Obesity
Conditions
Keywords
pharmacokinetics, obesity, piperacillin-tazobactam combination product, pharmacodynamics, piperacillin/tazobactam
Brief summary
Worldwide rates of obesity have doubled in the last 30 years, and obesity has been associated as a risk factor for hospital-acquired infections and increased occurrence of death in critically-ill patients. Piperacillin/tazobactam is a commonly prescribed antibiotic for critically ill patients with an infection, however, limited information exists for dosing this drug in obese patients. In these limited reports, standard doses of piperacillin/tazobactam given to the small number of obese patients resulted in lower blood concentrations, which could lead to inadequate killing of bacteria. The purpose of this study is to compare blood concentrations from standard piperacillin/tazobactam dosing compared to higher dosing regimens in obese patients. This study will also include information on the safety and tolerability of the higher dose regimens. The study investigators believe that the higher dosing regimen will produce adequate blood levels in obese patients and will not add any more risk of harm to obese patients receiving this higher dose.
Interventions
DRUGPiperacillin/Tazobactam Standard Dose to High Dose
Patients will receive a standard dose of piperacillin/tazobactam, then will have subsequent pharmacokinetic analyses on the blood concentrations drawn while on standard dose. Patients will be switched to higher dose after receiving the standard dose, with subsequent pharmacokinetic analyses performed on those blood concentrations while on higher dose. These pharmacokinetics of each dosing regimen will be compared.
Sponsors
Loma Linda University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 89 Years
Healthy volunteers
No
Inclusion criteria
* BMI greater than or equal to 30 kg/m2 * Weight at least 105 kg * Age 18-89 years of age * Prescribed piperacillin/tazobactam at standard doses for suspected or confirmed infection(s) * English or Spanish speaking * Central line access
Exclusion criteria
* Do not meet specified inclusion criteria * Hepatic impairment classified by Child-Pugh Class B or greater * Documented pre-existing seizure disorder * Documented pre-existing hematologic disorder * Pregnancy * Documented allergy or contraindication to beta-lactams or tazobactam
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum Maximum Concentrations for Piperacillin | 0, 1, 3, and 6 hours post-dose | Pharmacokinetic parameters for piperacillin of maximum serum concentration (Cmax) will be measured in both standard dosing and high dosing. |
| Serum Minimum Concentrations of Piperacillin | 0, 1, 3, and 6 hours post-dose | Minimum serum concentrations (Cmin) of piperacillin will be measured in both standard and high doses |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Half-life of Piperacillin | 0, 1, 3, and 6 hours post-dose | Half-life (t1/2) of piperacillin will be calculated from serum concentrations in both standard and high doses |
| Volume of Distribution of Piperacillin | 0, 1, 3, and 6 hours post-dose | Volume of distribution (Vd) of piperacillin will be calculated from serum concentrations in both standard and high doses |
Countries
United States
Participant flow
Pre-assignment details
438 obese patients receiving P-T were screened between June 2013 and January 2016. 67 patients fit inclusion criteria - 12 chose not to participate in the study or informed consent could not be obtained; 9 were excluded due to refusal of the primary care team; 13 had P-T discontinued prior to enrollment; and 4 were included previously in the study
