BL Infusion Trial:Beta-lactam Continuous Versus Intermittent Infusion and Associated Bacterial Resistance and Therapy Outcomes in Critically Ill Patients With Severe Pneumonia

Beta-lactam Continuous Versus Intermittent Infusion and Associated Bacterial Resistance and Therapy Outcomes in Critically Ill Patients With Severe Pneumonia

The study plans to randomize a total of 240 patients infected with Gram-negative bacterial pneumonia to receive beta-lactam (meropenem, cefepime, or piperacillin/tazobactam) continuous or intermittent infusion and collect baseline and regular follow-up respiratory cultures to assess the development of new resistance. The investigators will measure beta-lactam concentration to assess the impact of drug exposure on the bacterial resistance.

Study Overview

• Status: Terminated
• Conditions: Pneumonia
• Intervention / Treatment: Drug: Cefepime, Meropenem, or Piperacillin/Tazobactam

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Admission to the ICU with severe pneumonia (IDSA/ATS 2016/2019): presence of signs, symptoms and confirmatory chest imaging consistent with pneumonia (e.g. fever, cough and pulmonary infiltrate by chest radiograph)
• Age ≥18 years
• Positive respiratory culture (with or without an initial positive rapid identification test and/or Gram stain) for Gram-negative bacteria including, but not limited to, P. aeruginosa, K. pneumoniae, E. coli, S. marcescens, H. influenzae, Enterobacter spp., M. catarrhalis, A. baumannii, Achromobacter spp., P. mirabilis, and/or B. cepacia
• Received within the last 72 hours or will receive meropenem, cefepime, or piperacillin/tazobactam therapy

Exclusion Criteria:

• Pregnancy
• Prisoners
• Allergy to the beta-lactams to be administered in this study
• On renal replacement therapy at the time of randomization
• Baseline culture resistant to the beta-lactams in the study
• COVID patients enrolled in other trials

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Continuous Antibiotic Dose Over 24 hours Arm; Subjects will be receiving a continuous dose of antibiotic prescribed by their doctor for the duration they choose.	Drug: Cefepime, Meropenem, or Piperacillin/Tazobactam; A 1:1 randomization scheme based on the infusion duration (continuous over 24 hours or intermittent over 30 minutes) with stratification based on the beta-lactam prescribed (cefepime, meropenem, or piperacillin/tazobactam); Other Names: Maxipime, Merrem
Active Comparator: Intermittent Antibiotic Dose Over 30 minutes; Subjects will be receiving an intermittent dose of antibiotic prescribed by their doctor for the duration they choose.	Drug: Cefepime, Meropenem, or Piperacillin/Tazobactam; A 1:1 randomization scheme based on the infusion duration (continuous over 24 hours or intermittent over 30 minutes) with stratification based on the beta-lactam prescribed (cefepime, meropenem, or piperacillin/tazobactam); Other Names: Maxipime, Merrem

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gram-negative Bacterial Resistance Emergence Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens	Bacterial resistance is defined as new numeric increases (>/=2 fold) in the bacterial MIC during the follow-up period compared to the baseline when starting beta-lactam therapy. MICs were collected from respiratory samples and compared from study enrollment to end of the follow-up period for at least a 2 fold increase in MIC.	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Superinfection Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens.	Superinfection is defined as the growth of resistant Gram-negative bacteria during the follow-up period which was not isolated in baseline culture. Respiratory cultures during the follow up period were assessed for Gram-negative isolates resistant to the beta-lactams of interest that were not present in the initial respiratory cultures.	4 weeks
Microbiologic Eradication Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens	Microbiologic eradication is defined as the absence of bacterial growth during the follow-up period with no subsequent positive culture from any site. Respiratory cultures during the follow up period were assessed for the absence of bacterial growth.	4 weeks
Clinical Cure at Day 7 of Therapy Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens	Clinical cure is the resolution of infection-related symptoms at day 7 of therapy, including normalization of body temperature and white blood cell (WBC) count and taking the patient off mechanical ventilation or vasopressors, and non-initiation of a new antibiotic within 48 hours of stopping the original antibiotic.	7 Days
Clinical Cure at the End of Therapy Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens	Clinical cure is the resolution of infection-related symptoms at the end of therapy, including normalization of body temperature and white blood cell (WBC) count and taking the patient off mechanical ventilation or vasopressors, and non-initiation of a new antibiotic within 48 hours of stopping the original antibiotic. End of therapy could occur up to 4 weeks after enrollment.	4 weeks
Mortality Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens		4 weeks
Hospital Length of Stay Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens.		4 weeks (may extend beyond depending on patient length of stay in hospital)
Intensive Care Unit (ICU) Length of Stay Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens		4 weeks (may extend beyond depending on patient length of stay in ICU)
Percent of Time Free Drug Concentrations Remain Above the Minimum Inhibitory Concentration (%fT>MIC) in the Dosing Interval Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens	Beta-lactam bactericidal efficacy depends upon the percentage of time that free drug concentrations remain above the minimum inhibitory concentration (%fT>MIC) of the pathogen within the dosing interval. Pre-clinical animal studies demonstrate 40-70% fT>MIC is needed for adequate bacterial killing. However, clinical studies suggest higher exposures may be needed, potentially 100%fT>MIC to 100%fT>4xMIC. Patients had beta-lactam concentrations measured as part of therapeutic drug monitoring. Drug exposures were determined using a Bayesian-based software. Infusion arms were compared to determine if %fT>MIC was different between infusion arms.	4 weeks
Percent of Time Free Drug Concentrations Remain Above Four Multiples of the Minimum Inhibitory Concentration (%fT>4xMIC) in the Dosing Interval Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens	Beta-lactam bactericidal efficacy depends upon the percentage of time that free drug concentrations remain above the minimum inhibitory concentration (%fT>MIC) of the pathogen within the dosing interval. Pre-clinical animal studies demonstrate 40-70% fT>MIC is needed for adequate bacterial killing. However, clinical studies suggest higher exposures may be needed, potentially 100%fT>MIC to 100%fT>4xMIC. Patients had beta-lactam concentrations measured as part of therapeutic drug monitoring. Drug exposures were determined using a Bayesian-based software. Infusion arms were compared to determine if %fT>4xMIC was different between infusion arms.	4 weeks

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: Food and Drug Administration (FDA)
• Investigators: Principal Investigator: Charles Peloquin, University of Florida

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2021
• Primary Completion (Actual): February 28, 2023
• Study Completion (Actual): February 28, 2023

Study Registration Dates

• First Submitted: October 29, 2021
• First Submitted That Met QC Criteria: October 29, 2021
• First Posted (Actual): November 1, 2021

Study Record Updates

• Last Update Posted (Estimated): December 12, 2023
• Last Update Submitted That Met QC Criteria: November 17, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Pneumonia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Meropenem; Piperacillin; Tazobactam; Piperacillin, Tazobactam Drug Combination; Cefepime
• Other Study ID Numbers: IRB202101979 -A; OCR41108 (Other Identifier: UF OnCore)

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