Shorter Versus Extended Course of Antibiotic Therapy for Necrotizing Soft Tissue Infections

Study Overview
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Brief Summary
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Necrotizing soft tissue infection (NSTI) is a devastating disease that results in a high rate of in-hospital complications and despite advances in critical care, wound care, and early intervention, NSTI continues to be associated with a mortality rate of nearly 30%. The antibiotics used in this treatment are Clindamycin, Vancomycin, Piperacillin Tazobactam; these antibiotics may be administered combined or individually, based on individualized patient treatment. Although one of the tenets of management for NSTI is early broad-spectrum intravenous antibiotics (listed above), the duration of antibiotics needed is not well defined. Currently, there exists wide variation in the duration of antibiotics for NSTI ranging between 2-16 days. The objective of this study is to evaluate the safety of a shorter course of antibiotics hypothesizing that a short duration of antibiotics for 48-hours after source-control is achieved will have similar risk of morbidity and mortality compared to a 7-day course of antibiotics post source control. A second aim of this study will be to identify if serum procalcitonin levels/ratio correspond to resolution of systemic infection in patients with NSTI.

Detailed Description
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The objective of this study is to evaluate the safety of a shorter course of antibiotics hypothesizing that a short duration of antibiotics for 48-hours after source-control is achieved will have similar risk of morbidity and mortality compared to a 7-day course of antibiotics post source control. The proposed shortened duration is considered within standard of care as the IDSA suggests 48-72 hours of antibiotics after source control, however this was due mostly to expert opinion until a recent single-center study using historical controls demonstrated a 48-hour duration of antibiotics to be safe. A second aim of this study will be to identify if serum procalcitonin levels/ratio correspond to resolution of systemic infection in patients with NSTI. This pilot study may help limit use of antibiotics which are associated with both cost and significant adverse events including antimicrobial resistance and clostridium difficile infections. In addition, the data would support grant submission of a larger, multi-center study with sufficient power to demonstrate the safety profile and potential benefits of a shorter duration of antibiotics, which has been shown to be beneficial in previous large surgical infection studies. Specific Aims: Aim#1: Establish the safety of an abbreviated course (48 hours after source control) compared to a prolonged (7 days after source control) course of antibiotics in terms of in-hospital mortality. Aim#2: Compare the incidence of hospital length of stay and in-hospital complications including unplanned return to the operating room, ventilator days, and antibiotic associated complications (e.g., clostridium difficile infection) in the two comparison groups: abbreviated (48-hours) and prolonged antibiotics (7-days) after source control. Aim#3: Identify a critical threshold of biochemical procalcitonin or a % decrease in procalcitonin from the initial procalcitonin obtained upon admission that suggests resolution of systemic infection in patients with NSTI. This will be done by obtaining a serum procalcitonin upon admission and daily for up to 7 days from admission or once source control has been achieved.

Official Title
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Pilot Randomized Controlled Trial of Shorter Versus Extended Course of Antibiotic Therapy for Necrotizing Soft Tissue Infections

Conditions
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Necrotizing Soft Tissue Infection

Intervention / Treatment
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* Other: Antibiotic duration
* Other: Antibiotic duration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients 18 years of age or older with all following criteria: Presenting to the Emergency Department with history, exam and/or imaging concerning NSTI, AND Patients who undergo consultation by the Emergency General Surgery service, AND Patients included must have skin or soft tissue findings consistent with NSTI (erythema, crepitus, or pain out of proportion to exam), AND Systemic signs of infection including fever (temperature >38.0°C) or leukocytosis (≥11,000 peripheral white cells per cubic millimeter), AND Patients who undergo excisional debridement and/or amputation to achieve source control. Exclusion Criteria: Pregnant patients Prisoners Patients with bacteremia upon admission Patients unable to provide consent (including no legally authorized representative)

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Short course of antibiotics<br>Patients assigned to a 48-hour course of antibiotics. As the current standard of care, the antibiotics used in this treatment are Clindamycin, Vancomycin, Piperacillin-Tazobactam; these antibiotics may be administered combined or individually, based on individualized patient treatment. The specific choice of antibiotic therapy will not be dictated by the study protocol but by the attending surgeon taking care of the patient | Other: Antibiotic duration<br>* The patient will be enrolled in a 48-hour course of antibiotics.<br>|
| Long course of antibiotics<br>Patients assigned to a 7 day course of antibiotics. As the current standard of care, the antibiotics used in this treatment are Clindamycin, Vancomycin, Piperacillin-Tazobactam; these antibiotics may be administered combined or individually, based on individualized patient treatment. The specific choice of antibiotic therapy will not be dictated by the study protocol but by the attending surgeon taking care of the patient | Other: Antibiotic duration<br>* The patient will be enrolled in a 7 day course of antibiotics.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of the antibiotic course duration | In-hospital complications | Through study completion, an average of 1 year | 
| Mortality rate | In-hospital mortality | Through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Age | Age in years | Baseline, pre-intervention/procedure/surgery | 
| Sex | Sex (male/female) | Baseline, pre-intervention/procedure/surgery | 
| BMI (body mass index) | Body mass index (weight and height will be combined to report BMI in kg/m^2) | Baseline, pre-intervention/procedure/surgery | 
| Blood Pressure | Blood Pressure (mmHg) | Baseline, pre-intervention/procedure/surgery | 
| Heart Rate | Heart rate (beats/minute) | Baseline, pre-intervention/procedure/surgery | 
| Respiratory rate | Respiratory rate (breaths/minute) | Baseline, pre-intervention/procedure/surgery | 
| Temperature | Temperature (Fahrenheit) | Baseline, pre-intervention/procedure/surgery | 
| Comorbidities | Comorbidities (e.g., diabetes, hypertension, cirrhosis, chronic kidney disease, etc.) | Baseline, pre-intervention/procedure/surgery | 
| Transfusion requirements | Number of Packed Red Blood Cells transfused measured in milliliters | Baseline, pre-intervention/procedure/surgery | 
| NSTI location | Anatomical location of soft tissue infection | Baseline, pre-intervention/procedure/surgery | 
| Operations | Number of surgical procedures | Through study completion, an average of 1 year | 
| Serum concentration of procalcitonin | Procalcitonin ng/mL | Upon admission and daily blood sample for 7 days | 
| Serum concentration of white blood cell | White blood cell count cells per microliter (cells/μL) | Through study completion, an average of 1 year | 
| Serum concentration of hemoglobin | Hemoglobin grams/deciliter | Through study completion, an average of 1 year | 
| Serum concentration of sodium | Sodium millimoles per liter (mmol/L) | Through study completion, an average of 1 year | 
| Serum concentration of C-reactive protein | C-reactive protein milligrams/liter | Through study completion, an average of 1 year | 
| Serum concentration of glucose | Glucose milligrams/deciliter | Through study completion, an average of 1 year | 
| Serum concentration of creatinine | Creatinine milligram/deciliter | Through study completion, an average of 1 year | 
| Total hospital length of stay | Total days of hospital stay | Through study completion, an average of 1 year | 
| Total intensive care unit (ICU) | Total days of ICU stay | Through study completion, an average of 1 year | 
| Total ventilator days | Total days of ventilation support for the patient | Through study completion, an average of 1 year |