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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Necrotizing Soft Tissue Infection
• Intervention / Treatment: Other: Antibiotic duration; Other: Antibiotic duration

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Areg Grigorian, MD; Phone Number: 8184389093; Email: agrigori@hs.uci.edu
• Study Contact Backup: Name: Jeffry Nahmias, MD; Phone Number: 9493073035; Email: jnahmias@hs.uci.edu

Study Locations

• United States
  • California
    • Orange, California, United States, 92868
      • Recruiting
      • University of California Irvine Medical Center
      • Contact: Jeffry Nahmias, MD; Phone Number: 9493073035; Email: jnahmias@hs.uci.edu
      • Contact: Areg Grigorian, MD; Phone Number: 818-438-9093; Email: agrigori@hs.uci.edu
      • Principal Investigator: Areg Grigorian, MD
      • Sub-Investigator: Jeffry Nahmias, MD
      • Sub-Investigator: Sebastian Schubl, MD
      • Sub-Investigator: Lanny L Hsieh, MD
      • Sub-Investigator: Steven E Atallah, PharmD
      • Sub-Investigator: Claudia A Alvarez, MD
      • Sub-Investigator: Negaar Aryan, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult patients with a diagnosis of Necortizing Soft Tissue Infection who undergo consultation by the Emergency General Surgery service.

Description

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)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Short course of antibiotics; 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; The patient will be enrolled in a 48-hour course of antibiotics.; Other: Antibiotic duration; The patient will be enrolled in a 7 day course of antibiotics.
Long course of antibiotics; 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; The patient will be enrolled in a 48-hour course of antibiotics.; Other: Antibiotic duration; The patient will be enrolled in a 7 day course of antibiotics.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of California, Irvine
• Investigators: Principal Investigator: Areg Grigorian, MD, University of California, Irvine

Publications and helpful links

General Publications

• Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan SL, Montoya JG, Wade JC; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014 Jul 15;59(2):e10-52. doi: 10.1093/cid/ciu444. Erratum In: Clin Infect Dis. 2015 May 1;60(9):1448. Dosage error in article text.
• Schuetz P, Albrich W, Mueller B. Procalcitonin for diagnosis of infection and guide to antibiotic decisions: past, present and future. BMC Med. 2011 Sep 22;9:107. doi: 10.1186/1741-7015-9-107.
• Becker KL, Nylen ES, White JC, Muller B, Snider RH Jr. Clinical review 167: Procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab. 2004 Apr;89(4):1512-25. doi: 10.1210/jc.2002-021444. No abstract available.
• Yilmazlar T, Ozturk E, Alsoy A, Ozguc H. Necrotizing soft tissue infections: APACHE II score, dissemination, and survival. World J Surg. 2007 Sep;31(9):1858-1862. doi: 10.1007/s00268-007-9132-1.
• Childers BJ, Potyondy LD, Nachreiner R, Rogers FR, Childers ER, Oberg KC, Hendricks DL, Hardesty RA. Necrotizing fasciitis: a fourteen-year retrospective study of 163 consecutive patients. Am Surg. 2002 Feb;68(2):109-16.
• Hefny AF, Eid HO, Al-Hussona M, Idris KM, Abu-Zidan FM. Necrotizing fasciitis: a challenging diagnosis. Eur J Emerg Med. 2007 Feb;14(1):50-2. doi: 10.1097/01.mej.0000228447.48276.7b.
• Faraklas I, Yang D, Eggerstedt M, Zhai Y, Liebel P, Graves G, Dissanaike S, Mosier M, Cochran A. A Multi-Center Review of Care Patterns and Outcomes in Necrotizing Soft Tissue Infections. Surg Infect (Larchmt). 2016 Dec;17(6):773-778. doi: 10.1089/sur.2015.238. Epub 2016 Nov 11.
• Terzian WTH, Nunn AM, Call EB, Bliss SE, Swinarska JT, Rigdon J, Avery MD, Hoth JJ, Miller PR 3rd. Duration of Antibiotic Therapy in Necrotizing Soft Tissue Infections: Shorter is Safe. Surg Infect (Larchmt). 2022 Jun;23(5):430-435. doi: 10.1089/sur.2022.011. Epub 2022 Apr 22.
• May AK, Talisa VB, Wilfret DA, Bulger E, Dankner W, Bernard A, Yende S. Estimating the Impact of Necrotizing Soft Tissue Infections in the United States: Incidence and Re-Admissions. Surg Infect (Larchmt). 2021 Jun;22(5):509-515. doi: 10.1089/sur.2020.099. Epub 2020 Aug 21.

Study record dates

Study Major Dates

• Study Start (Actual): December 28, 2023
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: July 11, 2023
• First Submitted That Met QC Criteria: August 15, 2023
• First Posted (Actual): August 21, 2023

Study Record Updates

• Last Update Posted (Estimated): January 1, 2024
• Last Update Submitted That Met QC Criteria: December 28, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases; Soft Tissue Infections; Anti-Infective Agents; Antitubercular Agents; Anti-Bacterial Agents; Antibiotics, Antitubercular
• Other Study ID Numbers: 2826 (Kenya Medical Research Institute Ethics Review Committee)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The overall study results will be listed on Clinicaltrials.gov

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No