<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/NCT04488458</url>
  </required_header>
  <id_info>
    <org_study_id>2020-01471</org_study_id>
    <nct_id>NCT04488458</nct_id>
  </id_info>
  <brief_title>Susceptibility Testing of Biofilm to Guide Treatment of Periprosthetic Joint Infections</brief_title>
  <official_title>Treatment of Periprosthetic Joint Infections Guided by Minimum Biofilm Eradication Concentration (MBEC) in Addition to Minimum Inhibitory Concentration (MIC); a Prospective Randomized Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vastra Gotaland Region</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Göteborg University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Vastra Gotaland Region</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>
      The overall purpose of this clinical treatment research project is to explore novel&#xD;
      diagnostics that can guide the treatment of infections associated to orthopaedic implants, in&#xD;
      order to improve patient outcomes and reduce the development of antibiotic resistance.&#xD;
&#xD;
      The project aims are:&#xD;
&#xD;
      (i) To improve the current diagnostic approaches and treatments of periprosthetic joint&#xD;
      infections (PJI) (ii) To investigate the pathogenesis of PJI through the characterization of&#xD;
      the virulence carried by the causative pathogens&#xD;
&#xD;
      This multidisciplinary project addresses implant-associated infection and its contribution to&#xD;
      increasing antibiotic resistance. Both lead to longer hospital stays, higher medical costs&#xD;
      and increased morbidity and mortality. Antibiotic resistance is globally considered as one of&#xD;
      the greatest and most urgent risk in medicine. Implant-associated infections are commonly&#xD;
      caused by biofilms. Biofilms can be described as 'a community of bacterial cells connected by&#xD;
      their secreted extracellular matrix'. Since antibiotics are designed to fight planktonic&#xD;
      free-living bacteria, studying antibiotic resistance in biofilm communities poses a paradigm&#xD;
      shift. Furthermore, bacteria in biofilms are up to 1000 times more resistant to antibiotics&#xD;
      than planktonic bacteria. Mechanisms involved in a biofilm infection also play a crucial role&#xD;
      in the development of antibiotic resistance. Hospital-acquired infections are the fourth&#xD;
      leading cause of disease and 70% are associated with medical implants and caused by&#xD;
      staphylococcal biofilms. In addition, the level of antimicrobial resistance in bacteria&#xD;
      causing implant-associated infections has increased worldwide, leaving patients with fewer&#xD;
      treatment options.&#xD;
&#xD;
      In this study the investigators will randomize patients with PJI to either standard MIC&#xD;
      susceptibility or MIC and MBEC susceptibility guided treatment with oral antibiotic&#xD;
      combinations; (i) Non cell wall active standard of care antibiotic combination (MIC-guided)&#xD;
      for 6 weeks.&#xD;
&#xD;
      (ii) Or; non cell wall active antibiotic combination according to a MBEC-based decision&#xD;
      algorithm for 6 weeks.&#xD;
&#xD;
      In this pilot project, the primary endpoint is how often treatment changes with the MBEC&#xD;
      susceptibility testing compared to only MIC-susceptibility testing.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In the infectious process, biofilms may form early on biomaterials. There is ample evidence&#xD;
      to the several-fold increase in antimicrobial concentrations required to eradicate even&#xD;
      immature biofilms. In clinical practice the choice of antimicrobials is guided by&#xD;
      susceptibility testing based on minimum inhibitory concentrations (MIC), which poorly reflect&#xD;
      the increased antimicrobial resistance in biofilms. Minimum biofilm eradicating&#xD;
      concentrations (MBEC) might better correspond to in vivo efficacy in the treatment of PJI,&#xD;
      and other biofilm-centred infections. There is a need to develop methods, which are&#xD;
      reproducible, low-cost, and time-efficient, for in vitro susceptibility testing of clinical&#xD;
      biofilm bacteria.&#xD;
&#xD;
      This prospective randomized study aim to compare antibiotic treatment regimens for PJI guided&#xD;
      by MIC or MBEC combined with MIC, and how it affects infection resolution, drug tolerability&#xD;
      and relapse strain resistance patterns.&#xD;
&#xD;
      The investigors hypothesize that a standardised surgical debridement, antibiotics and implant&#xD;
      retention (DAIR) for PJI followed by antibiotic guiding MBEC-diagnostics on deep tissue&#xD;
      specimens will increase treatment efficacy and decrease the incidence of infection relapses&#xD;
