xml: <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/NCT06018792</url>
    </required_header>
    <id_info>
      <org_study_id>NL84592.018.23</org_study_id>
      <nct_id>NCT06018792</nct_id>
    </id_info>
    <brief_title>Molecular Culture for the Diagnosis of Pediatric Sepsis</brief_title>
    <acronym>CHAMPIONS</acronym>
    <official_title>Children's Health Assessment and Molecular Pathogen Identification for Optimized Novel Sepsis Therapy</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Jip Groen</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>InBiome</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        Babies and children have an increased risk of getting an infection with a bacteria in the&#xD;
        bloodstream (sepsis). It is often difficult for the doctor to determine whether a child has&#xD;
        an infection of the bloodstream, because the symptoms are often unclear and can also occur in&#xD;
        children who are not sick. To determine whether there is an infection, a little blood is&#xD;
        currently taken for a blood test (the blood culture) to investigate whether there is a&#xD;
        bacteria in the blood. However, it often takes at least 36 hours before the results of this&#xD;
        blood culture are available. That is why antibiotics are usually started immediately to treat&#xD;
        the possible infection.&#xD;
  &#xD;
        However, it often turns out that the blood culture is negative after 36 hours, which means&#xD;
        that no bacteria have been found in the blood. Usually the antibiotics are then stopped&#xD;
        because it turns out that there was no infection at all. There is currently no good test that&#xD;
        can predict whether (newborn) children have an infection or not. That is why too many&#xD;
        children are currently wrongly receiving antibiotics. These antibiotics can damage the&#xD;
        healthy bacteria in the intestines. There are many billions of 'beneficial bacteria' in the&#xD;
        intestine. These play an important role in the digestion of food and protect against external&#xD;
        infections. Antibiotics aim to kill bacteria that cause inflammation or infection.&#xD;
        Unfortunately, antibiotics also kill some of these beneficial bacteria. In addition,&#xD;
        unnecessary use of antibiotics contributes to antibiotic resistance. The aim of this research&#xD;
        is to investigate whether Molecular Culture, a PCR based test that can identify bacterial&#xD;
        pathogens in bodily fluids within 4 hours, has greater accuracy than traditional culturing&#xD;
        techniques for bacteria in blood. If proven, this could lead to faster identification or&#xD;
        exclusion of sepsis in children.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Newborns and children often receive antibiotics for a suspicion of sepsis. Sepsis has high&#xD;
        morbidity and mortality in newborns and children. Up to 50% of children in the Netherlands&#xD;
        are prescribed at least one course of antibiotics in the first 4 years of life. Postnatally,&#xD;
        antibiotics are often prescribed for presumed bacterial infections on neonatal and pediatric&#xD;
        wards, but in approximately 30% of these patients bacterial infection is not proven.&#xD;
  &#xD;
        Rapid diagnosis of sepsis in newborns and children is problematic because clinical signs&#xD;
        start subtle and are non-specific. The gold standard for diagnosis of bacterial sepsis is a&#xD;
        conventional blood culture. Unfortunately, bacterial culture is time-consuming (time to&#xD;
        result up to 36-72 hours) and lacks sensitivity in this population for sepsis. For this&#xD;
        reason, children and infants with risk factors for infection or clinical signs and symptoms&#xD;
        of infection are treated with antibiotics empirically at initial sepsis suspicion, awaiting&#xD;
        results of the conventional blood culture. Currently more than 85% of very preterm born&#xD;
        infants (gestational age &lt;30 weeks) receive antibiotics for the risk of early-onset sepsis&#xD;
        (EOS) in the Netherlands and approximately two-third are evaluated at least once for&#xD;
        late-onset sepsis (LOS) . Also older children are often prescribed antibiotics empirically&#xD;
        for presumed sepsis, awaiting results of the blood culture.&#xD;
  &#xD;
        There is increasing evidence that, apart from antibiotic resistance, the use of antibiotics&#xD;
        in the neonatal period and during childhood alters the microbiome with an increased risk of&#xD;
        immediate and long-term adverse effects, such as increased risk for asthma, obesity,&#xD;
        allergies and inflammatory bowel diseases (IBD). To avoid unnecessary treatment of&#xD;
        non-infected children, an early, quick, sensitive and specific laboratory test would be&#xD;
        helpful to guide clinicians to decide when to discontinue antibiotics as soon as possible.&#xD;
