<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02249273</url>
  </required_header>
  <id_info>
    <org_study_id>UC-CARE-001</org_study_id>
    <nct_id>NCT02249273</nct_id>
  </id_info>
  <brief_title>Diagnostic Tools in Patients With a Suspected Urinary Tract Infection in Primary Care</brief_title>
  <official_title>Diagnostic Process in Patients With a Suspected Urinary Trcat Infection in Danish Primary Care: Impact on Appropriate Use of Antibiotics and Patient's Recovery.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Copenhagen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Copenhagen</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background: Inappropriate use of antibiotics is one of the main causes for the increase of&#xD;
      antibiotic resistance strains. In Denmark general practice accounts for 90% of all prescribed&#xD;
      antibiotics and one of the most common reasons for prescribing antibiotics is the suspicion&#xD;
      of a urinary tract infection (UTI). The use of point-of-care test is meant to decrease the&#xD;
      uncertainty about the bacterial origin of the symptoms; however, there is a paucity of&#xD;
      knowledge about the validity of the different diagnostic approaches, thus impacting on the&#xD;
      proper use of antibiotics.&#xD;
&#xD;
      Objective: To assess the diagnostic validity of different diagnostic approaches in patients&#xD;
      with a suspected urinary tract infection and assess the impact on appropriate use of&#xD;
      antibiotics.&#xD;
&#xD;
      Methods: 70 practices at the capital region will consecutively include 15-20 patients. The&#xD;
      inclusion criteria of the patients comprise: a) Suspected Urinary tract infection, b) &gt; 18&#xD;
      years of age, c) patient consulting during office hours. Data at patient and GP level will be&#xD;
      gathered.&#xD;
&#xD;
      16 diagnostic approaches will be compared and proper use of antibiotics will be assessed as a&#xD;
      two-step process. The first step is the decision made during the consultation and the second&#xD;
      step is the decision made after the consultation. Sensitivity, specificity and predictive&#xD;
      values will be measure for each diagnostic approach using urine culture as a gold standard.&#xD;
      The impact on proper use of antibiotics will be assessed in a hierarchical multivariable&#xD;
      logistic model.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background&#xD;
&#xD;
      The latest report from the Staten Serum Institute (SSI)1 showed that primary health care in&#xD;
      Denmark represents 90% of all prescribed defined daily dose(DDD) of antibiotics, and that a&#xD;
      growing consumption of antibiotics is running alongside increasing resistance to E. coli,&#xD;
      specifically ESBL-producing E. coli (Extended Spectrum Beta Lactamase Producing E. coli) .&#xD;
&#xD;
      The main cause of E. coli infection at primary care level is a Urinary Tract Infection (UTI)&#xD;
      which is one of the most frequent reasons for consultation in general practice in Denmark.&#xD;
      Interestingly, there is no consensus yet about the most effective diagnostic approach to&#xD;
      identify those patients that will benefit from antibiotic therapy.&#xD;
&#xD;
      Currently in Denmark, a wide variety of diagnostic approaches can be identified in primary&#xD;
      care settings (i.e. only history taking, dipsticks, microscopy, culture and susceptibility&#xD;
      testing in practice). Nonetheless, there is not conclusive evidence yet about the diagnostic&#xD;
      validity of all these approaches and the association with appropriate prescription of&#xD;
      antibiotics(i.e. correct decision to prescribe and correct choice of antibiotics reflecting&#xD;
      the bacterial cause and resistance) and impact on patients' clinical and microbiological&#xD;
      cure.&#xD;
&#xD;
      For example, some studies that only include uncomplicated UTIs have shown that symptoms alone&#xD;
      have a very low predictive value leading to overuse of antibiotics2,3. However, Richards et&#xD;
      al after comparing the response to antibiotics of women with symptoms of UTI and a negative&#xD;
      dipstick test result, concluded that empirical antibiotic use guided only by symptoms was a&#xD;
      reasonable option4.&#xD;
&#xD;
      Furthermore, microscopy and more recent diagnostic tools such as a culture performed in&#xD;
      primary care settings have not been included in the latest pragmatic validation studies5,6.&#xD;
      Phase-contrast microscopy is widely used in primary care in Denmark, although the very few&#xD;
      studies on the subject show wide variation in sensitivity (60-100%) and specificity (49-100%)&#xD;
      of urine microscopy to predict significant bacteriuria.&#xD;
&#xD;
      Besides susceptibility testing at primary care level is only done in Denmark and the quality&#xD;
      control of the performance of these tests differs across the country. MIKAP (the Danish&#xD;
      agency in charge of the surveillance of the quality of the microbiological tests performed in&#xD;
      general practices) supervises only some Danish Regions and has not authority on the quality&#xD;
      control of the tests carried out in the capital region.&#xD;
&#xD;
