Postdiscontinuation Antibiotic Exposure in Hospitalized Infants at Risk for Late-onset Sepsis in the Neonatal Intensive Care Unit

Abstract

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.

FIGURE 1.

Simulated Plasma Concentration Profiles of Common Antibiotics Relative to Susceptibility Breakpoints of Common Pathogens. Black solid line denotes mean drug concentration; shaded area, the 2.5 to 97.5 percentile of concentration data points; vertical dashed line, time at last antibiotic dose; letter symbols (A, B, C) on X-axis indicate time points at which mean antibiotic concentrations decay to susceptibility breakpoint MIC for different bacteria post-antibiotic discontinuation. PDAE represents time between red line and symbol representing MIC on X-axis. Figures represent standard antibiotic exposures during a 72-hour course. A) Cefepime was administered every 12 hours and MIC susceptibility breakpoints ranged from 1–2 mcg/mL for Enterobacteriaceae to 8 mcg/mL for P. aeruginosa. B) Piperacillin-tazobactam was administered every 8 or 12 hours depending on infant’s postmenstrual and postnatal age. Concentration curves represents piperacillin component. MIC susceptibility breakpoints ranged from 8 to 16 mcg/mL for P. aeruginosa and Enterobacteriaceae. C) Tobramycin was administered every 24 hours. For Piperacillin, MIC susceptibility breakpoints ranged from 1–2 for P. aeruginosa and Enterobacteriaceae. CI, confidence interval; MIC, minimum inhibitory concentration; PDAE, post-discontinuation empiric antibiotic exposure.