  &#xD;
        Another technique to detect neonatal sepsis quickly and in an earlier stage compared to&#xD;
        conventional blood culture is Molecular Culture (MC). MC is a rapid molecular based culturing&#xD;
        technique that is able to identify bacteria within 4 hours after blood sampling. In short, MC&#xD;
        is a DNA-based profiling technique, differentiating between bacterial species based on&#xD;
        species-specific differences in 16S-23S rDNA interspacer (IS) region nucleotide length by&#xD;
        using phylum-specific fluorescently labelled polymerase chain reaction (PCR) primers. A&#xD;
        standard MC procedure consists of two separate PCRs. In the first PCR two different primers&#xD;
        are added, one primer fluorescently labeling members of the phyla Firmicutes, Actinobacter,&#xD;
        Fusobacteria and Verrucomicrobia (FAFV), whereas the second primer labels members of the&#xD;
        Bacteroidetes phylum. In the second PCR, a third labeled primer is added targeting members of&#xD;
        the phylum Proteobacteria. Subsequently, these PCR products can be amplified and DNA&#xD;
        fragments can be separated based on their nucleotide length. Eventually, a typical MC&#xD;
        microbial profile will be created, consisting of a set of color-labeled peaks. Each peak&#xD;
        representing an individual bacterial operational taxonomic unit (OTU) depending on the&#xD;
        nucleotide length of the IS fragment, length of these peaks demonstrating the concentration&#xD;
        of this particular OTU, whereas peak colors provides information about the present phyla&#xD;
        (FAFV, Bacteroidetes or Proteobacteria).&#xD;
  &#xD;
        In bacterial sepsis, a bacterium has reached the otherwise sterile bloodstream causing sepsis&#xD;
        as a result of dysregulation of the host immune response and/or a reaction of bacterial&#xD;
        endotoxins. Both blood culture and MC can detect bacteria and give a positive result (in case&#xD;
        a bacterium has been cultured) or a negative result (in case no bacteria was detected). In&#xD;
        case the tests are positive, both techniques also show which bacteria was found, which could&#xD;
        be used to change antibiotic regimen to target that specific cultured bacterium. However, the&#xD;
        process of MC can be finished within 4 hours, which is much shorter than the incubation&#xD;
        period of the gold standard blood culture which is 36-72 hours. When there is no sepsis (and&#xD;
        thus no bacteria in the bloodstream), the MC will turn out negative also within 4 hours and&#xD;
        thus may guide clinicians to stop antibiotics in uninfected children much faster compared to&#xD;
        the conventional blood culture.&#xD;
  &#xD;
        Blood cultures are still gold standard, but are generally assumed to have a low sensitivity&#xD;
        for the diagnosis of sepsis in newborns and children and are time consuming. Cases of sepsis&#xD;
        may be missed by cultures and a more sensitive diagnostic test such as molecular tests as the&#xD;
        MC may be useful. Advances in microbial technology have led to the development of rapid&#xD;
        molecular methods such as MC, that may be more sensitive than culture. Multiple novel&#xD;
        molecular techniques, such as quantitative PCR, broad range conventional PCR and multiplex&#xD;
        PCR, have been studied to detect neonatal sepsis. However, these techniques are directed at&#xD;
        specific species which makes it impossible to detect all bacterial species. Thus, anything&#xD;
        that is not explicitly searched for will be missed. In contrast, MC has the ability to detect&#xD;
        every bacterial species that can cause bacterial neonatal sepsis.&#xD;
  &#xD;
        The MC technique is validated to detect these pathogenic bacteria in bodily fluids. A series&#xD;
        of papers validating all aspects of the MC technique have been published last years.&#xD;
        Furthermore, MC is being used in hospitals on the intensive care unit to detect bacteria in&#xD;
        otherwise sterile specimens like blood, but also on samples obtained from abscesses. A proof&#xD;
        of principle study on 39 neonates, suspicious for EOS, of whom additional blood samples were&#xD;
        taken from both umbilical cords as well as from peripheral phlebotomy, showed that MC was&#xD;
        able to detect a pathogenic bacterial strain that was highly likely the causative organism&#xD;
        for sepsis in one infant that was clinically ill. Conventional culture did not yield any&#xD;
        results for this patient. 2 additional MC samples showed strains that were likely to be&#xD;
        contaminants in infants that were clinically well-appearing, were conventional culture&#xD;
        remained negative. No other discrepancies were seen. This study also showed that MC on blood&#xD;
        samples that were spiked with prevalent bacterial strains for neonatal sepsis, showed a very&#xD;
