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Updated: Jun 23, 2025
A Neonatal Imaging Model of Gram-Negative Bacterial Sepsis
Published on: August 12, 2020
Postdiscontinuation Antibiotic Exposure in Hospitalized Infants at Risk for Late-onset Sepsis in the Neonatal
Kelly C Wade1,2, Rachel G Greenberg3,4, Daniel K Benjamin3,4
1From the Department of Pediatrics, University of Pennsylvania School of Medicine.
Insights
Antibiotic exposure in neonates can last longer than expected after the last dose, especially for premature infants. This post-discontinuation antibiotic exposure (PDAE) duration is crucial for antibiotic stewardship in neonatal intensive care units.
Area of Science:
- Neonatal pharmacology
- Infectious disease in neonates
- Antibiotic stewardship
Background:
- Neonates in intensive care are susceptible to late-onset sepsis.
- Current antibiotic stewardship guidelines recommend discontinuing antibiotics when blood cultures are negative.
- The duration of antibiotic effectiveness after the final dose in neonates is not well-defined.
Purpose of the Study:
- To determine the duration of therapeutic antibiotic exposure after the last dose in neonates.
- To evaluate the impact of patient factors (gestational age, postnatal age) on post-discontinuation antibiotic exposure (PDAE).
- To inform antibiotic stewardship practices in neonatal intensive care units.
Main Methods:
- Retrospective cohort study utilizing population pharmacokinetic models.
- Simulated 72-hour antibiotic courses (cefepime, piperacillin-tazobactam, tobramycin) in preterm and term neonates (7-60 days postnatal age).
- Monte Carlo simulations to predict drug concentrations and calculate PDAE relative to minimum inhibitory concentration (MIC) targets.
Main Results:
- Mean PDAE varied from 19 to 68 hours, depending on the antibiotic and MIC.
- Cefepime showed the longest PDAE (68 hours) at MIC 1 mcg/mL for Enterobacteriaceae.
- Piperacillin had a mean PDAE of 25 hours at MIC 8 mcg/mL, and tobramycin had a mean PDAE of 19 hours.
Conclusions:
- Therapeutic antibiotic levels of piperacillin and cefepime persisted significantly beyond the typical 8- to 12-hour dosing interval.
- PDAE is a critical factor for antibiotic stewardship in neonates, especially premature infants and those within the first month of life.
Background:
In the neonatal intensive care unit, infants are at risk for late-onset sepsis. When blood cultures are negative, antibiotic stewardship efforts encourage stopping antibiotics, yet the duration of therapeutic exposure after the last dose is unknown.
Methods:
This retrospective cohort study of simulated antibiotic exposures used published population pharmacokinetic models within drug-specific neonatal intensive care unit cohorts of preterm and term infants, postnatal age 7-60 days and exposed to cefepime, piperacillin-tazobactam or tobramycin. Monte Carlo simulations (NONMEM 7.3) were used to predict steady-state exposures after a 72-hour antibiotic course per Neofax dosing. Exposure was assessed relative to drug-specific minimum inhibitory concentration (MIC) targets between 1 and 16 mcg/mL for Pseudomonas and Enterobacteriaceae species. Postdiscontinuation antibiotic exposure (PDAE) was defined as the time from the last dose to when antibiotic concentration decreased below a specific MIC.
Results:
Piperacillin-tazobactam, cefepime and tobramycin cohorts included infants with median gestation age 29, 32 and 32 weeks and postnatal age 17, 19 and 15 days, respectively. The mean PDAE was 19-68 hours, depending on the specific antibiotic/MIC combination. PDAE was longer for infants <28 days old and preterm (vs. term) infants. Cefepime exhibited the longest mean PDAE of 68 hours for Enterobacteriaceae MIC 1. Piperacillin mean PDAE was 25 hours for Enterobacteriaceae MIC 8. Tobramycin had a short mean PDAE of 19 hours.
Conclusions:
Piperacillin and cefepime exposures remained therapeutic long after the expected 8- to 12-hour dosing interval. PDAE is an important consideration for antibiotic stewardship among hospitalized infants, particularly premature infants and those within 1 month postbirth.
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