Pneumonia
Conditions
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.
Interventions
DRUGCefepime, 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)
Sponsors
Food and Drug Administration (FDA)
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| Mortality Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens | 4 weeks | — |
| 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. |
| 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 | 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. |
| 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. |
| 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) | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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) | 5 |
| 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) | 13 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | <72 Hours on study beta-lactam | 7 | 0 |
| Overall Study | Baseline cultures negative | 4 | 2 |
| Overall Study | Baseline cultures resistant to all study beta-lactams | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Intermittent Antibiotic Dose Over 30 Minutes | Continuous Antibiotic Dose Over 24 Hours Arm | Total |
|---|---|---|---|
| Age, Continuous | 69 years | 67 years | 69 years |
| Beta-Lactam at Randomization Cefepime | 7 Participants | 4 Participants | 11 Participants |
| Beta-Lactam at Randomization Meropenem | 2 Participants | 0 Participants | 2 Participants |
| Beta-Lactam at Randomization Piperacillin/tazobactam | 4 Participants | 1 Participants | 5 Participants |
| BMI (kg/m^2) | 22.4 kg/m^2 | 31.6 kg/m^2 | 24.8 kg/m^2 |
| Creatinine clearance (mL/min) | 83.7 mL/min | 92 mL/min | 86.7 mL/min |
| Height (m) | 1.65 meters | 1.75 meters | 1.68 meters |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 3 Participants | 12 Participants |
| Region of Enrollment United States | 13 participants | 5 participants | 18 participants |
| Serum Creatinine (mg/dL) | 0.67 mg/dL | 1.21 mg/dL | 0.76 mg/dL |
| Sex: Female, Male Female | 5 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Male | 8 Participants | 4 Participants | 12 Participants |
| Weight (kg) | 61.6 kg | 103.4 kg | 75.3 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 19 | 2 / 16 |
| other Total, other adverse events | 0 / 19 | 0 / 16 |
| serious Total, serious adverse events | 0 / 19 | 0 / 16 |
Outcome results
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.
Time frame: 4 weeks
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Continuous Antibiotic Dose Over 24 Hours Arm | Gram-negative Bacterial Resistance Emergence Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens | 4 Bacteria isolates |
| Intermittent Antibiotic Dose Over 30 Minutes | Gram-negative Bacterial Resistance Emergence Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens | 8 Bacteria isolates |
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.
Time frame: 7 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Continuous Antibiotic Dose Over 24 Hours Arm | Clinical Cure at Day 7 of Therapy Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens | 0 Participants |
| Intermittent Antibiotic Dose Over 30 Minutes | Clinical Cure at Day 7 of Therapy Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens | 5 Participants |
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.
Time frame: 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Continuous Antibiotic Dose Over 24 Hours Arm | Clinical Cure at the End of Therapy Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens | 3 Participants |
| Intermittent Antibiotic Dose Over 30 Minutes | Clinical Cure at the End of Therapy Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens | 8 Participants |
Secondary
Hospital Length of Stay Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens.
Time frame: 4 weeks (may extend beyond depending on patient length of stay in hospital)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Continuous Antibiotic Dose Over 24 Hours Arm | Hospital Length of Stay Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens. | 27 Days |
| Intermittent Antibiotic Dose Over 30 Minutes | Hospital Length of Stay Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens. | 18 Days |
Secondary
Intensive Care Unit (ICU) Length of Stay Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens
Time frame: 4 weeks (may extend beyond depending on patient length of stay in ICU)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Continuous Antibiotic Dose Over 24 Hours Arm | Intensive Care Unit (ICU) Length of Stay Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens | 23 Days |
| Intermittent Antibiotic Dose Over 30 Minutes | Intensive Care Unit (ICU) Length of Stay Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens | 9 Days |
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.
Time frame: 4 weeks
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Continuous Antibiotic Dose Over 24 Hours Arm | Microbiologic Eradication Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens | 1 Bacteria isolates |
| Intermittent Antibiotic Dose Over 30 Minutes | Microbiologic Eradication Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens | 4 Bacteria isolates |
Secondary
Mortality Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens
Time frame: 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Continuous Antibiotic Dose Over 24 Hours Arm | Mortality Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens | 2 Participants |
| Intermittent Antibiotic Dose Over 30 Minutes | Mortality Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens | 2 Participants |
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.
Time frame: 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Continuous Antibiotic Dose Over 24 Hours Arm | 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 |
| Intermittent Antibiotic Dose Over 30 Minutes | 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 |
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.
Time frame: 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Continuous Antibiotic Dose Over 24 Hours Arm | 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 |
| Intermittent Antibiotic Dose Over 30 Minutes | 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 |
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.
Time frame: 4 weeks
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Continuous Antibiotic Dose Over 24 Hours Arm | Superinfection Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens. | 0 Bacteria isolates |
| Intermittent Antibiotic Dose Over 30 Minutes | Superinfection Between Patients Treated With Continuous and Intermittent Infusion Beta-lactam Regimens. | 0 Bacteria isolates |