        high agreement with quantitative PCR as a control diagnostic.Larger studies are needed to&#xD;
        corroborate diagnostic accuracy given the very low incidence of culture proven sepsis.&#xD;
  &#xD;
        Results from another study using the MC technique to detect bacteria in human body fluid are&#xD;
        promising. In this study 66 samples were collected and tested by conventional culture and MC.&#xD;
        In 100% of samples with a positive culture, the MC was also positive. In five samples, the&#xD;
        conventional culture turned out to be negative, whereas the MC was positive. The case&#xD;
        histories of these five patients were obtained and suggested that the MC findings were highly&#xD;
        clinically relevant, and thus may have higher sensitivity compared to conventional blood&#xD;
        culture.&#xD;
  &#xD;
        In summary, the quick detection makes MC potentially better equipped to guide clinical&#xD;
        decision making for management of sepsis in newborns and children. However, the suitability&#xD;
        of MC in this specific population has not been investigated adequately. Therefore, a high&#xD;
        quality study should be performed to determine the diagnostic accuracy of the MC for sepsis&#xD;
        in neonates and children and whether this technique may replace the conventional blood&#xD;
        culture.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">November 1, 2023</start_date>
    <completion_date type="Anticipated">November 1, 2027</completion_date>
    <primary_completion_date type="Anticipated">November 1, 2026</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>diagnostic accuracy of MC for the result of the conventional blood culture in newborns and children suspected of sepsis</measure>
      <time_frame>Up to 2 weeks after sampling of blood</time_frame>
      <description>We will analyse test characteristics and provide test sensitivity, specificity and positive and negative predictive values. Based on previous studies, we hypothesize that MC will be positive in all samples that are positive by conventional blood culture. We hypothesize that MC will yield more false positives or contaminants than conventional culture.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>diagnostic accuracy of MC for (clinical) sepsis and compare this with the diagnostic accuracy of the conventional blood culture for (clinical) sepsis.</measure>
      <time_frame>Up to 2 weeks after sampling of blood</time_frame>
      <description>Clinical sepsis will be defined varyingly given lack of an international clinical syndrome definition</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>diagnostic accuracy of MC on blood samples drawn after initiation of empirical antibiotics, for the result of the conventional blood culture in samples, drawn at initial sepsis workup</measure>
      <time_frame>Up to 2 weeks after sampling of blood</time_frame>
      <description>we aim to study pathogen detectability loss, due to antibiotic administration</description>
    </secondary_outcome>
    <number_of_groups>4</number_of_groups>
    <enrollment type="Anticipated">1835</enrollment>
    <condition>Sepsis</condition>
    <condition>Sepsis Bacterial</condition>
    <condition>Sepsis, Neonatal</condition>
    <condition>Infection, Bacterial</condition>
    <condition>Antibiotic Side Effect</condition>
    <condition>Microbial Colonization</condition>
    <arm_group>
      <arm_group_label>Pediatric sepsis</arm_group_label>
      <description>Study participants aged 3 months - 18 years who undergo collection of blood for conventional blood culture</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Late onset sepsis</arm_group_label>
      <description>Study participants aged up to 3 months who undergo culturing of blood for conventional blood culture Preterm infants aged &lt;32 weeks gestational age as a subgroup</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Early onset sepsis</arm_group_label>
      <description>Study participants aged up to 3 days who undergo culturing of blood for conventional blood culture</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Post antibiotic initiation cohort</arm_group_label>
      <description>participants for whom venipuncture is performed for follow up of inflammatory parameters &lt;36h after antibiotic initiation and blood draw for conventional culture or for whom a repeat intravenous catheterization is performed due to failing of a previous one &lt;36h after antibiotic initiation and blood draw for conventional culture</description>
    </arm_group>
    <intervention>
      <intervention_type>Diagnostic Test</intervention_type>
      <intervention_name>Molecular Culture</intervention_name>
      <description>PCR based bacterial profiling technique, that creates a differentiating microbial signature based on amplification of the interspace region in bacterial ribosomal RNA. Results on gel capillary electrophoresis are analyzed with software to recognize these signatures.</description>
