Trial Outcomes & Findings for BL Infusion Trial:Beta-lactam Continuous Versus Intermittent Infusion and Associated Bacterial Resistance and Therapy Outcomes in Critically Ill Patients With Severe Pneumonia (NCT NCT05102162)
NCT ID: NCT05102162
Last Updated: 2023-12-12
Results Overview
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.
Recruitment status
TERMINATED
Study phase
PHASE4
Target enrollment
35 participants
Primary outcome timeframe
4 weeks
Results posted on
2023-12-12
Participant Flow
Participant milestones
| Measure |
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.
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)
|
Intermittent Antibiotic Dose Over 30 Minutes
Subjects will be receiving an intermittent dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
|---|---|---|
|
Overall Study
STARTED
|
19
|
16
|
|
Overall Study
COMPLETED
|
5
|
13
|
|
Overall Study
NOT COMPLETED
|
14
|
3
|
Reasons for withdrawal
| Measure |
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.
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)
|
Intermittent Antibiotic Dose Over 30 Minutes
Subjects will be receiving an intermittent dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
|---|---|---|
|
Overall Study
Withdrawal by Subject
|
3
|
0
|
|
Overall Study
Baseline cultures negative
|
4
|
2
|
|
Overall Study
<72 Hours on study beta-lactam
|
7
|
0
|
|
Overall Study
Baseline cultures resistant to all study beta-lactams
|
0
|
1
|
Baseline Characteristics
BL Infusion Trial:Beta-lactam Continuous Versus Intermittent Infusion and Associated Bacterial Resistance and Therapy Outcomes in Critically Ill Patients With Severe Pneumonia
Baseline characteristics by cohort
| Measure |
Continuous Antibiotic Dose Over 24 Hours Arm
n=5 Participants
Subjects will be receiving a continuous dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
Intermittent Antibiotic Dose Over 30 Minutes
n=13 Participants
Subjects will be receiving an intermittent dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
Total
n=18 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
67 years
n=5 Participants
|
69 years
n=7 Participants
|
69 years
n=5 Participants
|
|
Sex: Female, Male
Female
|
1 Participants
n=5 Participants
|
5 Participants
n=7 Participants
|
6 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
4 Participants
n=5 Participants
|
8 Participants
n=7 Participants
|
12 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
2 Participants
n=5 Participants
|
4 Participants
n=7 Participants
|
6 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
3 Participants
n=5 Participants
|
9 Participants
n=7 Participants
|
12 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
5 participants
n=5 Participants
|
13 participants
n=7 Participants
|
18 participants
n=5 Participants
|
|
Weight (kg)
|
103.4 kg
n=5 Participants
|
61.6 kg
n=7 Participants
|
75.3 kg
n=5 Participants
|
|
Serum Creatinine (mg/dL)
|
1.21 mg/dL
n=5 Participants
|
0.67 mg/dL
n=7 Participants
|
0.76 mg/dL
n=5 Participants
|
|
Creatinine clearance (mL/min)
|
92 mL/min
n=5 Participants
|
83.7 mL/min
n=7 Participants
|
86.7 mL/min
n=5 Participants
|
|
BMI (kg/m^2)
|
31.6 kg/m^2
n=5 Participants
|
22.4 kg/m^2
n=7 Participants
|
24.8 kg/m^2
n=5 Participants
|
|
Height (m)
|
1.75 meters
n=5 Participants
|
1.65 meters
n=7 Participants
|
1.68 meters
n=5 Participants
|
|
Beta-Lactam at Randomization
Cefepime
|
4 Participants
n=5 Participants
|
7 Participants
n=7 Participants
|
11 Participants
n=5 Participants
|
|
Beta-Lactam at Randomization
Meropenem
|
0 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
2 Participants
n=5 Participants
|
|
Beta-Lactam at Randomization
Piperacillin/tazobactam
|
1 Participants
n=5 Participants
|
4 Participants
n=7 Participants
|
5 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 4 weeksPopulation: The number of participants included in the analysis was 18. However, for the primary outcome measure, the bacteria isolates were analyzed for emergence of resistance. We were able to include 18 isolates in the intermittent infusion arm and 8 in the continuous infusion arm.
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.
Outcome measures
| Measure |
Continuous Antibiotic Dose Over 24 Hours Arm
n=8 Bacteria isolates
Subjects will be receiving a continuous dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
Intermittent Antibiotic Dose Over 30 Minutes
n=18 Bacteria isolates
Subjects will be receiving an intermittent dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
|---|---|---|
|
Gram-negative Bacterial Resistance Emergence Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens
|
4 Bacteria isolates
|
8 Bacteria isolates
|
SECONDARY outcome
Timeframe: 4 weeksPopulation: The number of participants included in the analysis was 18. However, for superinfection, the bacteria isolates were analyzed. We were able to include 18 Gram-negative isolates in the intermittent infusion arm and 8 Gram-negative isolates in the continuous infusion arm.
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.