      compared to standard of care.&#xD;
&#xD;
      Following standardised debridement and 14 days of parenteral antibiotics; cloxacillin for&#xD;
      methicillin sensitive staphylococci or vancomycin for methicillin resistant staphylococci,&#xD;
      patients will be randomized to receive oral antibiotic combinations with either cell wall&#xD;
      active standard of care antibiotic combination (MIC-guided) for 6 weeks or non cell wall&#xD;
      active antibiotic combination according to a MIC- and MBEC-guided decision algorithm for 6&#xD;
      weeks.&#xD;
&#xD;
      Patients will be included at the Orthopaedic Infection Centre (OIC), Sahlgrenska University&#xD;
      Hospital/Mölndal, which is a unit dedicated to optimizing management of orthopaedic&#xD;
      infections. Patient consent acquisitions and randomisations (20 patients in each group) will&#xD;
      be performed during post-operative hospitalisation. MIC determination and disk diffusion will&#xD;
      be performed at the SWEDAC (Swedish Accreditation Body) certified clinical bacteriological&#xD;
      laboratory. At the department of Biomaterials (University of Gothenburg), a previously&#xD;
      developed clinical diagnostic tool will be employed for the MBEC determination. It consists&#xD;
      of the combination of the Calgary Biofilm Device (MBECTM P&amp;G Assay, Innovotech) and a&#xD;
      custom-made susceptibility plate (Substrata department, Sahlgrenska Hospital) with 6&#xD;
      antimicrobial agents commonly used to treat orthopaedic infections.&#xD;
&#xD;
      Inclusion and exclusion criteria are described in section &quot;Eligibility&quot;.&#xD;
&#xD;
      The primary and secondary endpoints are described in section &quot;Outcome measures&quot;.&#xD;
&#xD;
      Treatment criteria: for all administered antimicrobials staphylococcal strains must be&#xD;
      susceptible in disc diffusion tests/MIC, regardless of MBEC-level. Antibiotic combinations&#xD;
      will be selected from 5 already recommended non-cell wall active anti-staphylococcal&#xD;
      antibiotics with high per-oral bio-availabilities and acceptable bone penetration used in the&#xD;
      treatment of PJIs: rifampicin (RIF), fusidic acid (FUS), ciprofloxacin (CIP)/levofloxacin&#xD;
      (LEV) and clindamycin (CLI).&#xD;
&#xD;
      Clinical breakpoints are expressed as MIC (EUCAST and CLSI) but are based on more than MIC&#xD;
      distributions (epidemiological cut-off) namely:&#xD;
&#xD;
        -  Pharmacokinetic and pharmacodynamic analyses of the antibiotic.&#xD;
&#xD;
        -  Relation between MIC and probability of cure in clinical trials.&#xD;
&#xD;
      If likely effective according to EUCAST clinical breakpoints, antibiotics are further ranked&#xD;
      in the MBEC treatment algorithm by bone penetration/susceptibility range and semi-arbitrarily&#xD;
      by clinical efficacy in prosthetic joint infections.&#xD;
&#xD;
      MBEC/MIC cut-off for replacing Rifampicin despite susceptibility according to MIC:&#xD;
&#xD;
        -  C-Max (oral dose of 750 mg) 10 mg/L x 0.4 (Bone/Serum) = 4 mg/L&#xD;
&#xD;
        -  RIF-MIC clinical breakpoint for staphylococci is 0.5 mg/L.&#xD;
&#xD;
        -  Clinical efficacy factor 1.&#xD;
&#xD;
        -  MBEC/MIC ≥ 8 times MIC.&#xD;
&#xD;
      MBEC/MIC cut-off for replacing Levofloxacin despite susceptibility according to MIC:&#xD;
&#xD;
        -  C-Max (oral dose of 750 mg) 12 mg/L x 0.6 (Bone/Serum) = 7,2 mg/L&#xD;
&#xD;
        -  LEV-MIC breakpoint for staphylococci is 1 mg/L&#xD;
&#xD;
        -  Clinical efficacy factor 0,75.&#xD;
&#xD;
        -  MBEC/MIC ≥ 5 x MIC.&#xD;
&#xD;
      MBEC/MIC cut-off for not choosing Fusidic acid as companion drug:&#xD;
&#xD;
        -  C-Max (500 mg) 30 mg/L x 0,2 (Bone/Serum) = 6 mg/L&#xD;
&#xD;
        -  FUS-MIC breakpoint for staphylococci is 1 mg/L.&#xD;
&#xD;
        -  Clinical efficacy factor 0,5.&#xD;
&#xD;
        -  MBEC 3 times the MIC or more if better companion drug.&#xD;
&#xD;
      MBEC/MIC cut-off for not choosing Clindamycin as companion drug:&#xD;
&#xD;
        -  C-Max (600 mg) 12 mg/L x 0.3 (Bone/Serum) = 3,6 mg/L&#xD;
&#xD;
        -  CLI-MIC breakpoint for staphylococci is 0.5 mg/L&#xD;
&#xD;
        -  Clinical efficacy factor 0,5.&#xD;
&#xD;
        -  MBEC/MIC 4 x MIC or more if better companion drug.&#xD;
&#xD;
      MBEC/MIC cut-off for not choosing Linezolid (LIN) as sole drug:&#xD;
&#xD;
        -  C-Max 21 mg/L x 0.4 (Bone/Serum) = 8,4 mg/L&#xD;
&#xD;
        -  LIN-MIC breakpoint for staphylococci is 4 mg/L&#xD;
&#xD;
        -  Clinical efficacy factor 0,5.&#xD;
&#xD;
        -  MBEC 2 times the MIC or more.&#xD;
&#xD;
      MBEC cut-off for not choosing Sulfamethoxazole (SMX)/Trimethoprim (TMP) as sole drug:&#xD;
&#xD;
        -  C-Max (3200/640 mg SMX/TMP) is 145 and 7.5 mg/L resp. x 0.25 (Bone/Serum) = 36 and 1,9&#xD;
