Trial document




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  DRKS00014583

Trial Description

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Title

Cefazolin versus flucloxacillin in bloodstream infections caused by methicillin-susceptible Staphylococcus aureus (MSSA): a quasi-randomized, prospective, observational study (CASABI)

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Trial Acronym

CASABI

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URL of the Trial

[---]*

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Brief Summary in Lay Language

Bloodstream infections due to Staphylococcus aureus are often severe and always warrant an intravenous antibiotic therapy of at least 2 weeks. In most places antistaphylococcal penicillins are the therapy of choice, whereas Cefazolin is degraded to an alternative - mainly due to presumably historic concerns about a reduced efficacy. Newer retrospective studies prompt a better tolerability of Cefazolin without evidence of a tradeoff in efficacy.
However solid data from prospective trials without selection bias are missing.

CASABI is a pilot study, its results will be used to plan a multicentric, randomised-controlled study to define the optimal treatment for bloodstream infections due to Staphylococcus aureus.

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Brief Summary in Scientific Language

Methicillin-susceptible Staphylococcus aureus (MSSA) is a leading cause of serious invasive infections often complicated by bacteraemia. For decades antistaphylococcal penicillins (ASPs) have been the unquestioned first line therapeutic agents. Cefazolin has been degraded to an alternative mainly due to concerns about a reduced efficacy in high inoculum infections - derived from an in-vitro phenomenon with unclear clinical significance. Newer, mainly retrospective studies demonstrated a similar clinical efficacy of ASPs and cefazolin in the treatment of both uncomplicated MSSA blood stream infections (BSI) and blood stream infections from a deep-seated source. They concluded equally that adequate source control and severity of disease may better predict clinical outcome than the choice of the antibiotic agent. Surprisingly there was a consistent trend towards a lower mortality in patients treated with Cefazolin which was highly significant in a large retrospective analysis of more than 3000 patients. However, substantial selection bias with a preferential choice of ASPs for more severe infections cannot be excluded despite vigorous efforts of authors for statistical adjusting for confounding factors. Another consistent finding was a relevant better tolerability of Cefazolin compared to various ASPs. Along with a more convenient dosing scheme and lower costs of cefazolin, it might be the time to rethink the role of ASPs in the management of invasive MSSA infections. However, prospective controlled studies evaluating the clinical efficacy and tolerability of cefazolin versus ASPs are missing. The ultimate goal of this proposal is to conduct such a trial. For a solid sample size calculation and evaluation of feasibility a prospective, observational pilot study is needed. We propose a quasi-randomised, propensity score matched comparison of current therapy standards at the university hospitals of Cologne (primary use of an ASP) and Frankfurt (primary use of cefazolin). An established, well-accepted infectious disease consultation service at both hospitals with routine consultation for all patients with MSSA-BSI represent ideal research conditions. The type, grade and frequency of adverse events will be captured precisely while clinical and microbiological efficacy will be analysed exploratory to assess formal progression criteria. If a better tolerability of cefazolin as compared to ASPs with a similar or better efficacy can be shown in this pilot trial, its results will be used to design a definite randomised trial to compare the efficacy of both regimens, i.e. presumably on the non-inferiority of cefazolin to flucloxacillin.

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Organizational Data

  •   DRKS00014583
  •   2019/02/04
  •   [---]*
  •   yes
  •   Approved
  •   18-156, Ethik-Kommission der Medizinischen Fakultät der Universität zu Köln
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Secondary IDs

  •   U1111-1227-0201 
  •   3159  (www.clinicalsite.org)
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Health Condition or Problem studied

  •   bloodstream infection due to Methicillin-susceptible Staphylococcus aureus (MSSA)
  •   A41.0 -  Sepsis due to Staphylococcus aureus
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Interventions/Observational Groups

  •   All Patients with MSSA (Methicillin-susceptible Staphylococcus aureus) bloodstream infection who give informed consent to participate in the study and who receive either flucloxacillin or cefazolin will be included in the study.
    Throughout the period of MSSA-specific i.v. antibiotic therapy all side effects will be recorded. After completion of therapy the effect of the clinical and microbiological response will be recorded. The observation period ends with a follow-up at 90 days.


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Characteristics

  •   Non-interventional
  •   Observational study
  •   Single arm study
  •   Open (masking not used)
  •   [---]*
  •   Uncontrolled/Single arm
  •   Treatment
  •   Single (group)
  •   N/A
  •   No
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Primary Outcome

Tolerability and safety of Cefazolin versus Flucloxacillin summarized as weighted sums of all side effects during therapy (grade of side effects according to CTCAE). Also the rate of premature discontinuation of therapy due to side effects for both substances will be recorded.

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Secondary Outcome

- Evaluation of the clinical and microbiological efficacy of Cefazolin versus Flucloxacillin for the therapy of bloodstream infections due to MSSA (Methicillin-susceptible Staphylococcus aureus) by categorical judgement at the end of i.v.-therapy, latest after 90 days.
- Follow-up after 90 days to record MSSA-specific and overall mortality
- sample size calculation and demonstration of the feasibility of a multicentric, randomised-controlled non-inferiority study

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
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Recruitment

  •   Planned
  •   2019/03/01
  •   75
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

1. patients (> 18 years) with their 1st episode of a monomicrobial bloodstream infection due to Methicillin-sensitive Staphylococcus aureus (MSSA), proven by ≥ 1 positive blood culture sample
2. patients willing and able to give written informed consent to participate in the study
3. Cefazolin or Flucloxacillin as part of the antibiotic regimen or planned transition to an antibiotic regimen that includes Cefazolin or Flucloxacillin

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Exclusion Criteria

1. patients with polymicrobial bloodstream infection
2. patients unable to give informed consent

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Addresses

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    • Uniklinik Köln
    • Kerpener Str. 62
    • 50937   Köln
    • Germany
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    • Uniklinik Köln, Klinik I für Innere Medizin, Klinische Infektiologie
    • Ms.  Dr.  Marianne  Breuninger 
    • Kerpener Str. 62
    • 50937  Köln
    • Germany
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    • Uniklinik Köln, Klinik I für Innere Medizin, Klinische Infektiologie
    • Ms.  Dr.  Marianne  Breuninger 
    • Kerpener Str. 62
    • 50937  Köln
    • Germany
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Sources of Monetary or Material Support

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    • Deutsche Forschungsgemeinschaft
    • Kennedyallee 40
    • 53175  Bonn
    • Germany
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Status

  •   Recruiting planned
  •   [---]*
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.