      <arm_group_label>Early onset sepsis</arm_group_label>
      <arm_group_label>Late onset sepsis</arm_group_label>
      <arm_group_label>Pediatric sepsis</arm_group_label>
      <arm_group_label>Post antibiotic initiation cohort</arm_group_label>
      <other_name>IS Pro</other_name>
    </intervention>
    <biospec_retention>Samples With DNA</biospec_retention>
    <biospec_descr>
      <textblock>
        Unprocessed blood&#xD;
      </textblock>
    </biospec_descr>
    <eligibility>
      <study_pop>
        <textblock>
          All minors aged &lt;18 years&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Non-Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Undergoing collection of blood for a conventional blood culture as part of standard&#xD;
               care OR&#xD;
  &#xD;
            -  Having undergone sepsis evaluation collection of blood for a conventional blood&#xD;
               culture as part of standard care in the past 72 hours&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Apart from an age criterion, there are no strict exclusion criteria. However, for the&#xD;
               analysis of the secondary outcome (I.e. the testing of diagnostic accuracy of both MC&#xD;
               as well as conventional culture for clinical sepsis), we plan to exclude all children&#xD;
               who ultimately have a clear alternative cause for clinical illness that does not&#xD;
               directly result from bacteraemia or bacterial sepsis. This will remain true in the&#xD;
               case of conventional culture positivity, either when considered a contaminant as well&#xD;
               as when considered a contributing factor in the presence of any of the causes of&#xD;
               clinical illness mentioned below. A potential subject who meets any of the following&#xD;
               criteria will be excluded from participation in this study These causes include, but&#xD;
               are not limited to:&#xD;
  &#xD;
            -  In case of the potential inclusion of a neonate suspicious for EOS, confirmed&#xD;
               congenital infection with TORCHES (toxoplasmosis, rubella, cytomegalovirus, syphilis&#xD;
               and herpes) will lead to exclusion particularly for the neonatal population&#xD;
  &#xD;
            -  Auto inflammatory disease&#xD;
  &#xD;
            -  Hemophagocytic syndrome&#xD;
  &#xD;
            -  SIRS (Systemic Inflammatory Response Syndrome following a severe viral infection&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>0 Years</minimum_age>
      <maximum_age>18 Years</maximum_age>
    </eligibility>
    <overall_official>
      <last_name>Tim de Meij, MD, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Tim de Meij, MD, PhD</last_name>
      <phone>+3120 566 9111</phone>
      <email>t.demeij@amsterdamumc.nl</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Jip Groen, MD</last_name>
      <phone>+3120 566 9111</phone>
      <email>j.groen5@amsterdamumc.nl</email>
    </overall_contact_backup>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 22, 2023</study_first_submitted>
    <study_first_submitted_qc>August 29, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 31, 2023</study_first_posted>
    <last_update_submitted>August 29, 2023</last_update_submitted>
    <last_update_submitted_qc>August 29, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 31, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor-Investigator</responsible_party_type>
      <investigator_affiliation>Amsterdam University Medical Centers (UMC), Location Academic Medical Center (AMC)</investigator_affiliation>
      <investigator_full_name>Jip Groen</investigator_full_name>
      <investigator_title>Medical Doctor, PhD candidate</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Sepsis</mesh_term>
      <mesh_term>Toxemia</mesh_term>
      <mesh_term>Communicable Diseases</mesh_term>
      <mesh_term>Infections</mesh_term>
      <mesh_term>Bacterial Infections</mesh_term>
      <mesh_term>Neonatal Sepsis</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06018792
  org study id: NL84592.018.23
  nct id: NCT06018792
  lead sponsor: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  Babies and children have an increased risk of getting an infection with a bacteria in the
        bloodstream (sepsis). It is often difficult for the doctor to determine whether a child has
        an infection of the bloodstream, because the symptoms are often unclear and can also occur in
        children who are not sick. To determine whether there is an infection, a little blood is
        currently taken for a blood test (the blood culture) to investigate whether there is a
        bacteria in the blood. However, it often takes at least 36 hours before the results of this
        blood culture are available. That is why antibiotics are usually started immediately to treat
        the possible infection.
