Quantifying Gram-negative Resistance to Empiric Therapy in the Intensive Care Unit (RESTART)

Quantifying Gram-negative Resistance to Empiric Therapy in the Intensive Care Unit - Repeat ExpoSure to AntimicRobial Therapy (RESTART)

Antimicrobial resistance is a global health emergency estimated to be responsible for 700,000 deaths per year worldwide, and it is well known that previous antibiotic exposure is the single most contributing factor. For example, the use of non-antipseudomonal agents can increase risk for any P. aeruginosa strain; however, the use of an agent with antipseudomonal activity would select for resistance to that particular antimicrobial agent or class. Demonstrated that each additional day of exposure to any antipseudomonal beta-lactam is associated with an increased risk of new resistance development.

The study seeks to determine whether the choice of empiric therapy (i.e., the same agent versus a different agent from prior antibiotic exposure) has any effect on the likelihood of in vitro activity against GN pathogens (GNPs) in a subsequent infection.

Study Overview

• Status: Completed
• Conditions: Gram-Negative Bacterial Infections
• Intervention / Treatment: Drug: IV antibiotic treatment from prior; Drug: differing IV antibiotic treatment

Detailed Description

Antimicrobials are the most commonly prescribed drugs in medicine, resulting in inappropriate use in approximately 50% of cases Misuse can have devastating effects through resistance development which further complicates selection of appropriate empiric antibiotics. In cases of severe illness, it is easy for clinicians to rely on broad spectrum antibiotics to cover the majority of likely pathogens when dealing with a presumed bacterial infection. However, this practice perpetuates the cycle of resistance. Inappropriate empiric therapy is associated with worse outcomes in resistant Gram-negative (GN) bacteremia and pneumonia, so clinicians should strive for targeted coverage that is specific to the pathogen of interest when possible. Johnson et al. showed that patients with recent antibiotic exposure had greater inappropriate initial antimicrobial therapy (45.4% vs. 21.2%; p < 0.001) and higher in-hospital mortality (51.3% vs. 34.0%; p < 0.001) compared with patients without recent antibiotic exposure.

The 2020 Infectious Diseases Society of America (IDSA) Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections reports an increased risk of resistance with antibiotic exposure in the past 30 days. Additionally, expert opinion prompts consideration of empiric coverage with a GN agent from a different class that offers comparable spectrum of activity from previous exposure. The 2019 Community-acquired Pneumonia (CAP) Guidelines from the American Thoracic Society and IDSA lists prior antibiotic use in the last 90 days as a risk factor for P. aeruginosa.The 2016 Hospital-acquired and Ventilator-associated Pneumonia (HAP, VAP) Guidelines from IDSA, list antibiotic use in the past 90 days as a risk factor for P. aeruginosa and other GN organisms in HAP. Additionally, antibiotic use in the past 90 days is listed as having an association with increased risk of multi-drug resistant VAP. The CAP, HAP, and VAP Guidelines do not mention using the same versus different agent as empiric choice if previous antibiotic exposure is to an anti-pseudomonal agent.

• Study Type: Observational
• Enrollment (Actual): 197

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75203
      • Methodist Dallas Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

sample size of 242 (121 patients in each group)

Description

Inclusion Criteria:

• ≥18 years of age
• GNP pneumonia or bacteremia during hospital admission
• Previous IV antibiotics for at least 48 hours in the past 90 days
• Culture MIC data available

Exclusion Criteria:

• Patients with a history of isolate resistance in the previous six months to antibiotics being studied
• Patients that received antibiotics within five days prior to study inclusion
• Patients on more than one anti-pseudomonal beta-lactam antibiotics (excluding emergency department doses) during previous exposure

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
repeat group; patients receiving empiric therapy with the same IV antibiotics from prior	Drug: IV antibiotic treatment from prior; patients receiving same IV antibiotic treatment from prior
change group; patients receiving differing IV antibiotics from prior	Drug: differing IV antibiotic treatment; patients receiving differing IV antibiotics from prior

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rates of resistance	Rates of resistance in patients receiving empiric therapy with the same IV antibiotics from prior (repeat group) compared to rates of resistance in patients receiving differing IV antibiotics from prior (change group)	charts from 4/1/2017 to 3/31/2021

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intensive Care Unite LOS(ICU LOS)	Intensive Care Unite LOS(ICU LOS)	charts from 4/1/2017 to 3/31/2021

Collaborators and Investigators

• Sponsor: Methodist Health System
• Investigators: Principal Investigator: Mathew Crotty, MD, Methodist

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2021
• Primary Completion (Actual): July 14, 2025
• Study Completion (Actual): July 14, 2025

Study Registration Dates

• First Submitted: December 9, 2021
• First Submitted That Met QC Criteria: December 9, 2021
• First Posted (Actual): December 28, 2021

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 24, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Negative Bacterial Infections; Anti-Infective Agents; Antitubercular Agents; Anti-Bacterial Agents; Antibiotics, Antitubercular
• Other Study ID Numbers: 038.PHA.2021.D

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No