Effect of hypothermia on the pharmacokinetics of antibiotics in neonates

Perinatal asphyxia may lead to hypoxic-ischemic encephalopathy (HIE) within hours after birth. HIE is a major cause of neonatal mortality, can cause acute neurologic disease and can negatively influence long-term cognitive and neuropsychological functioning. Hypothermia treatment initiated <6 hours after birth in post-asphyxiated (near) term neonates with moderate or severe HIE is the standard of care in NICUs. However, hypothermia can potentially change pharmacokinetic (PK) properties of drugs, which may have consequences for the administered dose. A multicenter prospective observational cohort trial, the PharmaCool Study, was performed to evaluate the effect of hypothermia on the frequently used antibiotics amoxicillin, benzylpenicillin, and gentamicin. In 183 patients, multiple plasma samples were drawn during all phases of hypothermia treatment (i.e. hypothermia (33.5°C, days 1-3), rewarming (0.4°C/hour, day 4), and normothermia (36.5°C , day 5)) and the antibiotic concentrations were analyzed using tandem-mass spectrometry. Together with clinical data, the population PK were evaluated and described using “non-linear mixed-effects modeling” (NONMEM). For gentamicin, clearance was reduced during the hypothermic and rewarming phases compared with normothermia. Birth weight and gestational age were correlated with gentamicin clearance. For amoxicillin and benzylpenicillin clearance was decreased as well during cooling. Postnatal age, gestational age, and urine output were other important factors influencing the rate of elimination. Our studies demonstrated that the clearances of these antibiotics are altered during hypothermia. Simulations were then performed and dosing regimens were developed to optimize treatment with amoxicillin, benzylpenicillin, and gentamicin in this specific patient population.