Outcome measures
| Measure |
Continuous Antibiotic Dose Over 24 Hours Arm
n=8 Bacteria Isolates
Subjects will be receiving a continuous dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
Intermittent Antibiotic Dose Over 30 Minutes
n=18 Bacteria Isolates
Subjects will be receiving an intermittent dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
|---|---|---|
|
Superinfection Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens.
|
0 Bacteria isolates
|
0 Bacteria isolates
|
SECONDARY outcome
Timeframe: 4 weeksPopulation: For microbiologic eradication, the bacteria isolates were analyzed. We were able to include 18 Gram-negative isolates in the intermittent infusion arm and 8 Gram-negative isolates in the continuous infusion arm.
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.
Outcome measures
| Measure |
Continuous Antibiotic Dose Over 24 Hours Arm
n=8 Bacteria Isolates
Subjects will be receiving a continuous dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
Intermittent Antibiotic Dose Over 30 Minutes
n=18 Bacteria Isolates
Subjects will be receiving an intermittent dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
|---|---|---|
|
Microbiologic Eradication Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens
|
1 Bacteria isolates
|
4 Bacteria isolates
|
SECONDARY outcome
Timeframe: 7 DaysClinical 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.
Outcome measures
| Measure |
Continuous Antibiotic Dose Over 24 Hours Arm
n=5 Participants
Subjects will be receiving a continuous dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
Intermittent Antibiotic Dose Over 30 Minutes
n=13 Participants
Subjects will be receiving an intermittent dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
|---|---|---|
|
Clinical Cure at Day 7 of Therapy Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens
|
0 Participants
|
5 Participants
|
SECONDARY outcome
Timeframe: 4 weeksClinical 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.
Outcome measures
| Measure |
Continuous Antibiotic Dose Over 24 Hours Arm
n=5 Participants
Subjects will be receiving a continuous dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
Intermittent Antibiotic Dose Over 30 Minutes
n=13 Participants
Subjects will be receiving an intermittent dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
|---|---|---|
|
Clinical Cure at the End of Therapy Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens
|
3 Participants
|
8 Participants
|
SECONDARY outcome
Timeframe: 4 weeksOutcome measures
| Measure |
Continuous Antibiotic Dose Over 24 Hours Arm
n=5 Participants
Subjects will be receiving a continuous dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
Intermittent Antibiotic Dose Over 30 Minutes
n=13 Participants
Subjects will be receiving an intermittent dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
|---|---|---|
|
Mortality Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens
|
2 Participants
|
2 Participants
|
SECONDARY outcome
Timeframe: 4 weeks (may extend beyond depending on patient length of stay in hospital)Outcome measures
| Measure |
Continuous Antibiotic Dose Over 24 Hours Arm
n=5 Participants
Subjects will be receiving a continuous dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
Intermittent Antibiotic Dose Over 30 Minutes
n=13 Participants
Subjects will be receiving an intermittent dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
|---|---|---|
|
Hospital Length of Stay Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens.
|
27 Days
Interval 12.0 to 32.0
|
18 Days
Interval 13.0 to 32.0
|
SECONDARY outcome
Timeframe: 4 weeks (may extend beyond depending on patient length of stay in ICU)Outcome measures
| Measure |
Continuous Antibiotic Dose Over 24 Hours Arm
n=5 Participants
Subjects will be receiving a continuous dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
Intermittent Antibiotic Dose Over 30 Minutes
n=13 Participants
Subjects will be receiving an intermittent dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
|---|---|---|
|
Intensive Care Unit (ICU) Length of Stay Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens
|
23 Days
Interval 7.0 to 26.0
|
9 Days
Interval 6.0 to 17.0
|
SECONDARY outcome
Timeframe: 4 weeksBeta-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.
Outcome measures
| Measure |
Continuous Antibiotic Dose Over 24 Hours Arm
n=5 Participants
Subjects will be receiving a continuous dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
Intermittent Antibiotic Dose Over 30 Minutes
n=13 Participants
Subjects will be receiving an intermittent dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
|---|---|---|
|
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
|
100 Percentage of time
Interval 100.0 to 100.0
|
100 Percentage of time
Interval 94.0 to 100.0
|
SECONDARY outcome
Timeframe: 4 weeksBeta-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.
Outcome measures
| Measure |
Continuous Antibiotic Dose Over 24 Hours Arm
n=5 Participants
Subjects will be receiving a continuous dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
Intermittent Antibiotic Dose Over 30 Minutes
n=13 Participants
Subjects will be receiving an intermittent dose of antibiotic prescribed by their doctor for the duration they choose.
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)
|
|---|---|---|
|
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
|
100 Percentage of time
Interval 50.0 to 100.0
|
100 Percentage of time
Interval 58.0 to 100.0
|
Adverse Events
Continuous Antibiotic Dose Over 24 Hours Arm
Serious events: 0 serious events
Other events: 0 other events
Deaths: 2 deaths
Intermittent Antibiotic Dose Over 30 Minutes
Serious events: 0 serious events
Other events: 0 other events
Deaths: 2 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
Adverse event data not reported
Additional Information
Nicole Maranchick
University of Florida College of Pharmacy
Phone: 352-273-6803
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place