TY - JOUR
T1 - Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Term Asphyxiated Neonates during Controlled Therapeutic Hypothermia
AU - van der Veer, Marlotte A. A.
AU - de Haan, Timo R.
AU - Franken, Linda G. W.
AU - Hodiamont, Caspar J.
AU - Groenendaal, Floris
AU - Dijk, Peter H.
AU - de Boode, Willem P.
AU - Simons, Sinno
AU - Dijkman, Koen P.
AU - van Straaten, Henrica L. M.
AU - Rijken, Monique
AU - Cools, Filip
AU - Nuytemans, Debbie H. G. M.
AU - van Kaam, Anton H.
AU - Bijleveld, Yuma A.
AU - Mathôt, Ron A. A.
N1 - Funding Information: This study was funded by the Dutch government (ZonMw grant number 40-41500-98-9002). Publisher Copyright: Copyright © 2023 American Society for Microbiology. All Rights Reserved.
PY - 2023/5/17
Y1 - 2023/5/17
N2 - Ceftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal asphyxia. We aimed to describe the population pharmacokinetics (PK) of ceftazidime in asphyxiated neonates during hypothermia, rewarming, and normothermia and propose a population-based rational dosing regimen with optimal PK/pharmacodynamic (PD) target attainment. Data were collected in the PharmaCool prospective observational multicenter study. A population PK model was constructed, and the probability of target attainment (PTA) was assessed during all phases of controlled TH using targets of 100% of the time that the concentration in the blood exceeds the MIC (T>MIC) (for efficacy purposes and 100% T>4×MIC and 100% T>5×MIC to prevent resistance). A total of 35 patients with 338 ceftazidime concentrations were included. An allometrically scaled one-compartment model with postnatal age and body temperature as covariates on clearance was constructed. For a typical patient receiving the current dose of 100 mg/kg of body weight/day in 2 doses and assuming a worst-case MIC of 8 mg/L for Pseudomonas aeruginosa, the PTA was 99.7% for 100% T>MIC during hypothermia (33.7°C; postnatal age [PNA] of 2 days). The PTA decreased to 87.7% for 100% T>MIC during normothermia (36.7°C; PNA of 5 days). Therefore, a dosing regimen of 100 mg/kg/day in 2 doses during hypothermia and rewarming and 150 mg/kg/day in 3 doses during the following normothermic phase is advised. Higher-dosing regimens (150 mg/kg/day in 3 doses during hypothermia and 200 mg/kg/day in 4 doses during normothermia) could be considered when achievements of 100% T>4×MIC and 100% T>5×MIC are desired.
AB - Ceftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal asphyxia. We aimed to describe the population pharmacokinetics (PK) of ceftazidime in asphyxiated neonates during hypothermia, rewarming, and normothermia and propose a population-based rational dosing regimen with optimal PK/pharmacodynamic (PD) target attainment. Data were collected in the PharmaCool prospective observational multicenter study. A population PK model was constructed, and the probability of target attainment (PTA) was assessed during all phases of controlled TH using targets of 100% of the time that the concentration in the blood exceeds the MIC (T>MIC) (for efficacy purposes and 100% T>4×MIC and 100% T>5×MIC to prevent resistance). A total of 35 patients with 338 ceftazidime concentrations were included. An allometrically scaled one-compartment model with postnatal age and body temperature as covariates on clearance was constructed. For a typical patient receiving the current dose of 100 mg/kg of body weight/day in 2 doses and assuming a worst-case MIC of 8 mg/L for Pseudomonas aeruginosa, the PTA was 99.7% for 100% T>MIC during hypothermia (33.7°C; postnatal age [PNA] of 2 days). The PTA decreased to 87.7% for 100% T>MIC during normothermia (36.7°C; PNA of 5 days). Therefore, a dosing regimen of 100 mg/kg/day in 2 doses during hypothermia and rewarming and 150 mg/kg/day in 3 doses during the following normothermic phase is advised. Higher-dosing regimens (150 mg/kg/day in 3 doses during hypothermia and 200 mg/kg/day in 4 doses during normothermia) could be considered when achievements of 100% T>4×MIC and 100% T>5×MIC are desired.
KW - antimicrobial therapy
KW - ceftazidime
KW - neonates
KW - population pharmacokinetics
KW - therapeutic hypothermia
UR - http://www.scopus.com/inward/record.url?scp=85159764445&partnerID=8YFLogxK
U2 - https://doi.org/10.1128/aac.01707-22
DO - https://doi.org/10.1128/aac.01707-22
M3 - Article
C2 - 37010414
SN - 0066-4804
VL - 67
SP - e0170722
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 5
ER -