           mg/L resp.&#xD;
&#xD;
        -  SMX/TMP-MIC breakpoint for staphylococci is 2 mg/L. (By EUCAST expressed as the&#xD;
           Trimethoprim konc.)&#xD;
&#xD;
        -  Clinical efficacy factor 0,5.&#xD;
&#xD;
        -  MBEC &gt; MIC&#xD;
&#xD;
        -  *Interpret as better than according to justification above.&#xD;
&#xD;
      All follow-up up to one year will be done according to clinical routines.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 15, 2021</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of changes in antimicrobial regimen other than standard of care</measure>
    <time_frame>6 weeks</time_frame>
    <description>Proportions of antimicrobial regimens other than standard of care through application of proposed MBEC-algorithm.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Repeat procedure, relapse or reinfection</measure>
    <time_frame>12 months</time_frame>
    <description>Number of repeat procedures, relapses or reinfections, according to MSIS-criteria of PJI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oxford Hip Score</measure>
    <time_frame>12 months</time_frame>
    <description>Hip specific patient-reported outcome measure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EQ-5D</measure>
    <time_frame>12 months</time_frame>
    <description>Generic health status patient-reported outcome measure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to revision</measure>
    <time_frame>12 months</time_frame>
    <description>A shorter time could potentially indicate that the right decision is taken at an earlier stage</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inpatient care</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Resource consumption measure (days).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Outpatient visits</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Resource consumption measure, number of visits, type of visits.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Discharge destination</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Resource consumption measure. The type of facility a patient is discharged to (rehab facility, nursing home, home, home care).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Heath care costs</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Compound measure using data from outcome 6-8 (currency EUR).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Development of additional antimicrobial resistance of the relapse causative strain</measure>
    <time_frame>12 months</time_frame>
    <description>At relapse surgery, the causative strain will be isolated by new biopsy cultures. Then the susceptibility of the causative strain will be tested again to evaluate any possible emergence of resistance against the antimicrobials previously used in the study. This will confirm if the given antimicrobial treatment has lead to antimicrobial resistance in a potential relapse strain isolated at a later occasion.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Correlation between the virulence properties of the causative bacteria and patient outcome (infection resolution versus recurrent infection)</measure>
    <time_frame>36 months</time_frame>
    <description>The staphylococcal strains isolated from the patients with PJI will be characterised by phenotypic tests and whole genome sequencing to determine their virulence properties and carriage of genes involved in biofilm formation, antimicrobial resistance and production of toxins. Then the particular virulence of the strains will be correlated to the patients outcome, to be able to assess if more virulence carriage correlates to worse outcome (recurrent infection)</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Prosthetic Joint Infection</condition>
  <condition>Prosthetic Infection</condition>
  <condition>Hip Prosthesis Infection</condition>
  <condition>Knee Prosthesis Infection</condition>
  <arm_group>
    <arm_group_label>MBEC and MIC susceptibility testing</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>For all administered antimicrobials staphylococcal strains must be susceptible in disc diffusion tests/MIC, regardless of MBEC-level. Antibiotic combinations will be selected from 5 already recommended non-cell wall active anti-staphylococcal antibiotics with high per-oral bio-availabilities and acceptable bone penetration used in the treatment of PJIs: rifampicin, fusidic acid, ciprofloxacin/levofloxacin and clindamycin.&#xD;
MBEC cut-off for replacement with 2nd or 3rd line antibiotic: RIF MBEC/MIC &gt; 8; LEV MBEC/MIC &gt; 5; FUS MBEC/MIC &gt; 3; CLI MBEC/MIC &gt; 4; LIN MBEC/MIC &gt; 2; T/S MBEC &gt; MIC&#xD;
Second line of treatment:&#xD;