  
        However, it often turns out that the blood culture is negative after 36 hours, which means
        that no bacteria have been found in the blood. Usually the antibiotics are then stopped
        because it turns out that there was no infection at all. There is currently no good test that
        can predict whether (newborn) children have an infection or not. That is why too many
        children are currently wrongly receiving antibiotics. These antibiotics can damage the
        healthy bacteria in the intestines. There are many billions of 'beneficial bacteria' in the
        intestine. These play an important role in the digestion of food and protect against external
        infections. Antibiotics aim to kill bacteria that cause inflammation or infection.
        Unfortunately, antibiotics also kill some of these beneficial bacteria. In addition,
        unnecessary use of antibiotics contributes to antibiotic resistance. The aim of this research
        is to investigate whether Molecular Culture, a PCR based test that can identify bacterial
        pathogens in bodily fluids within 4 hours, has greater accuracy than traditional culturing
        techniques for bacteria in blood. If proven, this could lead to faster identification or
        exclusion of sepsis in children.
  Newborns and children often receive antibiotics for a suspicion of sepsis. Sepsis has high
        morbidity and mortality in newborns and children. Up to 50% of children in the Netherlands
        are prescribed at least one course of antibiotics in the first 4 years of life. Postnatally,
        antibiotics are often prescribed for presumed bacterial infections on neonatal and pediatric
        wards, but in approximately 30% of these patients bacterial infection is not proven.
  
        Rapid diagnosis of sepsis in newborns and children is problematic because clinical signs
        start subtle and are non-specific. The gold standard for diagnosis of bacterial sepsis is a
        conventional blood culture. Unfortunately, bacterial culture is time-consuming (time to
        result up to 36-72 hours) and lacks sensitivity in this population for sepsis. For this
        reason, children and infants with risk factors for infection or clinical signs and symptoms
        of infection are treated with antibiotics empirically at initial sepsis suspicion, awaiting
        results of the conventional blood culture. Currently more than 85% of very preterm born
        infants (gestational age <30 weeks) receive antibiotics for the risk of early-onset sepsis
        (EOS) in the Netherlands and approximately two-third are evaluated at least once for
        late-onset sepsis (LOS) . Also older children are often prescribed antibiotics empirically
        for presumed sepsis, awaiting results of the blood culture.
  
        There is increasing evidence that, apart from antibiotic resistance, the use of antibiotics
        in the neonatal period and during childhood alters the microbiome with an increased risk of
        immediate and long-term adverse effects, such as increased risk for asthma, obesity,
        allergies and inflammatory bowel diseases (IBD). To avoid unnecessary treatment of
        non-infected children, an early, quick, sensitive and specific laboratory test would be
        helpful to guide clinicians to decide when to discontinue antibiotics as soon as possible.