Participants by arm
| Arm | Count |
|---|---|
| Piperacillin/Tazobactam Standard to High Dose Patients will receive a standard dose of piperacillin/tazobactam, then will have subsequent pharmacokinetic analyses on the blood concentrations drawn while on standard dose. Then, they will be switched to higher dose, with subsequent pharmacokinetic analyses performed on those blood concentrations while on higher dose. These pharmacokinetics of each dosing regimen will be compared. | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Piperacillin/Tazobactam Standard to High Dose | — |
|---|---|---|
| Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II Score Group 1 (CrCl >/= 80 mL/min) | 15.7 units on a scale | — |
| Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II Score Group 2 (CrCl >/= 40 to < 80 mL/min) | 16.6 units on a scale | — |
| Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II Score Group 3 (CrCl < 40 mL/min) | 22.8 units on a scale | — |
| Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II Score Group 4 (Hemodialysis) | 26.0 units on a scale | — |
| Age, Continuous Group 1 (CrCl >/= 80mL/min) | 46 years | — |
| Age, Continuous Group 2 (CrCl >/= 40 to < 80 mL/min) | 57 years | — |
| Age, Continuous Group 3 (CrCl < 40) | 60 years | — |
| Age, Continuous Group 4 (Hemodialysis) | 42 years | — |
| Body Mass Index (BMI) Group 1 (CrCl >/= 80 mL/min) | 41 kilograms per sqare meter | — |
| Body Mass Index (BMI) Group 2 (CrCl >/= 40 to < 80 mL/min) | 47 kilograms per sqare meter | — |
| Body Mass Index (BMI) Group 3 (CrCl < 40 mL/min) | 38 kilograms per sqare meter | — |
| Body Mass Index (BMI) Group 4 (Hemodialysis) | 49 kilograms per sqare meter | — |
| ICU Status Group 1 (CrCl >/= 80 mL/min) | 6 Participants | — |
| ICU Status Group 2 (CrCl >/= 40 to < 80 mL/min) | 7 Participants | — |
| ICU Status Group 3 (CrCl < 40 mL/min) | 5 Participants | — |
| ICU Status Group 4 (Hemodialysis) | 3 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 28 participants | — |
| Sequential Organ Failure Assessment (SOFA) Score Group 1 (CrCl >/= 80 mL/min) | 5.8 units on a scale | — |
| Sequential Organ Failure Assessment (SOFA) Score Group 2 (CrCl >/= 40 to < 80 mL/min) | 7.4 units on a scale | — |
| Sequential Organ Failure Assessment (SOFA) Score Group 3 (CrCl < 40 mL/min) | 9.4 units on a scale | — |
| Sequential Organ Failure Assessment (SOFA) Score Group 4 (Hemodialysis) | 9.3 units on a scale | — |
| Sex: Female, Male Female | 10 Participants | — |
| Sex: Female, Male Male | 18 Participants | — |
| Total Bilirubin Group 1 (CrCl >/= 80 mL/min) | 0.6 milligrams per deciliter | — |
| Total Bilirubin Group 2 (CrCl >/= 40 to < 80 mL/min) | 0.8 milligrams per deciliter | — |
| Total Bilirubin Group 3 (CrCl < 40 mL/min) | 1.3 milligrams per deciliter | — |
| Total Bilirubin Group 4 (Hemodialysis) | 0.5 milligrams per deciliter | — |
| Weight Group 1 (CrCl >/= 80 mL/min) | 127 kilograms | — |
| Weight Group 2 (CrCl >/= 40 to < 80 mL/min) | 142 kilograms | — |
| Weight Group 3 (CrCl < 40 mL/min) | 121 kilograms | — |
| Weight Group 4 (Hemodialysis) | 136 kilograms | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 29 |
| other Total, other adverse events | 6 / 29 |
| serious Total, serious adverse events | 1 / 29 |
Outcome results
Primary
Serum Maximum Concentrations for Piperacillin
Pharmacokinetic parameters for piperacillin of maximum serum concentration (Cmax) will be measured in both standard dosing and high dosing.