RIF and Fusidic acid 500 mg TID (ter in die) RIF and Clindamycin 450 - 600 mg TID LEV and Fusidic acid 500 mg TID LEV and Clindamycin 450 mg TID&#xD;
Third line of treatment:&#xD;
Linezolid 600 mg BID (bis in die) Sulfamethoxazole/Trimethoprim 800/160 mg TID Clindamycin 450 mg TID and Fusidic acid 500 mg TID</description>
  </arm_group>
  <arm_group>
    <arm_group_label>MIC susceptibility testing</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>If the causative bacterium is susceptible according to MIC diagnostics, the patient will follow the first line of treatment: Rifampicin 750-900 mg/day + Levofloxacin 750 mg BID</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>MIC or MBEC+MIC based treatment algorithm</intervention_name>
    <description>i) Non cell wall active standard of care antibiotic combination (MIC-guided) for 6 weeks.&#xD;
ii) Non cell wall active antibiotic combination according to a MBEC-based decision algorithm for 6 weeks.</description>
    <arm_group_label>MBEC and MIC susceptibility testing</arm_group_label>
    <arm_group_label>MIC susceptibility testing</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  first PJI in hip or knee according to Musculoskeletal Infection Society (MSIS)&#xD;
             definitions&#xD;
&#xD;
          -  first DAIR&#xD;
&#xD;
          -  mono-microbial staphylococcal infection&#xD;
&#xD;
          -  14 days of intravenous treatment with either cloxacillin or vancomycin&#xD;
&#xD;
          -  standardized administration of local antibiotics&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  allergy/previous toxic event/unacceptable drug interaction to most effective&#xD;
             antibiotic combination according to either MIC or MBEC&#xD;
&#xD;
          -  severe drug interactions to MBEC-guided compound&#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_contact>
    <last_name>Ola Rolfson, Professor</last_name>
    <phone>+46 313430852</phone>
    <email>ola.rolfson@vgregion.se</email>
  </overall_contact>
  <location>
    <facility>
      <name>Ortopedi, Sahlgrenska University Hospital</name>
      <address>
        <city>Mölndal</city>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ola Rolfson, PhD</last_name>
      <email>ola.rolfson@vgregion.se</email>
    </contact>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <reference>
    <citation>Zaborowska M, Tillander J, Branemark R, Hagberg L, Thomsen P, Trobos M. Biofilm formation and antimicrobial susceptibility of staphylococci and enterococci from osteomyelitis associated with percutaneous orthopaedic implants. J Biomed Mater Res B Appl Biomater. 2017 Nov;105(8):2630-2640. doi: 10.1002/jbm.b.33803. Epub 2016 Oct 25.</citation>
    <PMID>27779811</PMID>
  </reference>
  <verification_date>July 2021</verification_date>
  <study_first_submitted>July 10, 2020</study_first_submitted>
  <study_first_submitted_qc>July 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 28, 2020</study_first_posted>
  <last_update_submitted>August 18, 2021</last_update_submitted>
  <last_update_submitted_qc>August 18, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 24, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>staphylococci</keyword>
  <keyword>biofilm</keyword>
  <keyword>antimicrobial resistance</keyword>
  <keyword>periprosthetic infection</keyword>
  <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>Arthritis, Infectious</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>The main results will be presented at an aggregated level. In some cases, individual data may be presented (e.g. characteristics of a bacterial strain in relation to clinical outcome), but this information will be unidentified so that it cannot be deduced to the individual.&#xD;
All compiled personal data will be stored on a password-protected hospital server that only the research group has access to. No personal data will be reported in publications.&#xD;
The results of the study will be documented according to the study protocol and placed in a journal. Participants will be coded in a document together with the social security numbers.&#xD;
Information about the participants, their health and the code key will be collected at the Orthopaedic Clinic where it will be treated confidentially and securely for 10 years. The handling of the participants' information is regulated by the Personal Data Act (SFS 1998: 204).</ipd_description>
  </patient_data>
  <!-- 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/NCT04488458
org study id: 2020-01471
nct id: NCT04488458
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The overall purpose of this clinical treatment research project is to explore novel
      diagnostics that can guide the treatment of infections associated to orthopaedic implants, in
      order to improve patient outcomes and reduce the development of antibiotic resistance.