  
        Another technique to detect neonatal sepsis quickly and in an earlier stage compared to
        conventional blood culture is Molecular Culture (MC). MC is a rapid molecular based culturing
        technique that is able to identify bacteria within 4 hours after blood sampling. In short, MC
        is a DNA-based profiling technique, differentiating between bacterial species based on
        species-specific differences in 16S-23S rDNA interspacer (IS) region nucleotide length by
        using phylum-specific fluorescently labelled polymerase chain reaction (PCR) primers. A
        standard MC procedure consists of two separate PCRs. In the first PCR two different primers
        are added, one primer fluorescently labeling members of the phyla Firmicutes, Actinobacter,
        Fusobacteria and Verrucomicrobia (FAFV), whereas the second primer labels members of the
        Bacteroidetes phylum. In the second PCR, a third labeled primer is added targeting members of
        the phylum Proteobacteria. Subsequently, these PCR products can be amplified and DNA
        fragments can be separated based on their nucleotide length. Eventually, a typical MC
        microbial profile will be created, consisting of a set of color-labeled peaks. Each peak
        representing an individual bacterial operational taxonomic unit (OTU) depending on the
        nucleotide length of the IS fragment, length of these peaks demonstrating the concentration
        of this particular OTU, whereas peak colors provides information about the present phyla
        (FAFV, Bacteroidetes or Proteobacteria).
  
        In bacterial sepsis, a bacterium has reached the otherwise sterile bloodstream causing sepsis
        as a result of dysregulation of the host immune response and/or a reaction of bacterial
        endotoxins. Both blood culture and MC can detect bacteria and give a positive result (in case
        a bacterium has been cultured) or a negative result (in case no bacteria was detected). In
        case the tests are positive, both techniques also show which bacteria was found, which could
        be used to change antibiotic regimen to target that specific cultured bacterium. However, the
        process of MC can be finished within 4 hours, which is much shorter than the incubation
        period of the gold standard blood culture which is 36-72 hours. When there is no sepsis (and
        thus no bacteria in the bloodstream), the MC will turn out negative also within 4 hours and
        thus may guide clinicians to stop antibiotics in uninfected children much faster compared to
        the conventional blood culture.
  
        Blood cultures are still gold standard, but are generally assumed to have a low sensitivity
        for the diagnosis of sepsis in newborns and children and are time consuming. Cases of sepsis
        may be missed by cultures and a more sensitive diagnostic test such as molecular tests as the
        MC may be useful. Advances in microbial technology have led to the development of rapid
        molecular methods such as MC, that may be more sensitive than culture. Multiple novel
        molecular techniques, such as quantitative PCR, broad range conventional PCR and multiplex
        PCR, have been studied to detect neonatal sepsis. However, these techniques are directed at
        specific species which makes it impossible to detect all bacterial species. Thus, anything
        that is not explicitly searched for will be missed. In contrast, MC has the ability to detect
        every bacterial species that can cause bacterial neonatal sepsis.
  
        The MC technique is validated to detect these pathogenic bacteria in bodily fluids. A series
        of papers validating all aspects of the MC technique have been published last years.
        Furthermore, MC is being used in hospitals on the intensive care unit to detect bacteria in
        otherwise sterile specimens like blood, but also on samples obtained from abscesses. A proof
        of principle study on 39 neonates, suspicious for EOS, of whom additional blood samples were
        taken from both umbilical cords as well as from peripheral phlebotomy, showed that MC was
        able to detect a pathogenic bacterial strain that was highly likely the causative organism
        for sepsis in one infant that was clinically ill. Conventional culture did not yield any
        results for this patient. 2 additional MC samples showed strains that were likely to be
        contaminants in infants that were clinically well-appearing, were conventional culture
        remained negative. No other discrepancies were seen. This study also showed that MC on blood
        samples that were spiked with prevalent bacterial strains for neonatal sepsis, showed a very
        high agreement with quantitative PCR as a control diagnostic.Larger studies are needed to
        corroborate diagnostic accuracy given the very low incidence of culture proven sepsis.
  
        Results from another study using the MC technique to detect bacteria in human body fluid are
        promising. In this study 66 samples were collected and tested by conventional culture and MC.
