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Background Premature, very low birth weight (VLBW) neonates are at risk for early-onset sepsis and receive ampicillin and gentamicin post-birth. Antimicrobial stewardship supports short-course antibiotics, but how long antibiotic concentrations remain therapeutic post-last dose is unknown. Methods Using Monte Carlo simulations (NONMEM 7.3), we analyzed antibiotic exposures in a retrospective cohort of 34 689 neonates (<1500 g, 22-27 weeks of gestation). Therapeutic exposure for ampicillin and gentamicin was evaluated relative to the minimum inhibitory concentration (MIC) for common pathogens (MIC 0.25-8 mcg/mL for group B s treptococcus [GBS] and Escherichia coli). Post-discontinuation antibiotic exposure (PDAE) was defined as the time from the last dose to time when concentration decreased below MIC. Results Neonates had a median (range) gestational age of 26 (22-27) weeks and BW, 790 g (400-1497). All ampicillin dosing regimens (50-100 mg/kg every 8-12 hours for 2-6 doses) achieved therapeutic exposures > MIC range. After the last dose, the PDAE mean (95% confidence interval [CI]) ranged from 34 to 50 hours (17–79) for E. coli (MIC 8) and 82 to 104 hours (95% CI: 39-122) for GBS (MIC 0.25); longer PDAE occurred with higher dose, shorter interval, and longer course. Short-course ampicillin (2 doses, 50 mg/kg every 12 hours) provided PDAE 34 hours for E. coli and 82 hours for GBS. Single-dose 5 mg/kg gentamicin provided PDAE > MIC 2 for 26 hours. Conclusions In VLBW neonates, ampicillin exposure remains therapeutic long after the last dose. Short-course ampicillin provided therapeutic exposures throughout the typical blood culture incubation period. [ABSTRACT FROM AUTHOR]