      The project aims are:

      (i) To improve the current diagnostic approaches and treatments of periprosthetic joint
      infections (PJI) (ii) To investigate the pathogenesis of PJI through the characterization of
      the virulence carried by the causative pathogens

      This multidisciplinary project addresses implant-associated infection and its contribution to
      increasing antibiotic resistance. Both lead to longer hospital stays, higher medical costs
      and increased morbidity and mortality. Antibiotic resistance is globally considered as one of
      the greatest and most urgent risk in medicine. Implant-associated infections are commonly
      caused by biofilms. Biofilms can be described as 'a community of bacterial cells connected by
      their secreted extracellular matrix'. Since antibiotics are designed to fight planktonic
      free-living bacteria, studying antibiotic resistance in biofilm communities poses a paradigm
      shift. Furthermore, bacteria in biofilms are up to 1000 times more resistant to antibiotics
      than planktonic bacteria. Mechanisms involved in a biofilm infection also play a crucial role
      in the development of antibiotic resistance. Hospital-acquired infections are the fourth
      leading cause of disease and 70% are associated with medical implants and caused by
      staphylococcal biofilms. In addition, the level of antimicrobial resistance in bacteria
      causing implant-associated infections has increased worldwide, leaving patients with fewer
      treatment options.

      In this study the investigators will randomize patients with PJI to either standard MIC
      susceptibility or MIC and MBEC susceptibility guided treatment with oral antibiotic
      combinations; (i) Non cell wall active standard of care antibiotic combination (MIC-guided)
      for 6 weeks.