Time frame: 0, 1, 3, and 6 hours post-dose
Population: The # of participants in the rows below will be double the overall participant number because each patient had two different dosing regimens of pip/tazo In Group 3, 4.5g group N = 5 represents low and high dose - 2 patients receiving 4.5g upon enrollment and increased to 6.75g; 3 patients were receiving either 2.25g or 3.375g and increased to 4.5g
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Maximum Concentrations for Piperacillin | Group 1 (CrCl >/= 80 mL/min) on 3.375 grams | 136 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Maximum Concentrations for Piperacillin | Group 1 (CrCl >/= 80 mL/min) on 4.5 grams | 190 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Maximum Concentrations for Piperacillin | Group 1 (CrCl > 80 mL/min) on 6.75 grams | 237 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Maximum Concentrations for Piperacillin | Group 1 (CrCl >/= 80 mL/min) on 9 grams | 332 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Maximum Concentrations for Piperacillin | Group 2 (CrCl >/= 40 to < 80 mL/min) on 3.375 gram | 144 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Maximum Concentrations for Piperacillin | Group 2 (CrCl >/= 40 to < 80 mL/min) on 4.5 grams | 214 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Maximum Concentrations for Piperacillin | Group 2 (CrCl >/= 40 to < 80 mL/min) on 6.75 grams | 244 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Maximum Concentrations for Piperacillin | Group 2 (CrCl >/= 40 to < 80 mL/min) on 9 grams | 191 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Maximum Concentrations for Piperacillin | Group 3 (CrCl < 40 mL/min) on 2.25 grams | 176 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Maximum Concentrations for Piperacillin | Group 3 (CrCl < 40 mL/min) on 3.375 grams | 296 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Maximum Concentrations for Piperacillin | Group 3 (CrCl < 40 mL/min) on 4.5 grams | 265 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Maximum Concentrations for Piperacillin | Group 3 (CrCl < 40 mL/min) on 6.75 grams | 299 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Maximum Concentrations for Piperacillin | Group 4 (HD) on 2.25 grams | 158 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Maximum Concentrations for Piperacillin | Group 4 (HD) on 3.375 grams | 223 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Maximum Concentrations for Piperacillin | Group 4 (HD) on 4.5 grams | 275 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Maximum Concentrations for Piperacillin | Group 4 (HD) on 6.75 grams | 397 milligrams per liter |
Primary
Serum Minimum Concentrations of Piperacillin
Minimum serum concentrations (Cmin) of piperacillin will be measured in both standard and high doses
Time frame: 0, 1, 3, and 6 hours post-dose
Population: The # of participants in the rows below will be double the overall participant number because each patient had two different dosing regimens of pip/tazo In Group 3, 4.5g group N = 5 represents low and high dose - 2 patients receiving 4.5g upon enrollment and increased to 6.75g; 3 patients were receiving either 2.25g or 3.375g and increased to 4.5g