        In 100% of samples with a positive culture, the MC was also positive. In five samples, the
        conventional culture turned out to be negative, whereas the MC was positive. The case
        histories of these five patients were obtained and suggested that the MC findings were highly
        clinically relevant, and thus may have higher sensitivity compared to conventional blood
        culture.
  
        In summary, the quick detection makes MC potentially better equipped to guide clinical
        decision making for management of sepsis in newborns and children. However, the suitability
        of MC in this specific population has not been investigated adequately. Therefore, a high
        quality study should be performed to determine the diagnostic accuracy of the MC for sepsis
        in neonates and children and whether this technique may replace the conventional blood
        culture.
  observational model: Cohort
  time perspective: Prospective
  measure: diagnostic accuracy of MC for the result of the conventional blood culture in newborns and children suspected of sepsis
  time frame: Up to 2 weeks after sampling of blood
  description: We will analyse test characteristics and provide test sensitivity, specificity and positive and negative predictive values. Based on previous studies, we hypothesize that MC will be positive in all samples that are positive by conventional blood culture. We hypothesize that MC will yield more false positives or contaminants than conventional culture.
  measure: diagnostic accuracy of MC for (clinical) sepsis and compare this with the diagnostic accuracy of the conventional blood culture for (clinical) sepsis.
  time frame: Up to 2 weeks after sampling of blood
  description: Clinical sepsis will be defined varyingly given lack of an international clinical syndrome definition
  measure: diagnostic accuracy of MC on blood samples drawn after initiation of empirical antibiotics, for the result of the conventional blood culture in samples, drawn at initial sepsis workup
  time frame: Up to 2 weeks after sampling of blood
  description: we aim to study pathogen detectability loss, due to antibiotic administration
  arm group label: Pediatric sepsis
  description: Study participants aged 3 months - 18 years who undergo collection of blood for conventional blood culture
  arm group label: Late onset sepsis
  description: Study participants aged up to 3 months who undergo culturing of blood for conventional blood culture Preterm infants aged <32 weeks gestational age as a subgroup
  arm group label: Early onset sepsis
  description: Study participants aged up to 3 days who undergo culturing of blood for conventional blood culture
  arm group label: Post antibiotic initiation cohort
  description: participants for whom venipuncture is performed for follow up of inflammatory parameters <36h after antibiotic initiation and blood draw for conventional culture or for whom a repeat intravenous catheterization is performed due to failing of a previous one <36h after antibiotic initiation and blood draw for conventional culture
  intervention type: Diagnostic Test
  intervention name: Molecular Culture
  description: PCR based bacterial profiling technique, that creates a differentiating microbial signature based on amplification of the interspace region in bacterial ribosomal RNA. Results on gel capillary electrophoresis are analyzed with software to recognize these signatures.
  arm group label: Early onset sepsis
  arm group label: Late onset sepsis
  arm group label: Pediatric sepsis
  arm group label: Post antibiotic initiation cohort
  other name: IS Pro
  Unprocessed blood
  study pop: 
  sampling method: Non-Probability Sample
  criteria: 
  gender: All
  minimum age: 0 Years
  maximum age: 18 Years
  last name: Tim de Meij, MD, PhD
  role: Principal Investigator
  affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
  last name: Tim de Meij, MD, PhD
  phone: +3120 566 9111
  email: t.demeij@amsterdamumc.nl
  last name: Jip Groen, MD
  phone: +3120 566 9111
  email: j.groen5@amsterdamumc.nl
  responsible party type: Sponsor-Investigator
  investigator affiliation: Amsterdam University Medical Centers (UMC), Location Academic Medical Center (AMC)
  investigator full name: Jip Groen
  investigator title: Medical Doctor, PhD candidate
  mesh term: Sepsis
  mesh term: Toxemia
  mesh term: Communicable Diseases
  mesh term: Infections
  mesh term: Bacterial Infections
  mesh term: Neonatal Sepsis
  sharing ipd: No