<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/NCT02257931</url>
  </required_header>
  <id_info>
    <org_study_id>8414106</org_study_id>
    <nct_id>NCT02257931</nct_id>
  </id_info>
  <brief_title>Gram-negative Bacteremia in HSCT Recipients</brief_title>
  <acronym>GNB</acronym>
  <official_title>Resistance Pattern of Gram-negative Bacteria Isolated From Blood From HSCT Recipients.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>European Society for Blood and Marrow Transplantation</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>European Society for Blood and Marrow Transplantation</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      A significant increase in resistant bacteria emerging in HSCT recipients. For example, 25% -&#xD;
      42% of all enterobacteriaceae produce extended spectrum beta-lactamases; 8 - 72% of&#xD;
      Pseudomonas aeruginosa are resistant to at least one and 25 - 62% to three or more antibiotic&#xD;
      classes, 13% of Gram-negative bacteria are caused by a multidrug-resistant (MDR) strain&#xD;
      (Trecarichi JI 09, Mikulska BBMT 09, Oliveira BMT 07, Caselli Haemat 10, Gudiol, JAC 11).&#xD;
      These resistant bacteria may be associated with increased mortality and have limited&#xD;
      treatment options (Caselli Haemat 10, Poutsiaka BMT 07, DiazGranadoz JID 05). To provide the&#xD;
      currently best empirical coverage and to control the growing resistance, knowledge of trends&#xD;
      in antibiotic susceptibility, as well as risk factors is essential. For this reason we&#xD;
      propose to perform non-interventional prospective multicentre study in EBMT centres.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary objective:&#xD;
&#xD;
      To determine the incidence and pattern of antimicrobials resistance among Gram-negative&#xD;
      bacteria isolated from blood in HSCT patients during the first 6 months after the&#xD;
      transplantation.&#xD;
&#xD;
      Secondary Objective(s):&#xD;
&#xD;
      2) to determine whether the currently administered empirical therapy is appropriate; 3) to&#xD;
      determine mortality associated with resistant vs. sensitive Gram-negative bacteria&#xD;
&#xD;
      Primary endpoints:&#xD;
&#xD;
      The proportion of resistant pathogens among gram-negative bacterial pathogens isolated from&#xD;
      blood of HSCT recipients during the first 6 months post HSCT.&#xD;
&#xD;
        1. Pathogens resistant to either one of the following: ceftazidime or cefepime or&#xD;
           piperacillin-tazobactam&#xD;
&#xD;
        2. Pathogens with carbapenem resistance (not including ertapenem)&#xD;
&#xD;
        3. MDR pathogens&#xD;
&#xD;
      Secondary endpoints:&#xD;
&#xD;
        1. The proportion of resistant Gram-negative pathogens not listed in the primary end-point&#xD;
           among Gram-negative bacterial pathogens isolated from blood of HSCT recipients during&#xD;
           the first 6 months post HSCT:&#xD;
&#xD;
             -  Gram-negative pathogens resistant to fluoroquinolones&#xD;
&#xD;
             -  Gram-negative pathogens resistant to at least one of aminoglycosides&#xD;
&#xD;
             -  Gram-negative pathogens resistant to colistin&#xD;
&#xD;
             -  Gram-negative pathogens (other than Pseudomonas) resistant to tigecycline&#xD;
&#xD;
             -  Acinetobacter spp. resistant to ampicillin-sulbactam&#xD;
&#xD;
             -  Acinetobacter spp. resistant to tetracyclin or minocycline&#xD;
&#xD;
             -  Stenotrophomonas maltophilia resistant to trimethoprim-sulfamethoxazole&#xD;
&#xD;
             -  Stenotrophomonas maltophilia resistant to minocycline&#xD;
&#xD;
        2. The outcome of the infections caused by resistant pathogens vs. sensitive, including&#xD;
           mortality of any cause within 7 days and within 30 days;&#xD;
&#xD;
        3. The appropriateness of the currently administered empirical antimicrobial therapy;&#xD;
           Inappropriate initial antimicrobial therapy will be defined as empirical antibiotic&#xD;
           regimen, given in the first 48 hours following obtaining the blood cultures, that does&#xD;
           not include at least one antibiotic that is active in vitro against the infecting&#xD;
           microorganism.&#xD;
&#xD;
      Research design:&#xD;
&#xD;
      Data on all the episodes of Gram-negative bacteria blood stream infections will be collected&#xD;
      prospectively from the initiation of the conditioning treatment until the end of the first 6&#xD;
      months after the HSCT (or death or lost follow-up, if they occur earlier).&#xD;