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Minimum Concentrations of Piperacillin | Group 1 (CrCl >/= 80 mL/min) on 3.375 grams | 8.9 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Minimum Concentrations of Piperacillin | Group 1 (CrCl >/= 80 mL/min) on 4.5 grams | 11.1 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Minimum Concentrations of Piperacillin | Group 1 (CrCl >/= 80 mL/min) on 6.75 grams | 27.0 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Minimum Concentrations of Piperacillin | Group 1 (CrCl >/= 80 mL/min) on 9 grams | 10.3 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Minimum Concentrations of Piperacillin | Group 2 (CrCl >/= 40 to 80 mL/min) on 3.375 grams | 47.4 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Minimum Concentrations of Piperacillin | Group 2 (CrCl >/= 40 to 80 mL/min) on 4.5 grams | 52.5 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Minimum Concentrations of Piperacillin | Group 2 (CrCl >/= 40 to 80 mL/min) on 6.75 grams | 72.6 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Minimum Concentrations of Piperacillin | Group 2 (CrCl >/= 40 to 80 mL/min) on 9 grams | 54.1 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Minimum Concentrations of Piperacillin | Group 3 (CrCl < 40 mL/min) on 2.25 grams | 78.8 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Minimum Concentrations of Piperacillin | Group 3 (CrCl < 40 mL/min) on 3.375 grams | 207 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Minimum Concentrations of Piperacillin | Group 3 (CrCl < 40 mL/min) on 4.5 grams | 142 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Minimum Concentrations of Piperacillin | Group 3 (CrCl < 40 mL/min) on 6.75 grams | 148 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Minimum Concentrations of Piperacillin | Group 4 (HD) on 2.25 grams | 99 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Minimum Concentrations of Piperacillin | Group 4 (HD) on 3.375 grams | 143 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Minimum Concentrations of Piperacillin | Group 4 (HD) on 4.5 grams | 181 milligrams per liter |
| Standard Dose to High Dose Piperacillin/Tazobactam | Serum Minimum Concentrations of Piperacillin | Group 4 (HD) on 6.75 grams | 234 milligrams per liter |
Secondary
Half-life of Piperacillin
Half-life (t1/2) of piperacillin will be calculated from serum concentrations in both standard and high doses
Time frame: 0, 1, 3, and 6 hours post-dose
Population: The # of participants in the rows below will be double the overall participant number because each patient had two different dosing regimens of pip/tazo In Group 3, 4.5g group N = 5 represents low and high dose - 2 patients receiving 4.5g upon enrollment and increased to 6.75g; 3 patients were receiving either 2.25g or 3.375g and increased to 4.5g
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Standard Dose to High Dose Piperacillin/Tazobactam | Half-life of Piperacillin | Group 2 (CrCl >/= 40 to < 80 mL/min) on 3.375 gram | 3.9 hours |
| Standard Dose to High Dose Piperacillin/Tazobactam | Half-life of Piperacillin | Group 1 (CrCl >/= 80 mL/min) on 3.375 grams | 1.2 hours |
| Standard Dose to High Dose Piperacillin/Tazobactam | Half-life of Piperacillin | Group 1 (CrCl >/= 80 mL/min) on 4.5 grams | 1.5 hours |
| Standard Dose to High Dose Piperacillin/Tazobactam | Half-life of Piperacillin | Group 1 (CrCl >/= 80 mL/min) on 6.75 grams | 1.8 hours |
| Standard Dose to High Dose Piperacillin/Tazobactam | Half-life of Piperacillin | Group 1 (CrCl >/= 80 mL/min) on 9 grams | 0.9 hours |
| Standard Dose to High Dose Piperacillin/Tazobactam | Half-life of Piperacillin | Group 2 (CrCl >/= 40 to < 80 mL/min) on 4.5 grams | 2.7 hours |
| Standard Dose to High Dose Piperacillin/Tazobactam | Half-life of Piperacillin | Group 2 (CrCl >/= 40 to < 80 mL/min) on 6.75 grams | 3.8 hours |
| Standard Dose to High Dose Piperacillin/Tazobactam | Half-life of Piperacillin | Group 2 (CrCl >/= 40 to < 80 mL/min) on 9 grams | 2.5 hours |
| Standard Dose to High Dose Piperacillin/Tazobactam | Half-life of Piperacillin | Group 3 (CrCl < 40 mL/min) on 2.25 grams | 4.3 hours |
| Standard Dose to High Dose Piperacillin/Tazobactam | Half-life of Piperacillin | Group 3 (CrCl < 40 mL/min) on 3.375 grams | 10.7 hours |
