title: Association between vancomycin trough concentration and area under the concentration-time curve in neonates.
abstract: National treatment guidelines for invasive methicillin-resistant Staphylococcus aureus (MRSA) infections recommend targeting a vancomycin 24-h area under the concentration-time curve (AUC0-24)-to-MIC ratio of >400. The range of vancomycin trough concentrations that best predicts an AUC0-24 of >400 in neonates is not known. This understanding would help clarify target trough concentrations in neonates when treating MRSA. A retrospective chart review from a level III neonatal intensive care unit was performed to identify neonates treated with vancomycin over a 5-year period. Vancomycin concentrations and clinical covariates were utilized to develop a one-compartment population pharmacokinetic model and examine the relationships between trough and AUC0-24 in the study neonates. Monte Carlo simulations were performed to examine the effect of dose, postmenstrual age (PMA), and serum creatinine level on trough and AUC0-24 achievement. A total of 1,702 vancomycin concentrations from 249 neonates were available for analysis. The median (interquartile range) PMA was 39 weeks (32 to 42 weeks) and weight was 2.9 kg (1.6 to 3.7 kg). Vancomycin clearance was predicted by weight, PMA, and serum creatinine level. At a trough of 10 mg/liter, 89% of the study neonates had an AUC0-24 of >400. Monte Carlo simulations demonstrated that troughs ranging from 7 to 11 mg/liter were highly predictive of an AUC0-24 of >400 across a range of PMA, serum creatinine levels, and vancomycin doses. However, a trough of ≥10 mg/liter was not readily achieved in most simulated subgroups using routine starting doses. Higher starting doses frequently resulted in troughs of >20 mg/liter. A vancomycin trough of ∼10 mg/liter is likely adequate for most neonates with invasive MRSA infections based on considerations of the AUC0-24. Due to pharmacokinetic and clinical heterogeneity in neonates, consistently achieving this target vancomycin exposure with routine starting doses is difficult. More robust clinical dosing support tools are needed to help clinicians with dose individualization.
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California, USA frymoyer@stanford.edu.
authors.forename: Adam
authors.initials: A
authors.lastname: Frymoyer
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Hersh
authors.affiliation: Department of Pharmaceutics and Industrial Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
authors.forename: Mohammed H
authors.initials: MH
authors.lastname: El-Komy
authors.affiliation: Pharmacy Department, Lucile Packard Children's Hospital Stanford, Palo Alto, California, USA.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Gaskari
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California, USA.
authors.forename: Felice
authors.initials: F
authors.lastname: Su
authors.affiliation: Department of Anesthesia, Stanford University, Stanford, California, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Drover
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California, USA.
authors.forename: Krisa
authors.initials: K
authors.lastname: Van Meurs
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001835:Body Weight; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D012189:Retrospective Studies; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D014640:Vancomycin / Q000096:biosynthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin; D003404:Creatinine