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

Study Overview
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Brief Summary
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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.

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

Conditions
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Pneumonia

Intervention / Treatment
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* Drug: Cefepime, Meropenem, or Piperacillin/Tazobactam
* Drug: Cefepime, Meropenem, or Piperacillin/Tazobactam


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Continuous Antibiotic Dose Over 24 hours Arm<br>Subjects will be receiving a continuous dose of antibiotic prescribed by their doctor for the duration they choose. | Drug: Cefepime, Meropenem, or Piperacillin/Tazobactam<br>* 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)<br>* Other names: Maxipime, Merrem;|
| Active Comparator: Intermittent Antibiotic Dose Over 30 minutes<br>Subjects will be receiving an intermittent dose of antibiotic prescribed by their doctor for the duration they choose. | Drug: Cefepime, Meropenem, or Piperacillin/Tazobactam<br>* 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)<br>* Other names: Maxipime, Merrem;|

What is the study measuring?
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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 |