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

Author:

Wade Kelly C.12ORCID,Greenberg Rachel G.34,Benjamin Daniel K.34,Chen Lydia Li-Hui5,Vo Brandon6,Ang Berwyn Liselle5,Boutzoukas Angelique34,Zimmerman Kanecia34,Clark Reese H.7,Cohen-Wolkowiez Michael34,Le Jennifer5,

Affiliation:

1. From the Department of Pediatrics, University of Pennsylvania School of Medicine

2. Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

3. Department of Pediatrics, Duke University Medical Center

4. Duke Clinical Research Institute, Durham, North Carolina

5. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, California

6. University of California Riverside, Riverside, California

7. MEDNAX Center for Research, Education, Quality, and Safety, Sunrise, Florida.

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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