Efficacy and Safety of a Protocol Using C-reactive Protein to Guide Antibiotic Therapy

Study Overview
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Brief Summary
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The growing resistance of microorganisms to antimicrobials is a major threat to public health nowadays. Reducing the consumption of antibiotics is one of the main strategies to control this issue. Protocols using biomarkers to guide antimicrobial therapy have been studied, with promising results in safely reducing patient exposure to these drugs by reducing duration of treatments. Procalcitonin (PCT) and C-reactive protein (CRP) represent the most promising biomarkers in this context. Although less studied, CRP has the potential advantages of lower cost and wide availability when compared to PCT. However, decision algorithms involving biomarkers proposed in studies published so far are very far from daily medical practice in hospitals, mainly because there is poor accessibility to these protocols, and because most of them do not contemplate each patients clinical variables. The objective of this project is to evaluate the efficacy and safety of a multimodal protocol using clinical variables and the CRP value to guide antibiotic therapy in hospitalized patients. This protocol will be applied diretcly by the assistant medical teams through a digital clinical decision support tool available in the form of an application for mobile devices developed by the research team.

Detailed Description
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The research team will perform a randomized, controlled, concurrent, open, single-center clinical trial. The proposed intervention is the application of a protocol that uses clinical variables and the CRP value to guide the duration of antibiotic therapy in patients with suspected or confirmed bacterial infection. As for the control group, the duration of antibiotic therapy will be suggested according to the best available evidence, considering the primary site of infection and other characteristics of this process. For both groups, the study protocol will be applied through a digital application for use on smartphones or tablets, developed specifically for this project. Participants will be adults admitted to the internal medicine ward of the Hospital das Clínicas of the Federal University of Minas Gerais (HC-UFMG), for whom the assistant physician team has started antibiotic therapy in the last 72 hours. Patients will be allocated after signing a free and informed consent form. Follow-up will be carried out until hospital discharge, death or 90 days, whichever occurs first. The project was submitted for consideration to the Research Ethics Committee of the Federal University of Minas Gerais (COEP-UFMG) and approved. As primary outcome, the duration of antibiotic therapy will be evaluated for the infectious episode that motivated inclusion in the study. Duration of antibiotic therapy will be measured by antimicrobial days (defined by the aggregate of days a specific antimicrobial agent was administered to an individual patient) per 1000 present days (defined by the length of time during which a given patient is at risk for antimicrobial exposure at a given institution). As secondary outcomes, the investigators will assess total exposure to antimicrobials, antibiotic-free days, user satisfaction after using the digital tool, protocol adherence rate, length of stay, estimated cost of antimicrobial therapy, all-cause hospital mortality, therapeutic failure, reinfection rate, subsequent infections with multidrug-resistant microorganisms, Clostridioides difficile infection.

Official Title
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Efficacy and Safety of a Protocol Using C-reactive Protein to Guide Antibiotic Therapy Applied Through a Digital Clinical Decision Support Tool: a Randomized Clinical Trial

Conditions
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Systemic Infection

Intervention / Treatment
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* Other: C reactive protein


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients over 18 years of age, Clinical suspicion or microbiological confirmation of bacterial infection, with initiation of antibiotic therapy in the last 72 hours. Signing of the free and informed consent term by the patient or companion if the patient is unable to sign it (Annex 1). Patient admitted to the unit participating in the study. Exclusion Criteria: HIV-infected patients with a CD4 count < 200 cells/mm3; neutropenic with neutrophil count < 500 cells/mm3; solid organ or bone marrow transplants; patients who received chemotherapy in the last 14 days at high risk of febrile neutropenia (> 20%), defined by the assistant team responsible for the treatment of the neoplasm; use of immunosuppressants, such as cyclophosphamide, azathioprine, cyclosporine, rituximab, tacrolimus, sirolimus or TNF inhibitors; use of corticosteroid therapy at a dose greater than 0.5mg/Kg of prednisone (or equivalent) over the last 30 days or pulse therapy in the last 14 days with these drugs; primary immunodeficiency (eg, X-linked agammaglobulinemia, common variable immunodeficiency) or patients with another condition that determines a clear impairment of immunological defenses, whether humoral, cellular or mixed. Conditions that require prolonged antibiotic therapy (infective endocarditis, necrotizing pneumonia, deep abscesses, osteomyelitis, complicated soft tissue infections, S. aureus bacteremia, among others), identified before randomization (ie, up to 72 hours of antibiotic therapy) . Patients with the perspective of hospital discharge in less than 72 hours from inclusion. Patients in exclusive palliative care. Patients with life expectancy < 24h.