      In order to curb the development of resistance bacteria strains in patients with urinary&#xD;
      tract symptoms and infections, we need to increase our knowledge of the validity of the&#xD;
      different diagnostic approaches and its impact on proper use of antibiotics and recovery&#xD;
      across the heterogeneous group of patients seeking health care in primary care.&#xD;
&#xD;
      Objectives&#xD;
&#xD;
      The central research question will be answered throughout the following specific objectives:&#xD;
&#xD;
        1. To assess the diagnostic validity (i.e. sensitivity and specificity, positive and&#xD;
           negative predictive value) of different diagnostic approaches in ruling in or ruling out&#xD;
           a UTI in different sub-population groups in general practice.&#xD;
&#xD;
        2. To describe the impact of different diagnostic approaches on the appropriateness of&#xD;
           antibiotic therapy (i.e. decision to prescribe and choice of antibiotic).&#xD;
&#xD;
        3. To describe the impact of different diagnostic approaches on clinical and&#xD;
           microbiological cure.&#xD;
&#xD;
        4. To measure the prevalence of ESBL-resistant E.coli in patients with urinary tract&#xD;
           symptoms in general practice.&#xD;
&#xD;
      Materials and Methods:&#xD;
&#xD;
      Design and setting: Prospective observational study with comparison of different diagnostic&#xD;
      approaches to gold standard in general practice.&#xD;
&#xD;
      Data Collection: Before the index consultation, the participating GPs will be asked to&#xD;
      complete a background questionnaire about experience, organization of the service and access&#xD;
      to different diagnostic tools.&#xD;
&#xD;
      The day of the index consultation, when the GP types the ICPC code for dysuria (U01) or&#xD;
      frequency (U02), as a main motive of consultation, a pop-up will automatically appear with a&#xD;
      questionnaire about the anamnesis, diagnostic approach, treatment and other relevant&#xD;
      decisions made during the consultation; this questionnaire will be directly linked to&#xD;
      DAK-E/DAMD database (Danish General Practice database aimed at improving quality in the&#xD;
      delivery of primary medical care services). Afterwards, the patient will also be asked to&#xD;
      provide a urine sample which will be sent to the Staten's Serum Institute (SSI) for culture,&#xD;
      which will be used as the reference gold standard.&#xD;
&#xD;
      The following 14 days after the index consultation, the patients will complete a symptom&#xD;
      diary (attached). They will be asked to rate some symptoms each day until recovery (or for 7&#xD;
      days if symptoms are ongoing) on a 3 point scale from &quot;nothing &quot; to &quot;a lot&quot;. After 14 days&#xD;
      patients will have to send a control urine sample. Patients with a persistently positive&#xD;
      culture will be followed up after 1and 3 months.&#xD;
&#xD;
      Further information about patient background regarding co-morbidities, previous&#xD;
      hospitalizations, and previous use of antibiotics will be gathered from national registers&#xD;
      such as The Danish national patients register and The Danish national prescription register.&#xD;
&#xD;
      Biobank: 10 µl of urine will be stored following the safety and hygiene procedures of the&#xD;
      Staten's Serum Institute microbiological laboratory only for those urine samples positive for&#xD;
      ESBL-producing E. coli. After detection of a positive resistant strain, the samples will be&#xD;
      anonymized and stored for a period of 2 years after completion of the current study. We plan&#xD;
      to carry out further microbiological analysis of the resistant bacteria in collaboration with&#xD;
      experts in proteonomics and genomics within the bigger UC-CARE projects. The collection of&#xD;
      the urine sample does not represent any risk for the patients as it follows the normal&#xD;
      procedure in general practice, it means, the patients is requested to collect a random urine&#xD;
      sample in a plastic cup at the practice facility and 14 days after at home.&#xD;
&#xD;
      Data management: All data will be entered into a database which will be linked to different&#xD;
      national registers to obtain detailed data about background information at patient level.&#xD;
      Data will be screened for data entry errors and extreme values using tables, plots and&#xD;
      specific commands of the SAS 9.03.&#xD;
&#xD;
      Variables: considering the multidimensional and multivariable models that will have to be&#xD;
      constructed in order to accurately answer the objectives, the following variables with the&#xD;
      corresponding data source will be included:&#xD;
&#xD;
      Patient level&#xD;
&#xD;
      Patients' demographics (gender, age), dysuria, frequency, supra-pubic pressure, polyuria,&#xD;
      Fever (&gt;38oC), trembling, urine offensive smell, gynecological complaints (vaginal discharge,&#xD;
      pruritus), low back pain, blood in urine. Number of days since first symptom started.&#xD;
      Diagnostic test:, diagnose, treatment, severity of symptoms, bothersomeness, impact on daily&#xD;
      activities. Previous hospitalization within the last year: diagnosis, discharge date.&#xD;