&#xD;
      Data on the patients who will develop Gram-negative infection will be reported using special&#xD;
      MED C form and include data on the pathogen and antimicrobial susceptibility of the pathogen,&#xD;
      treatment and outcome, and presence of certain risk factors, in addition to the data present&#xD;
      in MED A form.&#xD;
&#xD;
      Patient's data such as age, gender, primary diagnosis and status of the disease, presence of&#xD;
      co-morbidities, HSCT type, donor type, conditioning regimen (myeloablative versus reduced&#xD;
      intensity), GVHD prophylaxis and outcome at the time of report will be obtained from the MED&#xD;
      A form.&#xD;
&#xD;
      Study Population:&#xD;
&#xD;
      Inclusion criteria: Allogeneic or autologous HSCT recipients, of all ages, for any&#xD;
      indications.&#xD;
&#xD;
      Exclusion criteria: Patients who are not willing to participate. Expected number of patients:&#xD;
      3650 HSCT patients to be recruited and followed in order to obtain data on 365 Gram negative&#xD;
      episodes.&#xD;
&#xD;
      Basis for calculations:&#xD;
&#xD;
      Clinical assumptions&#xD;
&#xD;
      ~30% of HSCT patients will have bacteremia, about a half of them due to Gram negatives=10-15%&#xD;
      of HSCT patients. Depending on local epidemiology, about a 40% of them will be resistant to&#xD;
      at least one of the antibiotics mentioned in the primary endpoint. Mortality in resistant GN&#xD;
      bacteremia is 30-50%. Mortality in sensitive bacteremia is 5-20%.&#xD;
&#xD;
      Statistical issues&#xD;
&#xD;
        -  The actual sample size for the analyses will be the number N* of episodes of&#xD;
           Gram-negative bacteremia observed. These will be observed in N≤N* patients. For&#xD;
           simplicity, we will assume that one patient ↔ one episode, i.e. N=N*.&#xD;
&#xD;
        -  The total number of transplants that we should have in the participating centers during&#xD;
           the recruitment period in order to observe N patients with (at least) an episode of&#xD;
           Gram-negative bacteremia will be indicated by T. We will assume that N = 10% of T.&#xD;
&#xD;
        -  Notice thus that these scenarios are &quot;conservative&quot;, as we could expect to observe more&#xD;
           patients with an episodes than 10%, and multiple episodes per patient.&#xD;
&#xD;
        -  We considered several scenarios computing the minimum sample size necessary to obtain an&#xD;
           estimation of the incidence of resistance among Gram-negative bacteremia episodes with&#xD;
           precision equal to 0.05 (preferably) or 0.1, assuming a value between 20% and 60% for&#xD;
           the incidence. (Confidence level for the interval estimate always equal to 95%).&#xD;
           Scenarios have also been considered for secondary objectives. All calculations were done&#xD;
           using the NCSS-PASS 2000 software.&#xD;
&#xD;
      T=365 transplants (N=3650 patients) is a minimum number of transplants necessary to be able&#xD;
      to get a 95%CI=(0.35,0.45) when the actual incidence of resistance is equal to 40%.&#xD;
&#xD;
      Data Collection &amp; Statistical Analysis Plan:&#xD;
&#xD;
      Center registration form will be sent to all EBMT centers before the beginning of the study.&#xD;
      It will assess their willingness to participate and provide some background information on&#xD;
      the number of transplants performed/year, names of the responsible persons, methods used by&#xD;
      laboratories, etc. All episodes of blood stream Gram-negative bacterial infections will be&#xD;
      collected prospectively since the initiation of the conditioning treatment and further on&#xD;
      during the 6 months after the transplantation. All the episodes of Gram-negative bacteremias&#xD;
      will be included, including multiple episodes in the same patient. For each episode of&#xD;
      Gram-negative bacteremia, additional information including relevant microbiological data will&#xD;
      be collected using MED C form. MED C form will include data on each Gram- negative isolate.&#xD;
      Note, each time that the patient has a new positive blood culture for Gram - negative&#xD;
      bacteria, a new MED C form should be filled. Repeated isolation of same pathogen, with same&#xD;
      in vitro susceptibility will be considered as one isolate. We ask that MED C forms will be&#xD;
      sent within 3 months from the end of the episode.&#xD;
&#xD;
      The baseline data on all the patients who will develop blood stream Gram-negative bacterial&#xD;