      (ii) Or; non cell wall active antibiotic combination according to a MBEC-based decision
      algorithm for 6 weeks.

      In this pilot project, the primary endpoint is how often treatment changes with the MBEC
      susceptibility testing compared to only MIC-susceptibility testing.
In the infectious process, biofilms may form early on biomaterials. There is ample evidence
      to the several-fold increase in antimicrobial concentrations required to eradicate even
      immature biofilms. In clinical practice the choice of antimicrobials is guided by
      susceptibility testing based on minimum inhibitory concentrations (MIC), which poorly reflect
      the increased antimicrobial resistance in biofilms. Minimum biofilm eradicating
      concentrations (MBEC) might better correspond to in vivo efficacy in the treatment of PJI,
      and other biofilm-centred infections. There is a need to develop methods, which are
      reproducible, low-cost, and time-efficient, for in vitro susceptibility testing of clinical
      biofilm bacteria.

      This prospective randomized study aim to compare antibiotic treatment regimens for PJI guided
      by MIC or MBEC combined with MIC, and how it affects infection resolution, drug tolerability
      and relapse strain resistance patterns.

      The investigors hypothesize that a standardised surgical debridement, antibiotics and implant
      retention (DAIR) for PJI followed by antibiotic guiding MBEC-diagnostics on deep tissue
      specimens will increase treatment efficacy and decrease the incidence of infection relapses
      compared to standard of care.

      Following standardised debridement and 14 days of parenteral antibiotics; cloxacillin for
      methicillin sensitive staphylococci or vancomycin for methicillin resistant staphylococci,
      patients will be randomized to receive oral antibiotic combinations with either cell wall
      active standard of care antibiotic combination (MIC-guided) for 6 weeks or non cell wall
      active antibiotic combination according to a MIC- and MBEC-guided decision algorithm for 6
      weeks.

      Patients will be included at the Orthopaedic Infection Centre (OIC), Sahlgrenska University
      Hospital/Mölndal, which is a unit dedicated to optimizing management of orthopaedic
      infections. Patient consent acquisitions and randomisations (20 patients in each group) will
      be performed during post-operative hospitalisation. MIC determination and disk diffusion will
      be performed at the SWEDAC (Swedish Accreditation Body) certified clinical bacteriological
      laboratory. At the department of Biomaterials (University of Gothenburg), a previously
      developed clinical diagnostic tool will be employed for the MBEC determination. It consists
      of the combination of the Calgary Biofilm Device (MBECTM P&G Assay, Innovotech) and a
      custom-made susceptibility plate (Substrata department, Sahlgrenska Hospital) with 6
      antimicrobial agents commonly used to treat orthopaedic infections.

      Inclusion and exclusion criteria are described in section "Eligibility".

      The primary and secondary endpoints are described in section "Outcome measures".

      Treatment criteria: for all administered antimicrobials staphylococcal strains must be
      susceptible in disc diffusion tests/MIC, regardless of MBEC-level. Antibiotic combinations
      will be selected from 5 already recommended non-cell wall active anti-staphylococcal
      antibiotics with high per-oral bio-availabilities and acceptable bone penetration used in the
      treatment of PJIs: rifampicin (RIF), fusidic acid (FUS), ciprofloxacin (CIP)/levofloxacin
      (LEV) and clindamycin (CLI).

      Clinical breakpoints are expressed as MIC (EUCAST and CLSI) but are based on more than MIC
      distributions (epidemiological cut-off) namely:

        -  Pharmacokinetic and pharmacodynamic analyses of the antibiotic.

        -  Relation between MIC and probability of cure in clinical trials.

      If likely effective according to EUCAST clinical breakpoints, antibiotics are further ranked
      in the MBEC treatment algorithm by bone penetration/susceptibility range and semi-arbitrarily
      by clinical efficacy in prosthetic joint infections.