      Consumption of antibiotics within the last year.&#xD;
&#xD;
      GP level Number of consultations during office hours due to dysuria and/or frequency as a&#xD;
      main motive of consultation, GPs' demographics, number of patients in the GPs' list,&#xD;
      point-of-care test for urine examination: type of point-of-care tests available in the&#xD;
      practice, brand and technical specifications for each test. Attendance to courses about&#xD;
      performance of the tests.&#xD;
&#xD;
      Statistical analysis: Data will be analyzed using SAS 9.03. A comparison of proportions will&#xD;
      be performed using the chi-square test. For the first two objectives, the result of the urine&#xD;
      culture will be used as the gold standard, a cut-off value of &gt;=103cfu/ml, or pure growth of&#xD;
      E.coli, and &gt; 10 4 for more unusual organisms or mixed growth will be used to define a&#xD;
      positive culture,and we will calculate sensitivity, specificity, negative predictive value&#xD;
      and positive predictive value for each diagnostic approach against the gold standard.&#xD;
&#xD;
      Regarding the third objective prescription of antibiotics and choice of the right antibiotic&#xD;
      will be operationalized as binary dependent variables in a logistic regression model, while&#xD;
      for the last two objectives number of days until symptomatic and microbiological cure will be&#xD;
      analyzed as continuous dependent variables in a multiple linear regression model. Depending&#xD;
      on the number of cases included in the one month and three months follow-up of&#xD;
      microbiological cure, a Poisson regression model will be developed.&#xD;
&#xD;
      The propensity score matching technic will be employed to adjust for pre-test imbalances in&#xD;
      the different groups of treatment approaches in order to produce unbiased estimates of the&#xD;
      tests effect on the main outcomes and create participant characteristic balance among the&#xD;
      groups.&#xD;
&#xD;
      Sample calculation Different samples sizes will be needed to compare proper use of&#xD;
      antibiotics between the 16 diagnostic profiles. Due to the observational design of the study,&#xD;
      we do not know yet with certainty the distribution of the diagnostic profiles, so at least&#xD;
      there are two samples sized we are aiming at. The first one aims to see a clinically relevant&#xD;
      10% difference in proper use of antibiotics when comparing the diagnostic profiles that&#xD;
      affect the decision during the consultation versus the diagnostic profiles that affect the&#xD;
      decision after the consultation.&#xD;
&#xD;
      The assumptions are: a) the 4 diagnostic profiles that influence the decision during the&#xD;
      consultation are use in 60% of the patients, b) the correct decision is taken in 60% of the&#xD;
      patients in this group, while c) the correct decision during the consultation is taken only&#xD;
      in 40% of the patients in which any of the remaining 12 diagnostic profiles are performed. We&#xD;
      will need 60 practices recruiting 15 patients each (n=900). Intra-class correlation =0.2,&#xD;
      α=0.05 and β=0.2.&#xD;
&#xD;
      The second sample size relates to the detection of a prevalence of ESBL-producing E. Coli&#xD;
      between 0 to 6% in patients with a suspected UTI in primary care. Our assumptions for the&#xD;
      sample calculation are as follows: a) 60% of patients with symptoms do not have a positive&#xD;
      culture, b) 80% of the patients with a positive culture are infected with a E.Coli strain.&#xD;
      Therefore, we need 1500 patients with a suspected UTI attending primary care to detect a&#xD;
      prevalence of ESBL-resistant E.coli between 0 to 6% with a 95% confidence interval.&#xD;
&#xD;
      Ethics&#xD;
&#xD;
      The study does not represent any risk for the patients due to the observational design. It&#xD;
      means the diagnostic process and the treatment will be register as it is done in every day&#xD;
      practice. Participation in the study implies for the patient that they have to fill in a&#xD;
      diary about symptoms for 7 days and they should be willing to be contacted 3 days and 14 days&#xD;
      after by the personnel from the practice to know whether they have filled in the diary, sent&#xD;
      it to the research unit and sent the second sample to the microbiological department.&#xD;
      Consequently, the course of the symptoms/disease is not affected by the fact of participating&#xD;
      or not in the study.&#xD;
&#xD;
      All the personnel at each practice will be informed about the study, so as soon as the&#xD;
      patient contacts the practice due to the symptoms listed at the inclusion criteria section,&#xD;
      they will receive the first information about the study.&#xD;
&#xD;
      The first contact person (i.e. secretary, nurse, general practitioner) will ask the patient&#xD;
      whether they are interested in participating in a project that aims to improve the management&#xD;
      of patients with a suspected urinary tract infection. If the person is interested in&#xD;
      participating in the study, then he/she will be given a leaflet with information about the&#xD;