      infections during the study period will be reported using the MED A form, which is routinely&#xD;
      filled for all patients in the centers that belong to the EBMT. We ask that it will be filled&#xD;
      within 3 months from the end of the 6 months after HSCT (or earlier if the patient ceased).&#xD;
&#xD;
      Resistance to antibiotics will be studied by in-vitro sensitivity tests performed by the&#xD;
      local laboratories. The characteristics of the local laboratories, including essential data&#xD;
      on methods used to determine susceptibility of isolates and guidelines used to determine&#xD;
      susceptibility will be reported in the Centre Registration Form.&#xD;
&#xD;
      The collaborator from each center will be responsible for the reports from laboratories.&#xD;
&#xD;
      Statistical analysis The analysis of the data will be mostly descriptive. The incidence of&#xD;
      resistance will be computed as a percentage, the denominator being the number of episodes of&#xD;
      Gram-negative bacteremia, and the numerator being the number of episodes classified as&#xD;
      &quot;resistant&quot;. The relationship between Resistance and prognostic factors / characteristics&#xD;
      will be investigated mostly in univariate analysis, applying standard summary measures&#xD;
      (tables, quantiles) and non-parametric tests (chi-squared or Fisher Exact, Mann-Whitney or&#xD;
      Kruskal-Wallis) - for categorical and continuous variables respectively. Possibly, a&#xD;
      multivariate analysis could also be applied, using logistic regression; random effects models&#xD;
      or GEE could be used to account for dependence of observations - nested by patient and&#xD;
      center. The short-term mortality (at 7 and 30 days) will be computed as a percentage - unless&#xD;
      a relevant proportion of loss to follow-up will be observed.&#xD;
&#xD;
      All data collection will be performed by the IDWP data office (Leiden) according to EBMT&#xD;
      guidelines.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>February 2014</start_date>
  <completion_date type="Actual">April 2017</completion_date>
  <primary_completion_date type="Actual">December 2016</primary_completion_date>
  <study_type>Observational [Patient Registry]</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <target_duration>6 Months</target_duration>
  <primary_outcome>
    <measure>The proportion of resistant pathogens among gram-negative bacterial pathogens isolated from blood of HSCT recipients during the first 6 months post HSCT.</measure>
    <time_frame>6 months after HSCT</time_frame>
    <description>Pathogens resistant to either one of the following: ceftazidime or cefepime or piperacillin-tazobactam&#xD;
Pathogens with carbapenem resistance (not including ertapenem)&#xD;
MDR pathogens</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The proportion of resistant Gram-negative pathogens not listed in the primary end-point among Gram-negative bacterial pathogens isolated from blood of HSCT recipients during the first 6 months post HSCT:</measure>
    <time_frame>6 months after HSCT</time_frame>
    <description>Gram-negative pathogens resistant to fluoroquinolones&#xD;
Gram-negative pathogens resistant to at least one of aminoglycosides&#xD;
Gram-negative pathogens resistant to colistin&#xD;
Gram-negative pathogens (other than Pseudomonas) resistant to tigecyclin&#xD;
Acinetobacter spp. resistant to ampicillin-sulbactam&#xD;
Acinetobacter spp. resistant to tetracyclin or minocycline&#xD;
Stenotrophomonas maltophilia resistant to trimethoprim-sulfamethoxazole&#xD;
Stenotrophomonas maltophilia resistant to minocycline</description>
  </secondary_outcome>
  <other_outcome>
    <measure>The outcome of the infections caused by resistant pathogens vs. sensitive, including mortality of any cause within 7 days and within 30 days;</measure>
    <time_frame>30 days after HSCT</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>The appropriateness of the currently administered empirical antimicrobial therapy</measure>
    <time_frame>6 months after HSCT</time_frame>
    <description>The appropriateness of the currently administered empirical antimicrobial therapy; Inappropriate initial antimicrobial therapy will be defined as empirical antibiotic regimen, given in the first 48 hours following obtaining the blood cultures, that does not include at least one antibiotic that is active in vitro against the infecting microorganism.</description>
  </other_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">591</enrollment>
  <condition>Allogeneic or Autologous HSCT</condition>
