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

Phase 4

Terminated

Conditions: Pneumonia

Interventions: Drug: Cefepime, Meropenem, or Piperacillin/Tazobactam

Registration Number: NCT05102162

Lead Sponsor: University of Florida

Brief 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 35

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Continuous Antibiotic Dose Over 24 hours Arm	Cefepime, Meropenem, or Piperacillin/Tazobactam	Subjects will be receiving a continuous dose of antibiotic prescribed by their doctor for the duration they choose.
Intermittent Antibiotic Dose Over 30 minutes	Cefepime, Meropenem, or Piperacillin/Tazobactam	Subjects will be receiving an intermittent dose of antibiotic prescribed by their doctor for the duration they choose.

Primary Outcome Measures

Name	Time	Method
Gram-negative Bacterial Resistance Emergence Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens	4 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Superinfection Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens.	4 weeks	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.
Microbiologic Eradication Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens	4 weeks	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.
Clinical Cure at Day 7 of Therapy Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens	7 Days	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.
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)
Clinical Cure at the End of Therapy Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens	4 weeks	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.
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	4 weeks	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.
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 Four Multiples of the Minimum Inhibitory Concentration (%fT>4xMIC) in the Dosing Interval Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens	4 weeks	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.