Characterization of the Population Pharmacokinetics of Ampicillin in Neonates Using an Opportunistic Study Design

Abstract

iAlthough ampicillin is the most commonly used drug in neonates, developmental pharmacokinetic (PK) data to guide dosing are lacking. Ampicillin is primarily renally eliminated, and developmental changes are expected to influence PK. We conducted an open-label, multicenter, opportunistic, prospective PK study of ampicillin in neonates stratified by gestational age (GA) (<34 or >34 weeks) and postnatal age (PNA) (<7 or >7 days). Drug concentrations were measured by tandem mass spectrometry. PK data were analyzed using population nonlinear mixed-effects modeling in NONMEM 7.2. Monte Carlo simulations were conducted to determine the probability of target attainment for the time in which the total steady-state ampicillin concentrations remained above the MIC (T>MIC) for 50%, 75%, and 100% of the dosing interval. A total of 142 PK samples from 73 neonates were analyzed (median [range] GA, 36 [24 to 41] weeks; PNA, 5 [0 to 25] days). The median ampicillin dose was 200 (100 to 350) mg/kg/day. Postmenstrual age and serum creatinine were covariates for ampicillin clearance (CL). A simplified dosing regimen of 50 mg/kg every 12 h for GA of <34 weeks and PNA of <7 days, 75 mg/kg every 12 h for GA of <34 weeks and PNA of >8 and <28 days, and 50 mg/kg every 8 h for GA of >34 weeks and PNA of <28 days achieved the prespecified surrogate efficacy target in 90% of simulated subjects. Ampicillin CL was associated with neonatal development. A simplified dosing regimen stratified by GA and PNA achieves the desired surrogate therapeutic target in the vast majority of neonates.

Electronic Health Records and Pharmacokinetic Modeling to Assess the Relationship between Ampicillin Exposure and Seizure Risk in Neonates

“…(14) We included infants 24–41 weeks gestational age (GA) and 500–5400 g birth weight (BW) first exposed to ampicillin prior to a postnatal age (PNA) of 25 days. We included only ampicillin courses started prior to 25 days PNA and completed prior to 60 days PNA, with a daily ampicillin dose ≥50 mg/kg/day (to avoid including prophylactic dosing regimens), and with a most recent serum creatinine of 0.2–2.5 mg/dL prior to the first dose of ampicillin.…”

“…(13) To overcome this limitation, we simulated ampicillin exposures using a population PK model developed from a cohort of infants enrolled in a PK study conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Pediatric Trials Network. (14)…”

Are postnatal ampicillin levels actually related to the duration of intrapartum antibiotic prophylaxis prior to delivery? A pharmacokinetic study in 120 neonates

“…This threshold was arbitrarily established in order to confirm the persistence of bactericidal levels after birth. We considered the neonatal ampicillin half-life (approximately 4 hours)17 and, as starting point, the interruption of maternal ampicillin supply at delivery.…”

Adverse consequences of neonatal antibiotic exposure

“…[90] Only in the last year have we had dosing guidance for ampicillin derived from pharmacokinetics (pK) studied in a NICU cohort. [91] Vancomycin pK has also recently been examined, and modifications in dosing based on individual variations may result in more infants reaching targeted trough levels. [92*, 93] Work by the Pediatric Trials Network has identified dosing regimens based on gestational and postnatal age for piperacillin tazobactam, metronidazole, meropenem, and antifungals.…”