      study. This leaflet can be read while waiting for the consultation.&#xD;
&#xD;
      If the patient has further questions, they will be answered during the consultation to&#xD;
      guarantee privacy. The patient is welcome to have a companion, in case they consider it is&#xD;
      necessary in order to make a well-informed and thorough decision. However, due to the fact&#xD;
      that these symptoms are acute and non-life-threatening complaints, in every day practice the&#xD;
      patient uses to come alone. It means, to guarantee that the patient makes a non-influenced&#xD;
      decision, the personnel is instructed to emphasize to the patients that they have as much&#xD;
      time as the want to think about, they can ask questions and they can be sure that they&#xD;
      refusal to participating in the project won't change the normal diagnostic process and&#xD;
      treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>December 2014</start_date>
  <completion_date type="Actual">December 2015</completion_date>
  <primary_completion_date type="Actual">December 2015</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of patients with appropriate antibiotic treatment decisions for each diagnostic approach during the consultation.</measure>
    <time_frame>8 months</time_frame>
    <description>We will compare appropriate use of antibiotics within the different diagnostic approaches</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of days until clinical cure.</measure>
    <time_frame>8 months</time_frame>
    <description>Number of days until clinical cure (i.e. first day without urinary symptoms)and number of days to become symptoms free.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of days until microbiological cure.</measure>
    <time_frame>8 months</time_frame>
    <description>Number of days until microbiological cure (i.e. culture reported as negative).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevalence of resistant strains</measure>
    <time_frame>8 months</time_frame>
    <description>Sensibility test</description>
  </secondary_outcome>
  <enrollment type="Actual">500</enrollment>
  <condition>Urinary Tract Infections</condition>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Diagnostic approaches</intervention_name>
    <description>General practitioners will register the diagnostic process in patients with a suspected urinary tract infection</description>
    <other_name>Stix, microscopy, culture</other_name>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Urine sample&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients &gt;0 18 years old attending primary care services during offcie hours with a&#xD;
        suspected urinary tract infection&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Suspected Urinary tract infection&#xD;
&#xD;
          -  &gt; 18 years of age&#xD;
&#xD;
          -  Patient consulting during office hours.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients currently taking antibiotics&#xD;
&#xD;
          -  Inability to complete a diary and send two urine samples during the time of the study&#xD;
&#xD;
          -  Patients with a urinary catheter as they have a closer follow-up between first and&#xD;
             secondary care.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lars Bjerrum, Professor</last_name>
    <role>Study Director</role>
    <affiliation>Department of general practice, University of Copenhagen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Lægerne Simonsen og Grubbe</name>
      <address>
        <city>Copenhague</city>
        <zip>2300</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <link>
    <url>http://uc-care.ku.dk/</url>
    <description>University of Copenhagen research center for control of antibiotic resistance</description>
  </link>
  <verification_date>October 2017</verification_date>
  <study_first_submitted>September 22, 2014</study_first_submitted>
  <study_first_submitted_qc>September 22, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 25, 2014</study_first_posted>
  <last_update_submitted>October 6, 2017</last_update_submitted>
  <last_update_submitted_qc>October 6, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">October 9, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Copenhagen</investigator_affiliation>
    <investigator_full_name>Gloria Cristina Cordoba</investigator_full_name>
    <investigator_title>MD-MPH</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Communicable Diseases</mesh_term>
    <mesh_term>Urinary Tract Infections</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02249273
org study id: UC-CARE-001
nct id: NCT02249273
lead sponsor: 
has dmc: No
Background: Inappropriate use of antibiotics is one of the main causes for the increase of
      antibiotic resistance strains. In Denmark general practice accounts for 90% of all prescribed
      antibiotics and one of the most common reasons for prescribing antibiotics is the suspicion
      of a urinary tract infection (UTI). The use of point-of-care test is meant to decrease the
      uncertainty about the bacterial origin of the symptoms; however, there is a paucity of
      knowledge about the validity of the different diagnostic approaches, thus impacting on the
      proper use of antibiotics.

