Impact of a Procalcitonin Testing and Treatment Algorithm on Antibiotic Use and Outcomes in the Pediatric Intensive Care Unit
Condition: Sepsis; Procalcitonin; Antimicrobial Stewardship
Study type: Interventional

Summary: 
      The timely use of antibiotics can reduce morbidity and mortality associated with bacterial
      infections, particularly in the intensive care unit setting (ICU). Long courses of
      antibiotics, however, are associated with the emergence of multi-drug resistant organisms and
      antibiotic-associated adverse events, such as C. difficile infections. Thus, antibiotic
      de-escalation is an important goal of antimicrobial stewardship programs.

      Procalcitonin (PCT) has been investigated as a biomarker for critically ill adult patients
      with bacterial infection, particularly pneumonia and sepsis. The proposed project will
      evaluate whether a PCT testing and treatment algorithm, implemented through daily
      antimicrobial stewardship audit and feedback, can promote early and safe antibiotic
      de-escalation in the pediatric ICU.
    

Detailed description: 
      The timely use of effective antibiotics can markedly reduce the morbidity and mortality
      associated with bacterial infections, particularly in the intensive care unit (ICU). However,
      in this setting, much antibiotic use is empiric, and administered to patients with
      non-bacterial or non-infectious causes of inflammation that do not respond to antibiotics.
      This widespread empiric use of antibiotics drives the emergence of multi-drug resistant
      organisms and antibiotic-associated adverse events, such as C. difficile infections.
      De-escalation of broad-spectrum empiric antibiotics for ICU patients without proven bacterial
      infections can reduce unnecessary antibiotic use, slow the development of antibiotic
      resistance, and reduce complications associated with antibiotic therapy. Thus, antibiotic
      de-escalation is an important goal of antimicrobial stewardship programs. Specific tests and
      pathways to predict which patients have bacterial infections and those that would benefit
      from antibiotic therapy would accelerate de-escalation and greatly facilitate antimicrobial
      stewardship efforts.

      Procalcitonin (PCT) has been investigated as a biomarker for critically ill adult patients
      with bacterial infection, particularly pneumonia and sepsis. Following bacteria-induced
      activation of monocytes and adherence of monocytes to endothelial surfaces, procalcitonin is
      expressed and secreted. PCT levels have been shown to rise rapidly and remain elevated during
      ongoing bacterial infections, and PCT levels are more specific for bacterial infections than
      CRP or total white blood cell count. PCT rises approximately 4 hours after bacterial
      exposure, peaks between 12-24 hours, and has a half-life of 24 hours once the infectious
      stimulus is removed.

      In many adult trials investigating PCT-guided algorithms for antibiotic cessation (refer to
      section 3.0), a high proportion of providers (up to 50%) chose not to follow algorithm
      guidance for subjects randomized to the PCT-guided group. Thus, although PCT appears to be a
      useful guide for safe antibiotic de-escalation in the ICU, the ideal method for implementing
      the test and integrating it into clinical care in order to maximize its impact in the
      pediatric population is unclear. Notably, none of the prior trials evaluated PCT-associated
      outcomes in critically ill children nor integrated PCT testing into antimicrobial stewardship
      activities.

      The investigators propose the evaluation of a PCT testing and treatment algorithm on patient
      outcomes in the pediatric ICU, a setting in which PCT-guided antibiotic de-escalation has not
      been previously studied.

      The proposed project will evaluate whether a procalcitonin (PCT) testing and treatment
      algorithm, implemented through daily antimicrobial stewardship audit and feedback, can
      promote early and safe antibiotic de-escalation in the pediatric ICU. The investigators will
      conduct a pragmatic, prospective randomized controlled trial comparing antimicrobial use and
      outcomes among children admitted to the ICU who receive either: 1) Routine laboratory testing
      and treatment with antimicrobial stewardship review (control), or 2) PCT testing and
      treatment with antimicrobial stewardship review (intervention). In both arms, baseline daily
      review of antimicrobial management by the stewardship team will occur. In the intervention
      arm, the stewardship provider also will recommend PCT testing and antibiotic modifications
      using a PCT-based treatment algorithm. PCT levels will be measured a total of four times in
      the intervention arm - on enrollment, then daily through day 3 post-randomization and on day
      5 post-randomization. This research is not to determine if PCT is a good test; this has
      already been established and evaluated as part of the FDA approval process. This pragmatic
      outcomes trial is evaluating if use of the PCT, implemented together with antimicrobial
      stewardship program oversight, improves the quality of care the investigators can provide for
      children at Vanderbilt Children's Hospital. The investigators hypothesize that patients in
      the intervention arm will have shorter duration of antibiotic therapy and similar outcomes,
      as compared to patients in the control arm.

      Specific Aims

        1. Compare antimicrobial utilization among children in the ICU who receive standard-of-care
           testing plus stewardship vs. PCT-based treatment plus stewardship. The investigators
           will compare days of antibiotic therapy in the first 14 days following randomization
           between the study arms. The investigators will test the hypothesis that duration of
           antibiotic therapy will be 2 days shorter in the group with PCT-guided management vs.
           the group with standard of care testing and treatment.

        2. Compare clinical outcomes and safety among children in the ICU who receive
           standard-of-care testing plus stewardship vs. PCT-based treatment plus stewardship. The
           investigators will compare mortality, length of stay, recurrence of infection, and
           antibiotic-associated adverse events (rash, myelosuppression, renal impairment,
           hepatotoxicity, C. difficile infection) between the study arms. The investigators will
           test the hypothesis that outcomes and safety will be comparable between the study arms.
    

Intervention name(s): Procalcitonin-Guided Antimicrobial Stewardship; Baseline Antimicrobial Stewardship
Intervention type(s): Other; Other
Intervention description(s): In addition to baseline audit of antimicrobial orders, the stewardship team will additionally recommend procalcitonin (PCT) testing and treatment per algorithm. PCT will be used in conjunction with clinical status and exam, and results of radiographic and laboratory studies, to make medical decisions about antibiotic therapy.; Baseline audit of antimicrobial orders with feedback to providers by the antimicrobial stewardship team.
Intervention MeSH terms: Anti-Infective Agents; Anti-Bacterial Agents
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Infection