Ampicillin dosing in premature infants for early-onset sepsis: exposure-driven efficacy, safety, and stewardship

Abstract

Objective: Define optimal ampicillin dosing for empiric early-onset sepsis (EOS) therapy in preterm neonates.

Study design: We simulated ampicillin concentrations in newborns (birthweight < 1500 g; gestational age 22-27 weeks), summarizing three 48 h regimens: high 100 mg/kg Q8hr, medium 100 mg/kg Q12hr, and standard 50 mg/kg Q12hr. Concentration data were analyzed for concentration above minimum inhibitory concentration (MIC), below neurotoxicity threshold (C_max ≤ 140 mcg/mL), and duration limited to 48 h.

Results: Among 34,689 newborns, all dosing regimens provided concentrations above MIC through 48 h, but C_max exceeded the neurotoxicity threshold. With the 4-dose standard regimen, >90% maintained concentrations >MIC beyond 48 h. With the 2-dose regimen, newborns maintained the mean concentration >MIC within the 48 h culture window and below neurotoxicity level. Infants 22-24 weeks' gestation had higher drug concentrations and more prolonged exposure duration than 25-27 weeks' gestation.

Conclusions: For EOS in preterm infants, two ampicillin doses (50 mg/kg) provided optimal bactericidal exposures, while minimizing potential toxicity.

Figure 1.. Probability of therapeutic target attainment over time from therapy initiation

Among VLBW neonates receiving different ampicillin regimens, graphs represent the probability that neonates will reach the desired therapeutic target attainment (PTA) with ampicillin concentration above the MIC for 100% of dosing time interval (fT>MIC =100%) over time from start of therapy and for different MIC breakpoints of 0.25 mcg/mL for GBS, 1 mcg/mL for Streptococcus sp. and Listeria, and 8 mcg/mL for E. coli. Black line represents 90% target attainment. X marks time of doses administered. GBS, group B Streptococcus; hr, hour; MIC, minimum inhibitory concentration; PTA, probability of target attainment; VLBW, very low birth weight

Figure 2.. Mean predicted concentration versus time curve of ampicillin 50mg/kg/dose.

Mean predicted concentration versus time curve of ampicillin 50mg/kg/dose for 2 (A), and 4 (B) doses for VLBW neonates in two gestational age groups. Concentrations inside the black box are within the concentration metrics, accounting for efficacy (>MIC 1 mcg/mL), safety (≤140 mcg/mL), and stewardship ending at 48-hour culture incubation window. MIC, minimum inhibitory concentration; VLBW, very low birth weight