      Objective: To assess the diagnostic validity of different diagnostic approaches in patients
      with a suspected urinary tract infection and assess the impact on appropriate use of
      antibiotics.

      Methods: 70 practices at the capital region will consecutively include 15-20 patients. The
      inclusion criteria of the patients comprise: a) Suspected Urinary tract infection, b) > 18
      years of age, c) patient consulting during office hours. Data at patient and GP level will be
      gathered.

      16 diagnostic approaches will be compared and proper use of antibiotics will be assessed as a
      two-step process. The first step is the decision made during the consultation and the second
      step is the decision made after the consultation. Sensitivity, specificity and predictive
      values will be measure for each diagnostic approach using urine culture as a gold standard.
      The impact on proper use of antibiotics will be assessed in a hierarchical multivariable
      logistic model.
Background

      The latest report from the Staten Serum Institute (SSI)1 showed that primary health care in
      Denmark represents 90% of all prescribed defined daily dose(DDD) of antibiotics, and that a
      growing consumption of antibiotics is running alongside increasing resistance to E. coli,
      specifically ESBL-producing E. coli (Extended Spectrum Beta Lactamase Producing E. coli) .

      The main cause of E. coli infection at primary care level is a Urinary Tract Infection (UTI)
      which is one of the most frequent reasons for consultation in general practice in Denmark.
      Interestingly, there is no consensus yet about the most effective diagnostic approach to
      identify those patients that will benefit from antibiotic therapy.

      Currently in Denmark, a wide variety of diagnostic approaches can be identified in primary
      care settings (i.e. only history taking, dipsticks, microscopy, culture and susceptibility
      testing in practice). Nonetheless, there is not conclusive evidence yet about the diagnostic
      validity of all these approaches and the association with appropriate prescription of
      antibiotics(i.e. correct decision to prescribe and correct choice of antibiotics reflecting
      the bacterial cause and resistance) and impact on patients' clinical and microbiological
      cure.

      For example, some studies that only include uncomplicated UTIs have shown that symptoms alone
      have a very low predictive value leading to overuse of antibiotics2,3. However, Richards et
      al after comparing the response to antibiotics of women with symptoms of UTI and a negative
      dipstick test result, concluded that empirical antibiotic use guided only by symptoms was a
      reasonable option4.

      Furthermore, microscopy and more recent diagnostic tools such as a culture performed in
      primary care settings have not been included in the latest pragmatic validation studies5,6.
      Phase-contrast microscopy is widely used in primary care in Denmark, although the very few
      studies on the subject show wide variation in sensitivity (60-100%) and specificity (49-100%)
      of urine microscopy to predict significant bacteriuria.

      Besides susceptibility testing at primary care level is only done in Denmark and the quality
      control of the performance of these tests differs across the country. MIKAP (the Danish
      agency in charge of the surveillance of the quality of the microbiological tests performed in
      general practices) supervises only some Danish Regions and has not authority on the quality
      control of the tests carried out in the capital region.

      In order to curb the development of resistance bacteria strains in patients with urinary
      tract symptoms and infections, we need to increase our knowledge of the validity of the
      different diagnostic approaches and its impact on proper use of antibiotics and recovery
      across the heterogeneous group of patients seeking health care in primary care.

      Objectives

      The central research question will be answered throughout the following specific objectives:

        1. To assess the diagnostic validity (i.e. sensitivity and specificity, positive and
           negative predictive value) of different diagnostic approaches in ruling in or ruling out
           a UTI in different sub-population groups in general practice.

        2. To describe the impact of different diagnostic approaches on the appropriateness of
           antibiotic therapy (i.e. decision to prescribe and choice of antibiotic).

