Use of Inflammatory Biomarkers to Guide Antibiotic Therapy in Patients With Severe Infections

Study Overview
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Brief Summary
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In this study the investigators aim to test if C-reactive protein (CRP)or procalcitonin(PCT) - guided strategy allows to reduce the antibiotic use in patients wiht severe sepsis and septic shock. Therefore, the safety of this intervention will be carefully measured.

Detailed Description
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Methods Patients and settings: Prospective controlled randomized open interventional study of antibiotic therapy in adult with severe sepsis or septic shock, admitted to the intensive care unit. The study will be conducted in the intensive care unit (ICU) of the University Hospital Risoleta Tolentino Neves of the Federal University of Minas Gerais, Brazil. This is a 30-bed ICU with medical and surgical patients. All patients with suspected severe sepsis or septic shock admitted to the ICU will be assessed for eligibility. Patients developing severe sepsis or septic shock during their ICU stay will be also considered for enrollment. Cultures of urine, blood, bronchoalveolar lavage ﬂuid, and tracheal aspirates will be performed on admission and during ICU stay as clinically indicated. Blood gases and imaging exams will also be performed as clinically indicated, similarly in both groups. Interventions: All adult (> 17 years old) patients with diagnosis of severe sepsis or septic shock will receive initial antibiotic therapy based on local guidelines and susceptibility patterns, according to the decision of the treating physician. They will have circulating PCT and CRP levels measured at baseline and daily until day 4 in both groups. Eligible patients will be reassessed on day 4 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 - CRP group: the duration of antibiotic therapy will be based on circulating CRP levels. Group 2 - PCT group: the duration of antibiotic therapy will be based on circulating PCT levels. Patients enrolled in the study will undergo daily measurements of plasma CRP (Dry Chemistry - Johnsons & Johnsons) and PCT (BRAHMS PCT VIDAS) levels up to stopping antibiotic therapy, every 48hr for two measurements in patients remaining in the ICU, and then, every 5 days.Patients will be followed up 28 days, or until death or hospital transference, which comes first. PCT and CRP results will be released in sealed envelopes. During the study period, only the results corresponding to the patient randomization group will be open; i.e., CRP for CRP group patients and PCT for PCT group patients. - Criteria for antibiotic interruption: The investigators will propose the interruption of antibiotics if: The patients is clinically stable, without signs of active infection CRP group: a relative reduction of 50% in baseline CRP levels, or a value lower than 25mg/dl is reached. PCT group: a relative reduction of 90% in baseline PCT levels, or if a absolute value lower than 0.1 ng/ml is reached. The final decision regarding antibiotic therapy will be always let to the discretion of the treating physician.

Official Title
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Comparative Study of C-reactive Protein vs. Procalcitonin to Guide Antibiotic Therapy in Patients With Severe Sepsis and Septic Shock Admitted to the Intensive Care Unit.

Conditions
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Severe Sepsis, Septic Shock

Intervention / Treatment
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* Other: C-reactive protein guided antibiotic therapy
* Other: Procalcitonin guided antibiotic therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age > 17 years patients in intensive care unit signed informed consent suspected or confirmed severe sepsis or septic shock Exclusion Criteria: Infections caused by Listeria spp, Legionella pneumophilia, Mycobacterium tuberculosis Bacteremia due S. aureus Infections requiring prolonged therapies, such as endocarditis, cerebral abscess, chronic osteomyelitis Suspected or confirmed infection caused by virus, parasites Infections caused by P. aeruginosa ou A. baumannii Severe immunosuppression (ex: AIDS, post bone-marrow transplant,cystic fibrosis) Traumatism latest five days Surgery latest 5 days Carcinoid tumor, lung cancer, medullary thyroid cancer

Ages Eligible for Study
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Minimum Age: 18 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 - C-reactive protein (CRP) guided ab therapy<br>Intervention on antibiotic therapy will be based on circulating CRP levels | Other: C-reactive protein guided antibiotic therapy<br>* plasma CRP measurement to guide the duration of antibiotic therapy<br>|
| Active Comparator: Group 2 - procalcitonin (PCT) guided ab therapy<br>Intervention on antibiotic therapy will be based on circulating PCT levels | Other: Procalcitonin guided antibiotic therapy<br>* plasma PCT measurement to guide the duration of antibiotic therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of antibiotic therapy for the first episode of infection |  | 28 days | 
| Total antibiotic exposure days per 1,000 days |  | 28 days | 
| Days alive without antibiotics |  | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All cause 28-day mortality |  | 28 days | 
| clinical cure rate |  | 28 days | 
| Infection relapse (diagnosed less than 48h after antibiotic discontinuation) |  | 48 hours | 
| Length of ICU stay |  | Whole hospitalization | 
| Nosocomial infection rate |  | 28 days | 
| In-hospital mortality |  | 28 days | 
| sepsis-associated death |  | 28 days | 
| Nosocomial superinfection (diagnosed more than 48hous after discontinuation of the antibiotic therapy given to the first episode of infection) |  | 28 days | 
| Isolation of resistant bacteria |  | 28 days | 
| Length of hospital stay |  | The whole hospitalization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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C-reactive protein, procalcitonin, sepsis, antibiotic therapy