Procalcitonin Protocol to Shorten the Antibiotic Therapy in Febrile Neutropenia

Study Overview
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Brief Summary
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In this study the investigators aim to test if a procalcitonin (PCT) - guided strategy allows to reduce the antibiotic use in patients with febrile neutropenia hospitalized in a Brazilian tertiary university hospital, causing no harm.

Detailed Description
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Methods Patients and setting: Prospective controlled randomized interventional study of antibiotic therapy in adult with febrile neutropenia. The study will be conducted in the University Hospital of the Federal University of Minas Gerais, Brazil. This is a 600-bed tertiary hospital, with approximately 1.6 thousands hospitalizations/month. Roughly 120 episodes of febrile neutropenia were recorded in the first semester of 2007, occurring in 100 patients with hematological leucosis or post-BMT. This number rises if one considers other groups of neutropenic patients, such as those with neutropenia due chemotherapy for solid tumors, patients with BM aplasia, myelo dysplasia, among others, Interventions: As long as the core objective of the study is to test if a PCT-guided protocol allows to guide the antibiotic withdrawn in neutropenic patients, only patients with febrile neutropenia under antibiotic therapy will be included in the study. They will be submitted to the following exams: Bood samples will be drawn at baseline to blood culture, CRP, blood cells count, ions, liver profile and renal function tests. These exams will be repeated according to the local protocol followed by the Service of Hematology (see appendix). A plasma galactomannan test will be performed at baseline in all patients considered for inclusion in the study, and repeated at any moment if there is suspicion of Aspergillus infection during the follow up. A chest radiography will also be performed in all participants at baseline, and according to clinical indication afterwards. All patients with abnormal chest radiography at baseline will be submitted to a contrasted chest CT (or without contrast if creatinine clearance < 50 ml/min). Additional complementary exams will be performed as clinically needed. Circulating PCT measurements will be performed at baseline, and then on day 3 (if initial PCT < 0.5) or on day 5 (if initial PCT >0.5). Eligible patients will be reassessed for on day 3 (if initial PCT < 0.5) or on day 5 (if initial PCT >0.5), and randomized at 1:1 basis to one of the two groups since any exclusion criteria (see below) is present at that time: Group 1 - PCT group: the interventions on antibiotic therapy will be based on circulating PCT levels. Group 2 - Control group: antibiotic therapy will be guided by appropriate guidelines, and will be left at the discretion of caregivers. Patients randomized to the study will undergo daily measurements of plasma PCT levels, and kept under antibiotic therapy until a relative reduction of 90% in baseline PCT levels, or a value lower than 0.5 ng/ml is reached, and then maintained for additional 48h (two measure). Therefore, plasma PCT levels will be measured every 5 days up to the 28th day of follow-up or until death or transference, if either occurs first. Patients included in the interventional group will be observed for at least 48 hours following antibiotic discontinuation before being discharged from the hospital. Extra PCT tests will be performed according to the clinical course. Apart from the antibiotic therapy, all participants will be managed according to the appropriate guidelines. Patients with febrile neutropenia hospitalized in the University Hospital of the Federal University of Minas Gerais are routinely cared by an experienced hematology specialist together with an infectious diseases consultant. This standard care will be offered to all patients included in the study. The final decision regarding antibiotic therapy will be always let to the discretion of these specialists.

Official Title
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The Use of a Procalcitonin (PCT)-Guided Protocol to Shorten the Duration of Antibiotic Therapy in Febrile Neutropenic Patients. An Interventional Study.

Conditions
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Febrile Neutropenia

Intervention / Treatment
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* Other: procalcitonin
* Drug: antibiotic therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age > 18 years febrile neutropenia to be under antibiotic therapy signed informed consent Exclusion Criteria: patients under antibiotic therapy for more than 72 hours before inclusion patients post allogenic bone-marrow transplant (BMT) patients presenting one or more of the following conditions at the time of randomization: severe mucositis all-trans retinoic acid (ATRA) syndrome disseminated intravascular coagulation hypotension (systolic blood pressure < 90 mmHg or need for vasopressor to maintain blood pressure) respiratory failure (arterial oxygen pressure < 60 mmHg while breathing room air) or need for mechanical ventilation severe renal failure requiring hemodialysis patients with suspected (positive galactomannan assay in peripheral blood, nodular lesions with halo in the chest CT) or microbiologically confirmed fungal infection bacteremia due to S. aureus microbiologically confirmed carbapenem resistant P. aeruginosa or A. baumanii infection microbiologically confirmed pneumonia due to P. aeruginosa, A. baumanii or Stenotrophomonas maltophilla suspected or confirmed infection caused by atypical microorganisms (virus, parasites, P. jiroveci). Patients with localized HSV infection (e.g., labial) will be accepted for inclusion infections requiring prolonged therapies, such as endocarditis and cerebral abscess clearly focal bacterial infections

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 - PCT group<br>interventions on antibiotic therapy will be based on circulating PCT levels | Other: procalcitonin<br>* plasma PCT measurement<br>Drug: antibiotic therapy<br>* antibiotic therapy use<br>|
| Active Comparator: Group 2 - Control group<br>antibiotic therapy will be guided by appropriate guidelines, and will be left at the discretion of caregivers. | Other: procalcitonin<br>* plasma PCT measurement<br>Drug: antibiotic therapy<br>* antibiotic therapy use<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antibiotic exposure, measured by: - incidence density of ''antibiotic exposure days'' - incidence rate ratio (IRR) of antibiotic exposure |  | 28 days | 
| Number of days alive without antibiotics |  | 28 days | 
| Duration of antibiotic therapy for the first episode of fever |  | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of hospital stay |  | 6 m | 
| All cause and infection-related 28-day mortality |  | 28 days | 
| All cause 90-day mortality |  | 90 days | 
| Clinical cure rate |  | 28 days | 
| Nosocomial superinfection (diagnosed more than 48 hours after discontinuation of the antibiotic(s) given to the first episode of infection) |  | 28 days | 
| Infection relapse (diagnosed less than 48 h after antibiotic discontinuation) |  | 48 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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procalcitonin, neutropenia, febrile neutropenia, antibiotic therapy, neutropenic patients