        3. To describe the impact of different diagnostic approaches on clinical and
           microbiological cure.

        4. To measure the prevalence of ESBL-resistant E.coli in patients with urinary tract
           symptoms in general practice.

      Materials and Methods:

      Design and setting: Prospective observational study with comparison of different diagnostic
      approaches to gold standard in general practice.

      Data Collection: Before the index consultation, the participating GPs will be asked to
      complete a background questionnaire about experience, organization of the service and access
      to different diagnostic tools.

      The day of the index consultation, when the GP types the ICPC code for dysuria (U01) or
      frequency (U02), as a main motive of consultation, a pop-up will automatically appear with a
      questionnaire about the anamnesis, diagnostic approach, treatment and other relevant
      decisions made during the consultation; this questionnaire will be directly linked to
      DAK-E/DAMD database (Danish General Practice database aimed at improving quality in the
      delivery of primary medical care services). Afterwards, the patient will also be asked to
      provide a urine sample which will be sent to the Staten's Serum Institute (SSI) for culture,
      which will be used as the reference gold standard.

      The following 14 days after the index consultation, the patients will complete a symptom
      diary (attached). They will be asked to rate some symptoms each day until recovery (or for 7
      days if symptoms are ongoing) on a 3 point scale from "nothing " to "a lot". After 14 days
      patients will have to send a control urine sample. Patients with a persistently positive
      culture will be followed up after 1and 3 months.

      Further information about patient background regarding co-morbidities, previous
      hospitalizations, and previous use of antibiotics will be gathered from national registers
      such as The Danish national patients register and The Danish national prescription register.

      Biobank: 10 µl of urine will be stored following the safety and hygiene procedures of the
      Staten's Serum Institute microbiological laboratory only for those urine samples positive for
      ESBL-producing E. coli. After detection of a positive resistant strain, the samples will be
      anonymized and stored for a period of 2 years after completion of the current study. We plan
      to carry out further microbiological analysis of the resistant bacteria in collaboration with
      experts in proteonomics and genomics within the bigger UC-CARE projects. The collection of
      the urine sample does not represent any risk for the patients as it follows the normal
      procedure in general practice, it means, the patients is requested to collect a random urine
      sample in a plastic cup at the practice facility and 14 days after at home.

      Data management: All data will be entered into a database which will be linked to different
      national registers to obtain detailed data about background information at patient level.
      Data will be screened for data entry errors and extreme values using tables, plots and
      specific commands of the SAS 9.03.

      Variables: considering the multidimensional and multivariable models that will have to be
      constructed in order to accurately answer the objectives, the following variables with the
      corresponding data source will be included:

      Patient level

      Patients' demographics (gender, age), dysuria, frequency, supra-pubic pressure, polyuria,
      Fever (>38oC), trembling, urine offensive smell, gynecological complaints (vaginal discharge,
      pruritus), low back pain, blood in urine. Number of days since first symptom started.
      Diagnostic test:, diagnose, treatment, severity of symptoms, bothersomeness, impact on daily
      activities. Previous hospitalization within the last year: diagnosis, discharge date.
      Consumption of antibiotics within the last year.

      GP level Number of consultations during office hours due to dysuria and/or frequency as a
      main motive of consultation, GPs' demographics, number of patients in the GPs' list,
      point-of-care test for urine examination: type of point-of-care tests available in the
      practice, brand and technical specifications for each test. Attendance to courses about
      performance of the tests.

      Statistical analysis: Data will be analyzed using SAS 9.03. A comparison of proportions will
      be performed using the chi-square test. For the first two objectives, the result of the urine
      culture will be used as the gold standard, a cut-off value of >=103cfu/ml, or pure growth of
      E.coli, and > 10 4 for more unusual organisms or mixed growth will be used to define a
      positive culture,and we will calculate sensitivity, specificity, negative predictive value
      and positive predictive value for each diagnostic approach against the gold standard.

      Regarding the third objective prescription of antibiotics and choice of the right antibiotic
      will be operationalized as binary dependent variables in a logistic regression model, while
      for the last two objectives number of days until symptomatic and microbiological cure will be
      analyzed as continuous dependent variables in a multiple linear regression model. Depending
      on the number of cases included in the one month and three months follow-up of
      microbiological cure, a Poisson regression model will be developed.

