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

Pneumonia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT05102162
• Other study ID #: IRB202101979 -A
• Secondary ID: OCR41108
• Status: Terminated
• Phase: Phase 4
• Start date: December 17, 2021
• Est. completion date: February 28, 2023

Study information

• Verified date: May 2023
• Source: University of Florida
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 35
• Est. completion date: February 28, 2023
• Est. primary completion date: February 28, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

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

Related Conditions & MeSH terms

• Pneumonia

Intervention

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)
• 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)

Locations

Country	Name	City	State
United States	University of Florida	Gainesville	Florida

Sponsors (2)

Lead Sponsor	Collaborator
University of Florida	Food and Drug Administration (FDA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Mortality Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens		4 weeks
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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