the operationalization of the uncomplicated versus complicated
DANMAP 2014 a p-value variable. Thus, we cannot rule out that some pa-tients may have
Our study
Ampicillin 39% 34% 0.19 been miss-classified as having uncomplicated UTI by their GP.
Sulfamethoxazole 32% 28% 0.2 Currently, there is no agreement about the criteria of classifying a
Trimethoprim N/A 20% N/A patient as a uUTI or cUTI [16]. We chose to take into consideration
Pivmecillinam 5% 4% 0.74 the GPs assessment because it reflects more accurately the
challenges for classifying patients as uUTI and cUTI during
Ciprofloxacin 9% 8% 0.5
everyday practice.
Nitrofurantoin N/A 0 N/A
3rd gen. Cephalosporins 4% 4% 0.96
b Comparison with other studies
+ clavulanate
The distribution of resistant E. coli in uncomplicated cases is
N/A no data from the National Surveillance program DANMAP
2014 aUncomplicated and complicated cases bESBL- resistant similar to the distribution reported in other studies from
E. coli Greece, Germany, Austria, Sweden, Portugal and the United
Kingdom, in which ampicillin has the highest resist-ance and
care in Denmark. There was no statistically and clinically nitrofurantoin the lowest resistance rate [13, 17 20]. It
significant difference in the distribution of resistant E. confirms that E. coli resistant to antibiotics com-monly used
coli, in suspected uncomplicated vs complicated cases. in primary care is an increasing problem, even in low
Data from the National Surveillance program (DAN-MAP prevalence settings such as the Danish context.
2014) can be used to guide the selection of first and
ESBL-producing E. coli was found in both uncompli-cated
second line antibiotics to treat UTI in primary care in
and complicated cases seeking care at primary care level.
Denmark.
Previous studies have already pointed out that ESBL-
producing E. coli strains have the potential for spread be-
Strengths and limitations
yond the hospital environment [21, 22]. Studies carried out
The pragmatic design of the study enabled the inclusion of a
in China [23] and Spain [24] have shown the constant
wide variety of patients seeking care in primary care due to
increase of healthy carriers colonized with ESBL-producing
urinary tract symptoms, thus uncomplicated and complicated
E. coli. Thus, treating community-acquired urinary tract
cases were equally likely to be included in the study. It
infections caused by ESBL-producing E. coli is a growing
maximized generalizability to the patient popula-tion seeking
problem to be dealt with at primary care level as the
care in primary care settings in Denmark.
therapeutic options are limited [25].
Furthermore, all patients had a urine culture inter-preted
at the same reference laboratory. The laboratory
technician had no access to clinical data. It minimized the Relevance
risk for review bias and inter-observer variability. In Denmark, there are different guidelines made by dif-
The main limitation of our study is the small sample ferent health authorities [2628]. All guidelines agree on
size resulting in lack of power to counteract the type II recommending pivmecillinam and sulfametizol as the first
error (i.e. accepting the null hypothesis of lack of differ- line options in patients with suspected uncompli-cated
ence, when there is a difference between the groups). UTI. All agree on pivmecillinam as first line op-tions in
Nonetheless, the results of this study should be inter- patients with suspected complicated UTI, while only two
preted considering clinically relevant differences rather suggest trimethroprim as an option too.
than statistically significant differences. IDSA recommends that the selection of empirical anti-
For example, in DANMAP 2014 the resistance rate of biotics takes into consideration that resistance rates
E. coli isolates to Sulfamethoxazole was 32%, while in should not exceed 10% for fluoroquinolones and 20% for
our study it was 28%. The difference between estimates trimethoprim-sulfamethoxazole [10].
was not statistically significant and is not clinically rele- Based on the results of our study pivmecillinam is a good
vant too. The Infectious Disease Society of America first option, while the routine use of sulfamethizol needs to
(IDSA) recommends that resistance rates above 20% is be re-considered. In other countries, nitrofurantoin has
the threshold at which sulfamethoxazole is no longer started to gain importance as part of the first line antibiotics
recommended for empirical treatment [10]. for the management of UTIs in primary care [10, 11]. A re-
Another example is the lower percentage of E.coli iso- cent systematic reviews [29] about the efficacy and toxicity
lates from the uUTI group resistant to pivmecillinam in of short-term use (i.e. <14 days) of nitrofurantoin reported no
comparison to the cUTI group. Due to the small sample differences in the rates for adverse events when com-pared to
size, we cannot rule out that the difference in the point other antimicrobial agents and did not report cases of
estimate was caused by chance. pulmonary fibrosis and hepatotoxicity.
Crdoba et al. BMC Infectious Diseases (2017) 17:670 Page 5 of 6

Another alternative is Fosfomicyn [30]. It gives good Publishers Note

bacterial coverage with low toxicity and limited effect in Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
fecal flora, although it has low efficacy against Staphylo-
coccus saprophyticus. A systematic review reported fewer Author details
1
adverse effect of fosfomicyn in pregnant women in com- The Research Unit for General Practice and Section of General Practice,
Department of Public Health, University of Copenhagen; ster
parison to other antibiotics used in primary care [31]. Farimagsgade 5, 1014 Copenhagen, Denmark. 2Department for Bacteria,
However, fosfomicyn is not licensed for use in Denmark; Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark.
hence, it was not included for assessment in this study.
Received: 21 June 2017 Accepted: 3 October 2017

Conclusion
Antimicrobial resistance is a rising problem that do not References
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