      The propensity score matching technic will be employed to adjust for pre-test imbalances in
      the different groups of treatment approaches in order to produce unbiased estimates of the
      tests effect on the main outcomes and create participant characteristic balance among the
      groups.

      Sample calculation Different samples sizes will be needed to compare proper use of
      antibiotics between the 16 diagnostic profiles. Due to the observational design of the study,
      we do not know yet with certainty the distribution of the diagnostic profiles, so at least
      there are two samples sized we are aiming at. The first one aims to see a clinically relevant
      10% difference in proper use of antibiotics when comparing the diagnostic profiles that
      affect the decision during the consultation versus the diagnostic profiles that affect the
      decision after the consultation.

      The assumptions are: a) the 4 diagnostic profiles that influence the decision during the
      consultation are use in 60% of the patients, b) the correct decision is taken in 60% of the
      patients in this group, while c) the correct decision during the consultation is taken only
      in 40% of the patients in which any of the remaining 12 diagnostic profiles are performed. We
      will need 60 practices recruiting 15 patients each (n=900). Intra-class correlation =0.2,
      α=0.05 and β=0.2.

      The second sample size relates to the detection of a prevalence of ESBL-producing E. Coli
      between 0 to 6% in patients with a suspected UTI in primary care. Our assumptions for the
      sample calculation are as follows: a) 60% of patients with symptoms do not have a positive
      culture, b) 80% of the patients with a positive culture are infected with a E.Coli strain.
      Therefore, we need 1500 patients with a suspected UTI attending primary care to detect a
      prevalence of ESBL-resistant E.coli between 0 to 6% with a 95% confidence interval.

      Ethics

      The study does not represent any risk for the patients due to the observational design. It
      means the diagnostic process and the treatment will be register as it is done in every day
      practice. Participation in the study implies for the patient that they have to fill in a
      diary about symptoms for 7 days and they should be willing to be contacted 3 days and 14 days
      after by the personnel from the practice to know whether they have filled in the diary, sent
      it to the research unit and sent the second sample to the microbiological department.
      Consequently, the course of the symptoms/disease is not affected by the fact of participating
      or not in the study.

      All the personnel at each practice will be informed about the study, so as soon as the
      patient contacts the practice due to the symptoms listed at the inclusion criteria section,
      they will receive the first information about the study.

      The first contact person (i.e. secretary, nurse, general practitioner) will ask the patient
      whether they are interested in participating in a project that aims to improve the management
      of patients with a suspected urinary tract infection. If the person is interested in
      participating in the study, then he/she will be given a leaflet with information about the
      study. This leaflet can be read while waiting for the consultation.

      If the patient has further questions, they will be answered during the consultation to
      guarantee privacy. The patient is welcome to have a companion, in case they consider it is
      necessary in order to make a well-informed and thorough decision. However, due to the fact
      that these symptoms are acute and non-life-threatening complaints, in every day practice the
      patient uses to come alone. It means, to guarantee that the patient makes a non-influenced
      decision, the personnel is instructed to emphasize to the patients that they have as much
      time as the want to think about, they can ask questions and they can be sure that they
      refusal to participating in the project won't change the normal diagnostic process and
      treatment.
observational model: Cohort
time perspective: Prospective
measure: Percentage of patients with appropriate antibiotic treatment decisions for each diagnostic approach during the consultation.
time frame: 8 months
description: We will compare appropriate use of antibiotics within the different diagnostic approaches
measure: Number of days until clinical cure.
time frame: 8 months
description: Number of days until clinical cure (i.e. first day without urinary symptoms)and number of days to become symptoms free.
measure: Number of days until microbiological cure.
time frame: 8 months
description: Number of days until microbiological cure (i.e. culture reported as negative).
measure: Prevalence of resistant strains
time frame: 8 months
description: Sensibility test
intervention type: Other
intervention name: Diagnostic approaches
description: General practitioners will register the diagnostic process in patients with a suspected urinary tract infection
other name: Stix, microscopy, culture
Urine sample
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lars Bjerrum, Professor
role: Study Director
affiliation: Department of general practice, University of Copenhagen
facility: 
country: Denmark
url: http://uc-care.ku.dk/
description: University of Copenhagen research center for control of antibiotic resistance
responsible party type: Principal Investigator
investigator affiliation: University of Copenhagen
investigator full name: Gloria Cristina Cordoba
investigator title: MD-MPH
mesh term: Infections
mesh term: Communicable Diseases
mesh term: Urinary Tract Infections