      MBEC/MIC cut-off for replacing Rifampicin despite susceptibility according to MIC:

        -  C-Max (oral dose of 750 mg) 10 mg/L x 0.4 (Bone/Serum) = 4 mg/L

        -  RIF-MIC clinical breakpoint for staphylococci is 0.5 mg/L.

        -  Clinical efficacy factor 1.

        -  MBEC/MIC ≥ 8 times MIC.

      MBEC/MIC cut-off for replacing Levofloxacin despite susceptibility according to MIC:

        -  C-Max (oral dose of 750 mg) 12 mg/L x 0.6 (Bone/Serum) = 7,2 mg/L

        -  LEV-MIC breakpoint for staphylococci is 1 mg/L

        -  Clinical efficacy factor 0,75.

        -  MBEC/MIC ≥ 5 x MIC.

      MBEC/MIC cut-off for not choosing Fusidic acid as companion drug:

        -  C-Max (500 mg) 30 mg/L x 0,2 (Bone/Serum) = 6 mg/L

        -  FUS-MIC breakpoint for staphylococci is 1 mg/L.

        -  Clinical efficacy factor 0,5.

        -  MBEC 3 times the MIC or more if better companion drug.

      MBEC/MIC cut-off for not choosing Clindamycin as companion drug:

        -  C-Max (600 mg) 12 mg/L x 0.3 (Bone/Serum) = 3,6 mg/L

        -  CLI-MIC breakpoint for staphylococci is 0.5 mg/L

        -  Clinical efficacy factor 0,5.

        -  MBEC/MIC 4 x MIC or more if better companion drug.

      MBEC/MIC cut-off for not choosing Linezolid (LIN) as sole drug:

        -  C-Max 21 mg/L x 0.4 (Bone/Serum) = 8,4 mg/L

        -  LIN-MIC breakpoint for staphylococci is 4 mg/L

        -  Clinical efficacy factor 0,5.

        -  MBEC 2 times the MIC or more.

      MBEC cut-off for not choosing Sulfamethoxazole (SMX)/Trimethoprim (TMP) as sole drug:

        -  C-Max (3200/640 mg SMX/TMP) is 145 and 7.5 mg/L resp. x 0.25 (Bone/Serum) = 36 and 1,9
           mg/L resp.

        -  SMX/TMP-MIC breakpoint for staphylococci is 2 mg/L. (By EUCAST expressed as the
           Trimethoprim konc.)

        -  Clinical efficacy factor 0,5.

        -  MBEC > MIC

        -  *Interpret as better than according to justification above.