  <arm_group>
    <arm_group_label>HSCT recipient</arm_group_label>
    <description>Allogeneic or autologous HSCT recipients, of all ages, for any indications. From this group we take those with a gram-negative bacteremia within 6 months after HSCT.</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        eligible patients from EBMT centres&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Allogeneic or autologous HSCT recipients, of all ages, for any indications.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who are not willing to participate.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dina Averbuch, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hadassah University Hospital, Pediatric Infectious Diseases Unit, Jerusalem, Israel</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Dan Engelhard, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hadassah University Hospital, Pediatric Infectious Diseases Unit, Jerusalem, Israel</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Simone Cesaro, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Policlinico G.B. Rossi, paediatric haematology oncology, Verona, Italy</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Hospital Gasthuisberg</name>
      <address>
        <city>Leuven</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>First Affiliated Hospital of Soochow University</name>
      <address>
        <city>Suzhou</city>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Center Rebro</name>
      <address>
        <city>Zagreb</city>
        <country>Croatia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Muenster</name>
      <address>
        <city>Muenster</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitaetsklinikum Wuerzburg</name>
      <address>
        <city>Wuerzburg</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rambam Medical Center</name>
      <address>
        <city>Haifa</city>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Inst. Portugues de Oncologia do Porto</name>
      <address>
        <city>Porto</city>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Federal Research Centre for Pediatric Hematology</name>
      <address>
        <city>Moscow</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Karolinska University Hospital</name>
      <address>
        <city>Stockholm</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Anadolu Medical Center</name>
      <address>
        <city>Kocaeli</city>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>China</country>
    <country>Croatia</country>
    <country>Germany</country>
    <country>Israel</country>
    <country>Portugal</country>
    <country>Russian Federation</country>
    <country>Sweden</country>
    <country>Turkey</country>
  </location_countries>
  <verification_date>April 2017</verification_date>
  <study_first_submitted>October 2, 2014</study_first_submitted>
  <study_first_submitted_qc>October 6, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 7, 2014</study_first_posted>
  <last_update_submitted>April 28, 2017</last_update_submitted>
  <last_update_submitted_qc>April 28, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">May 1, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>infection</keyword>
  <keyword>bacteria</keyword>
  <keyword>gram-negative</keyword>
  <keyword>HSCT</keyword>
  <keyword>allogeneic</keyword>
  <keyword>autologous</keyword>
  <keyword>recipients, of all ages, for any indications</keyword>
  <!-- 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/NCT02257931
org study id: 8414106
nct id: NCT02257931
lead sponsor: 
has dmc: No
A significant increase in resistant bacteria emerging in HSCT recipients. For example, 25% -
      42% of all enterobacteriaceae produce extended spectrum beta-lactamases; 8 - 72% of
      Pseudomonas aeruginosa are resistant to at least one and 25 - 62% to three or more antibiotic
      classes, 13% of Gram-negative bacteria are caused by a multidrug-resistant (MDR) strain
      (Trecarichi JI 09, Mikulska BBMT 09, Oliveira BMT 07, Caselli Haemat 10, Gudiol, JAC 11).
      These resistant bacteria may be associated with increased mortality and have limited
      treatment options (Caselli Haemat 10, Poutsiaka BMT 07, DiazGranadoz JID 05). To provide the
      currently best empirical coverage and to control the growing resistance, knowledge of trends
      in antibiotic susceptibility, as well as risk factors is essential. For this reason we
      propose to perform non-interventional prospective multicentre study in EBMT centres.
Primary objective:

