Impact of a Procalcitonin Testing and Treatment Algorithm on Antibiotic Use and Outcomes in the Pediatric Intensive Care Unit

Study Overview
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Brief Summary
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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
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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 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. 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.

Official Title
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Prospective, Randomized Controlled Trial to Evaluate the Impact of a Procalcitonin Testing and Treatment Algorithm on Antibiotic Use and Outcomes in the Pediatric Intensive Care Unit

Conditions
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Sepsis, Procalcitonin, Antimicrobial Stewardship

Intervention / Treatment
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* Other: Procalcitonin-Guided Antimicrobial Stewardship
* Other: Baseline Antimicrobial Stewardship


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or younger Prescribed or administered antibiotics in the hospital less than or equal to 24 hours prior to enrollment Have parents or legal guardians who provide informed consent Provide assent (if > 7 years of age) Exclusion Criteria: Are not prescribed antibiotics in the hospital Receive intravenous antibiotics within 7 days prior to identification for study enrollment Primary or secondary immune deficiency History of malignancy, bone marrow transplant or solid organ transplant A diagnosis of cystic fibrosis Neonates < 34 weeks gestation Patients receiving treatment for endocarditis, osteomyelitis, meningitis, mediastinitis or other invasive infection, for which long duration of antibiotics is needed Do not provide informed consent/assent

Ages Eligible for Study
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Minimum Age: 2 Hours
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Baseline Antimicrobial Stewardship<br>Baseline audit of antimicrobial orders with feedback to providers by the antimicrobial stewardship team. | Other: Procalcitonin-Guided Antimicrobial Stewardship<br>* 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.<br>Other: Baseline Antimicrobial Stewardship<br>* Baseline audit of antimicrobial orders with feedback to providers by the antimicrobial stewardship team.<br>|
| Experimental: Procalcitonin-Guided Antimicrobial Stewardship<br>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. | Other: Procalcitonin-Guided Antimicrobial Stewardship<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days of Antibiotic Therapy in the First 14 Days Following Randomization | Days of antibiotic therapy a participant receives following randomization will be measured | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Broad-spectrum Antibiotic Therapy | Defined as vancomycin, daptomycin, amikacin, ceftazidime, cefepime, piperacillin/tazobactam, aztreonam, carbapenems | up to14 days | 
| Number of Patients With an Antibiotic Change | Number of patients with an appropriate antibiotic escalation or de-escalation based on patient's clinical status and available supporting laboratory evidence, or lack thereof, of specific type of infection | up to 14 days | 
| 30-day Mortality | All-cause mortality | up to 30 days | 
| Re-initiation of Antibiotics for a Bacterial Infection | Re-initiation of any antibiotic for a proven or suspected bacterial infection | up to 30 days | 
| Length of Intensive Care Unit Stay | Hospital days spent in the intensive care unit | up to 14 days | 
| Length of Overall Hospital Stay | Hospital days admitted to the hospital | Until hospital discharge, an average of 7 days | 
| Ventilator Days | Days spent using invasive ventilation methods (not including supplementary oxygen via nasal cannula or Vapotherm support) | up to 14 days | 
| Number of Participants With Antibiotic-associated Complications | Antibiotic-associated complications including rash, neutropenia, thrombocytopenia, acute kidney injury [defined as increase in serum creatinine > 0.3 mg per dL or > 1.5-fold from baseline, or urine output < 0.5 mL per kg per hour for more than six hours], hepatotoxicity [defined as > 2-fold increase in alanine aminotransferase, ALT, or conjugated bilirubin], or C. difficile infection will be recorded | up to 14 days | 
| Infection With a Multi-drug Resistant Organism | Identification/growth of a multi-drug resistant organism from a sterile culture site. Multi-drug resistant organisms will be defined as methicillin-resistant S. aureus, vancomycin-resistant Enterococcus, 3rd generation cephalosporin non-susceptible Enterobacteriaceae, multi-drug resistant Pseudomonas aeruginosa [resistant to aminoglycosides, cephalosporins, floroquinolones and carbepenems], carbepenem-resistant Acinetobacter, and Candida spp obtained from otherwise sterile sites [i.e. blood or urine cultures] | up to 30 days | 
| Antibiotic Cost | Cost of antibiotic course will be obtained from hospital billing data | up to 14 days | 
| Number of Participants Whose Provider Adhered to the Procalcitonin-guided Algorithm | Rate of clinical provider compliance with adherence to suggested antibiotic escalation or de-escalation made by the antimicrobial stewardship team based on procalcitonin levels will be tracked | up to 5 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infection