| Standard Dose to High Dose Piperacillin/Tazobactam | Half-life of Piperacillin | Group 3 (CrCl < 40 mL/min) on 4.5 grams | 6.2 hours |
| Standard Dose to High Dose Piperacillin/Tazobactam | Half-life of Piperacillin | Group 3 (CrCl < 40 mL/min) on 6.75 grams | 5.5 hours |
| Standard Dose to High Dose Piperacillin/Tazobactam | Half-life of Piperacillin | Group 4 (HD) on 2.25 grams | 9.8 hours |
| Standard Dose to High Dose Piperacillin/Tazobactam | Half-life of Piperacillin | Group 4 (HD) on 3.375 grams | 8.6 hours |
| Standard Dose to High Dose Piperacillin/Tazobactam | Half-life of Piperacillin | Group 4 (HD) on 4.5 grams | 9.1 hours |
| Standard Dose to High Dose Piperacillin/Tazobactam | Half-life of Piperacillin | Group 4 (HD) on 6.75 grams | 7.4 hours |
Secondary
Volume of Distribution of Piperacillin
Volume of distribution (Vd) of piperacillin will be calculated from serum concentrations in both standard and high doses
Time frame: 0, 1, 3, and 6 hours post-dose
Population: The # of participants in the rows below will be double the overall participant number because each patient had two different dosing regimens of pip/tazo In Group 3, 4.5g group N = 5 represents low and high dose - 2 patients receiving 4.5g upon enrollment and increased to 6.75g; 3 patients were receiving either 2.25g or 3.375g and increased to 4.5g
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Standard Dose to High Dose Piperacillin/Tazobactam | Volume of Distribution of Piperacillin | Group 1 (CrCl >/= 80 mL/min) on 3.375 grams | 19.0 liters |
| Standard Dose to High Dose Piperacillin/Tazobactam | Volume of Distribution of Piperacillin | Group 1 (CrCl >/= 80 mL/min) on 4.5 grams | 20.9 liters |
| Standard Dose to High Dose Piperacillin/Tazobactam | Volume of Distribution of Piperacillin | Group 1 (CrCl >/= 80 mL/min) on 6.75 grams | 27.7 liters |
| Standard Dose to High Dose Piperacillin/Tazobactam | Volume of Distribution of Piperacillin | Group 1 (CrCl >/= 80 mL/min) on 9 grams | 20.1 liters |
| Standard Dose to High Dose Piperacillin/Tazobactam | Volume of Distribution of Piperacillin | Group 2 (CrCl >/= 40 to < 80 mL/min) on 3.375 gram | 31.6 liters |
| Standard Dose to High Dose Piperacillin/Tazobactam | Volume of Distribution of Piperacillin | Group 2 (CrCl >/= 40 to < 80 mL/min) on 4.5 gram | 20.3 liters |
| Standard Dose to High Dose Piperacillin/Tazobactam | Volume of Distribution of Piperacillin | Group 2 (CrCl >/= 40 to < 80 mL/min) on 6.75 gram | 31.7 liters |
| Standard Dose to High Dose Piperacillin/Tazobactam | Volume of Distribution of Piperacillin | Group 2 (CrCl >/= 40 to < 80 mL/min) on 9 gram | 48.8 liters |
| Standard Dose to High Dose Piperacillin/Tazobactam | Volume of Distribution of Piperacillin | Group 3 (CrCl < 40mL/min) on 2.25 grams | 22.9 liters |
| Standard Dose to High Dose Piperacillin/Tazobactam | Volume of Distribution of Piperacillin | Group 3 (CrCl < 40mL/min) on 3.375 grams | 30.5 liters |
| Standard Dose to High Dose Piperacillin/Tazobactam | Volume of Distribution of Piperacillin | Group 3 (CrCl < 40mL/min) on 4.5 grams | 26.3 liters |
| Standard Dose to High Dose Piperacillin/Tazobactam | Volume of Distribution of Piperacillin | Group 3 (CrCl < 40mL/min) on 6.75 grams | 29.9 liters |
| Standard Dose to High Dose Piperacillin/Tazobactam | Volume of Distribution of Piperacillin | Group 4 (HD) on 2.25 grams | 34.9 liters |
| Standard Dose to High Dose Piperacillin/Tazobactam | Volume of Distribution of Piperacillin | Group 4 (HD) on 3.375 grams | 28.9 liters |
| Standard Dose to High Dose Piperacillin/Tazobactam | Volume of Distribution of Piperacillin | Group 4 (HD) on 4.5 grams | 24.6 liters |
| Standard Dose to High Dose Piperacillin/Tazobactam | Volume of Distribution of Piperacillin | Group 4 (HD) on 6.75 grams | 34.0 liters |