      To determine the incidence and pattern of antimicrobials resistance among Gram-negative
      bacteria isolated from blood in HSCT patients during the first 6 months after the
      transplantation.

      Secondary Objective(s):

      2) to determine whether the currently administered empirical therapy is appropriate; 3) to
      determine mortality associated with resistant vs. sensitive Gram-negative bacteria

      Primary endpoints:

      The proportion of resistant pathogens among gram-negative bacterial pathogens isolated from
      blood of HSCT recipients during the first 6 months post HSCT.

        1. Pathogens resistant to either one of the following: ceftazidime or cefepime or
           piperacillin-tazobactam

        2. Pathogens with carbapenem resistance (not including ertapenem)

        3. MDR pathogens

      Secondary endpoints:

        1. The proportion of resistant Gram-negative pathogens not listed in the primary end-point
           among Gram-negative bacterial pathogens isolated from blood of HSCT recipients during
           the first 6 months post HSCT:

             -  Gram-negative pathogens resistant to fluoroquinolones

             -  Gram-negative pathogens resistant to at least one of aminoglycosides

             -  Gram-negative pathogens resistant to colistin

             -  Gram-negative pathogens (other than Pseudomonas) resistant to tigecycline

             -  Acinetobacter spp. resistant to ampicillin-sulbactam

             -  Acinetobacter spp. resistant to tetracyclin or minocycline

             -  Stenotrophomonas maltophilia resistant to trimethoprim-sulfamethoxazole

             -  Stenotrophomonas maltophilia resistant to minocycline

        2. The outcome of the infections caused by resistant pathogens vs. sensitive, including
           mortality of any cause within 7 days and within 30 days;

        3. The appropriateness of the currently administered empirical antimicrobial therapy;
           Inappropriate initial antimicrobial therapy will be defined as empirical antibiotic
           regimen, given in the first 48 hours following obtaining the blood cultures, that does
           not include at least one antibiotic that is active in vitro against the infecting
           microorganism.

      Research design:

      Data on all the episodes of Gram-negative bacteria blood stream infections will be collected
      prospectively from the initiation of the conditioning treatment until the end of the first 6
      months after the HSCT (or death or lost follow-up, if they occur earlier).

      Data on the patients who will develop Gram-negative infection will be reported using special
      MED C form and include data on the pathogen and antimicrobial susceptibility of the pathogen,
      treatment and outcome, and presence of certain risk factors, in addition to the data present
      in MED A form.

      Patient's data such as age, gender, primary diagnosis and status of the disease, presence of
      co-morbidities, HSCT type, donor type, conditioning regimen (myeloablative versus reduced
      intensity), GVHD prophylaxis and outcome at the time of report will be obtained from the MED
      A form.

      Study Population:

      Inclusion criteria: Allogeneic or autologous HSCT recipients, of all ages, for any
      indications.

      Exclusion criteria: Patients who are not willing to participate. Expected number of patients:
      3650 HSCT patients to be recruited and followed in order to obtain data on 365 Gram negative
      episodes.

      Basis for calculations:

      Clinical assumptions

      ~30% of HSCT patients will have bacteremia, about a half of them due to Gram negatives=10-15%
      of HSCT patients. Depending on local epidemiology, about a 40% of them will be resistant to
      at least one of the antibiotics mentioned in the primary endpoint. Mortality in resistant GN
      bacteremia is 30-50%. Mortality in sensitive bacteremia is 5-20%.

      Statistical issues

        -  The actual sample size for the analyses will be the number N* of episodes of
           Gram-negative bacteremia observed. These will be observed in N≤N* patients. For
           simplicity, we will assume that one patient ↔ one episode, i.e. N=N*.

        -  The total number of transplants that we should have in the participating centers during
           the recruitment period in order to observe N patients with (at least) an episode of
           Gram-negative bacteremia will be indicated by T. We will assume that N = 10% of T.

        -  Notice thus that these scenarios are "conservative", as we could expect to observe more
           patients with an episodes than 10%, and multiple episodes per patient.

        -  We considered several scenarios computing the minimum sample size necessary to obtain an
           estimation of the incidence of resistance among Gram-negative bacteremia episodes with
           precision equal to 0.05 (preferably) or 0.1, assuming a value between 20% and 60% for
           the incidence. (Confidence level for the interval estimate always equal to 95%).
           Scenarios have also been considered for secondary objectives. All calculations were done
           using the NCSS-PASS 2000 software.

      T=365 transplants (N=3650 patients) is a minimum number of transplants necessary to be able
      to get a 95%CI=(0.35,0.45) when the actual incidence of resistance is equal to 40%.

      Data Collection & Statistical Analysis Plan:

      Center registration form will be sent to all EBMT centers before the beginning of the study.
      It will assess their willingness to participate and provide some background information on
      the number of transplants performed/year, names of the responsible persons, methods used by
      laboratories, etc. All episodes of blood stream Gram-negative bacterial infections will be
      collected prospectively since the initiation of the conditioning treatment and further on
      during the 6 months after the transplantation. All the episodes of Gram-negative bacteremias
      will be included, including multiple episodes in the same patient. For each episode of
      Gram-negative bacteremia, additional information including relevant microbiological data will
      be collected using MED C form. MED C form will include data on each Gram- negative isolate.
      Note, each time that the patient has a new positive blood culture for Gram - negative
      bacteria, a new MED C form should be filled. Repeated isolation of same pathogen, with same
      in vitro susceptibility will be considered as one isolate. We ask that MED C forms will be
      sent within 3 months from the end of the episode.