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
Interventional Model Description: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: C reactive protein<br>For the patients assigned to the intervention group, the attending physicians will be instructed to follow a flowchart created by the research team that uses clinical variables and the serum CRP value to guide the prescription and the duration of antibiotic therapy, that will be available in the application for mobile devices developed specifically for this study. Antibiotic suspension will be encouraged when CRP value is < 35mg/L and after a minimal duration of 3 days (if peak CRP is below 100mg/L), or when CRP value reduces by 50% and after a minimal duration of 5 days (if peak CRP is above 100mg/L or if the patient fills the criteria for sepsis or septic shock). Before suspension, the physician will be instructed to make sure the patient is in clinical improvement, without any signs of persistent infectious focus and if the Sequential Organ Failure Assessment (SOFA) score is stable or in decrease. | Other: C reactive protein<br>* The attending physicians will be instructed to follow a flowchart created by the research team that uses clinical variables and the serum CRP value to guide the prescription and the duration of antibiotic therapy. This flowchart will be available in the application for mobile devices developed specifically for this study. CRP levels will be collected on a daily basis. Antibiotic suspension will be encouraged when CRP value is < 35mg/L and after a minimal duration of 3 days (if peak CRP is below 100mg/L), or when CRP value reduces by 50% and after a minimal duration of 5 days (if peak CRP is above 100mg/L or if the patient fills the criteria for sepsis or septic shock). Before suspension, the physician will be instructed to make sure the patient is in clinical improvement, without any signs of persistent infectious focus and if the SOFA score is stable or in decrease.<br>|
| No Intervention: Best practice<br>For patients in the control group, it will be encouraged that the prescription and duration of antimicrobial therapy be carried out in accordance according to the best current evidence avaiable. Through the digital clinical decision support tool, the therapy duration for each participant will be suggested, based on the infectious focus and response to treatment. Such recommendations will be based on best practices for the use of antibiotic therapy available in the medical literature. As well as in the intervention group, the final responsibility for the prescription, choice of antibiotic treatment regimen(s) and duration of treatment will be entirely with the assistant team. For participants allocated to the control group, it will be recommended to stop monitoring CRP levels after 72 hours of antibiotic therapy, a period in which this biomarker can help in the diagnosis of the infectious condition. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of antibiotic therapy | Measured by antimicrobial days (defined by the aggregate of days a specific antimicrobial agent was administered to an individual patient) per 1000 present days (defined by the length of time during which a given patient is at risk for antimicrobial exposure at a particular institution). | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total exposure to antimicrobials | Defined by the number of days of exposure to antibiotics considering all therapeutic cycles during patient follow-up. | 90 days | 
| Antibiotic-free days | Defined by the ratio of the number of days of follow-up without the use of antibiotics by the number of days of follow-up in total, corrected by a denominator of 100. | 90 days | 
| Evaluation of users satisfaction after using the clinical decision support tool | Measured through an objective questionnaire to be applied at the end of the study, evaluating the feasibility of applying the tool and its usefulness in daily clinical practice, as well as the user's satisfaction. A higher score means a better outcome. | 2 years | 
| Adherence rate to the protocol | The investigators will consider non-adherence to the protocol any case in where the treating team chose not to follow the investigators' recommendations, either stopping antibiotics earlier or later than recommended by the protocol. | 90 days | 
| Length of hospital stay | Measured in days. | 90 days | 
| Cost estimate of antimicrobial therapy. | Considering Brazilian market prices. | 2 years | 
| All-cause 90 days mortality | All-cause 90 days mortality. | 90 days | 
| Therapeutic failure | Defined as persistence or recurrence of signs and symptoms of the same focus of infection that motivates resumption of antibiotic therapy in less than 48 hours after suspension. | 2 days | 
| Reinfection rate | Defined as a new episode of infection with a different focus or with isolation of new microorganisms or after 48 hours of discontinuation of antibiotic therapy directed at the initial infectious condition. | 90 days | 
| Subsequent infections by multidrug-resistant microorganisms | Measured by the ratio of cultured isolates per 100 patients. | 90 days | 
| Clostridioides difficile infection | Measured by diagnostic methods avaiable in Hospital das Clínicas da Universidade Federal de Minas Gerais. | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Systemic infection, Sepsis, Biomarkers, C reactive protein, Antibiotic, Antibiotic stewardship