Presenting Author:

Erin Bradley, M.D.

Principal Investigator:

Erin Bradley, M.D.

Department:

Pediatrics

Keywords:

Sepsis, Ceftazidime, Pharmacokinetics

Location:

Ryan Family Atrium, Robert H. Lurie Medical Research Center

C83 - Clinical

Pharmacokinetic and Pharmacodynamics of Ceftazidime in Pediatric ICU Patients

Background: Mortality benefit has been proven with early antibiotic use in sepsis. Antimicrobial therapy should be based on early achievement of effective drug concentrations by optimizing the pharmacodynamics (PD) of individual drugs. Ceftazidime is the preferred β-lactam for empiric treatment of sepsis at Lurie Children’s, however, most pharmacokinetic (PK) data currently published in pediatrics does not include ICU patients. With β-lactams, the major pharmacodynamic driver is time of free drug concentration above the minimum inhibitory concentration (t>MIC) of the bacteria over the duration of antibiotic dosing interval. Adult PK/PD data suggest that critically ill adults with high level of illness severity may benefit from continuous/extended infusion β-lactam therapy to optimize t>MIC particularly for pathogens that are relatively resistant. Benefits of extended infusion are associated with reduced mortality and length of stay, and increased ventilator free days. With children experiencing changes in physiology with critical illness leading to alteration in antibiotic clearance, additional data are needed to determine if current dosing strategies are achieving optimal antibiotic exposure. Understanding the changing PK/PD of ceftazidime with progression of illness in the ICU may help determine if current dosing regimens are adequate to maintain appropriate t>MIC. Methods: Patients between 2 months and 18 years admitted to the PICU/CICU who will receive ceftazidime with an expected duration ≥ 48 hours who meet inclusion criteria will be enrolled in this prospective, non-interventional, PK study. Using standard dosing, sample collection will start within the first 24 hours of admission at times: 0 min (predose), 30 min, 1 hr, and 4 hr. During the second 24 hours of therapy, one sample will be drawn between hours 2 and 4 post-dose. If therapy continues, samples will be drawn daily between hours 2 and 4 post-dose, up to 7 days. Covariate data will also be collected with respect to patient volume status, kidney and cardiac function, and illness severity. Ceftazidime concentrations will be analyzed as a function of dose, time, and individual patient variables by non-liner mixed-effect analysis with Bayesian post-hoc simulation. Anticipated Results: A subset of patients with markers of enhanced renal clearance and larger volumes of distribution will be associated with suboptimal ceftazidime exposure and will not maintain adequate T>MIC for commonly isolated bacterial pathogens in the PICU. Using the population pK (pop pK) model, this patient population will have predicted target attainment that will be < 90% based on current MIC data as determined by Monte Carlo Simulations. Conclusion: A pop pK model for pediatric ICU patients will be developed. A subset of critically ill pediatric patients will be associated with subtherapeutic concentrations. Simulation using derived PK parameters and patient covariates will be suggest to improve dosing regimens.