      The baseline data on all the patients who will develop blood stream Gram-negative bacterial
      infections during the study period will be reported using the MED A form, which is routinely
      filled for all patients in the centers that belong to the EBMT. We ask that it will be filled
      within 3 months from the end of the 6 months after HSCT (or earlier if the patient ceased).

      Resistance to antibiotics will be studied by in-vitro sensitivity tests performed by the
      local laboratories. The characteristics of the local laboratories, including essential data
      on methods used to determine susceptibility of isolates and guidelines used to determine
      susceptibility will be reported in the Centre Registration Form.

      The collaborator from each center will be responsible for the reports from laboratories.

      Statistical analysis The analysis of the data will be mostly descriptive. The incidence of
      resistance will be computed as a percentage, the denominator being the number of episodes of
      Gram-negative bacteremia, and the numerator being the number of episodes classified as
      "resistant". The relationship between Resistance and prognostic factors / characteristics
      will be investigated mostly in univariate analysis, applying standard summary measures
      (tables, quantiles) and non-parametric tests (chi-squared or Fisher Exact, Mann-Whitney or
      Kruskal-Wallis) - for categorical and continuous variables respectively. Possibly, a
      multivariate analysis could also be applied, using logistic regression; random effects models
      or GEE could be used to account for dependence of observations - nested by patient and
      center. The short-term mortality (at 7 and 30 days) will be computed as a percentage - unless
      a relevant proportion of loss to follow-up will be observed.

      All data collection will be performed by the IDWP data office (Leiden) according to EBMT
      guidelines.
observational model: Case-Control
time perspective: Prospective
measure: The proportion of resistant pathogens among gram-negative bacterial pathogens isolated from blood of HSCT recipients during the first 6 months post HSCT.
time frame: 6 months after HSCT
description: Pathogens resistant to either one of the following: ceftazidime or cefepime or piperacillin-tazobactam
Pathogens with carbapenem resistance (not including ertapenem)
MDR pathogens
measure: The proportion of resistant Gram-negative pathogens not listed in the primary end-point among Gram-negative bacterial pathogens isolated from blood of HSCT recipients during the first 6 months post HSCT:
time frame: 6 months after HSCT
description: Gram-negative pathogens resistant to fluoroquinolones
Gram-negative pathogens resistant to at least one of aminoglycosides
Gram-negative pathogens resistant to colistin
Gram-negative pathogens (other than Pseudomonas) resistant to tigecyclin
Acinetobacter spp. resistant to ampicillin-sulbactam
Acinetobacter spp. resistant to tetracyclin or minocycline
Stenotrophomonas maltophilia resistant to trimethoprim-sulfamethoxazole
Stenotrophomonas maltophilia resistant to minocycline
measure: The outcome of the infections caused by resistant pathogens vs. sensitive, including mortality of any cause within 7 days and within 30 days;
time frame: 30 days after HSCT
measure: The appropriateness of the currently administered empirical antimicrobial therapy
time frame: 6 months after HSCT
description: The appropriateness of the currently administered empirical antimicrobial therapy; Inappropriate initial antimicrobial therapy will be defined as empirical antibiotic regimen, given in the first 48 hours following obtaining the blood cultures, that does not include at least one antibiotic that is active in vitro against the infecting microorganism.
arm group label: HSCT recipient
description: Allogeneic or autologous HSCT recipients, of all ages, for any indications. From this group we take those with a gram-negative bacteremia within 6 months after HSCT.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Dina Averbuch, MD
role: Principal Investigator
affiliation: Hadassah University Hospital, Pediatric Infectious Diseases Unit, Jerusalem, Israel
last name: Dan Engelhard, MD
role: Principal Investigator
affiliation: Hadassah University Hospital, Pediatric Infectious Diseases Unit, Jerusalem, Israel
last name: Simone Cesaro, MD
role: Study Chair
affiliation: Policlinico G.B. Rossi, paediatric haematology oncology, Verona, Italy
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country: Belgium
country: China
country: Croatia
country: Germany
country: Israel
country: Portugal
country: Russian Federation
country: Sweden
country: Turkey
responsible party type: Sponsor