      All follow-up up to one year will be done according to clinical routines.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Number of changes in antimicrobial regimen other than standard of care
time frame: 6 weeks
description: Proportions of antimicrobial regimens other than standard of care through application of proposed MBEC-algorithm.
measure: Repeat procedure, relapse or reinfection
time frame: 12 months
description: Number of repeat procedures, relapses or reinfections, according to MSIS-criteria of PJI
measure: Oxford Hip Score
time frame: 12 months
description: Hip specific patient-reported outcome measure
measure: EQ-5D
time frame: 12 months
description: Generic health status patient-reported outcome measure
measure: Time to revision
time frame: 12 months
description: A shorter time could potentially indicate that the right decision is taken at an earlier stage
measure: Inpatient care
time frame: Up to 12 months
description: Resource consumption measure (days).
measure: Outpatient visits
time frame: Up to 12 months
description: Resource consumption measure, number of visits, type of visits.
measure: Discharge destination
time frame: Up to 12 months
description: Resource consumption measure. The type of facility a patient is discharged to (rehab facility, nursing home, home, home care).
measure: Heath care costs
time frame: Up to 12 months
description: Compound measure using data from outcome 6-8 (currency EUR).
measure: Development of additional antimicrobial resistance of the relapse causative strain
time frame: 12 months
description: At relapse surgery, the causative strain will be isolated by new biopsy cultures. Then the susceptibility of the causative strain will be tested again to evaluate any possible emergence of resistance against the antimicrobials previously used in the study. This will confirm if the given antimicrobial treatment has lead to antimicrobial resistance in a potential relapse strain isolated at a later occasion.
measure: Correlation between the virulence properties of the causative bacteria and patient outcome (infection resolution versus recurrent infection)
time frame: 36 months
description: The staphylococcal strains isolated from the patients with PJI will be characterised by phenotypic tests and whole genome sequencing to determine their virulence properties and carriage of genes involved in biofilm formation, antimicrobial resistance and production of toxins. Then the particular virulence of the strains will be correlated to the patients outcome, to be able to assess if more virulence carriage correlates to worse outcome (recurrent infection)
arm group label: MBEC and MIC susceptibility testing
arm group type: Experimental
description: For all administered antimicrobials staphylococcal strains must be susceptible in disc diffusion tests/MIC, regardless of MBEC-level. Antibiotic combinations will be selected from 5 already recommended non-cell wall active anti-staphylococcal antibiotics with high per-oral bio-availabilities and acceptable bone penetration used in the treatment of PJIs: rifampicin, fusidic acid, ciprofloxacin/levofloxacin and clindamycin.
MBEC cut-off for replacement with 2nd or 3rd line antibiotic: RIF MBEC/MIC > 8; LEV MBEC/MIC > 5; FUS MBEC/MIC > 3; CLI MBEC/MIC > 4; LIN MBEC/MIC > 2; T/S MBEC > MIC
Second line of treatment:
RIF and Fusidic acid 500 mg TID (ter in die) RIF and Clindamycin 450 - 600 mg TID LEV and Fusidic acid 500 mg TID LEV and Clindamycin 450 mg TID
Third line of treatment:
Linezolid 600 mg BID (bis in die) Sulfamethoxazole/Trimethoprim 800/160 mg TID Clindamycin 450 mg TID and Fusidic acid 500 mg TID
arm group label: MIC susceptibility testing
arm group type: Active Comparator
description: If the causative bacterium is susceptible according to MIC diagnostics, the patient will follow the first line of treatment: Rifampicin 750-900 mg/day + Levofloxacin 750 mg BID
intervention type: Diagnostic Test
intervention name: MIC or MBEC+MIC based treatment algorithm
description: i) Non cell wall active standard of care antibiotic combination (MIC-guided) for 6 weeks.
ii) Non cell wall active antibiotic combination according to a MBEC-based decision algorithm for 6 weeks.
arm group label: MBEC and MIC susceptibility testing
arm group label: MIC susceptibility testing
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ola Rolfson, Professor
phone: +46 313430852
email: ola.rolfson@vgregion.se
facility: 
status: Recruiting
contact: 
country: Sweden
citation: Zaborowska M, Tillander J, Branemark R, Hagberg L, Thomsen P, Trobos M. Biofilm formation and antimicrobial susceptibility of staphylococci and enterococci from osteomyelitis associated with percutaneous orthopaedic implants. J Biomed Mater Res B Appl Biomater. 2017 Nov;105(8):2630-2640. doi: 10.1002/jbm.b.33803. Epub 2016 Oct 25.
PMID: 27779811
responsible party type: Sponsor
mesh term: Infections
mesh term: Communicable Diseases
mesh term: Arthritis, Infectious
sharing ipd: No
ipd description: The main results will be presented at an aggregated level. In some cases, individual data may be presented (e.g. characteristics of a bacterial strain in relation to clinical outcome), but this information will be unidentified so that it cannot be deduced to the individual.
All compiled personal data will be stored on a password-protected hospital server that only the research group has access to. No personal data will be reported in publications.
The results of the study will be documented according to the study protocol and placed in a journal. Participants will be coded in a document together with the social security numbers.
Information about the participants, their health and the code key will be collected at the Orthopaedic Clinic where it will be treated confidentially and securely for 10 years. The handling of the participants' information is regulated by the Personal Data Act (SFS 1998: 204).