Evaluating the Relationship between Vancomycin Trough Concentration and 24-Hour Area under the Concentration-Time Curve in Neonates [PublishAheadOfPrint]

Bacterial sepsis is a major cause of morbidity and mortality in neonates, especially those involving methicillin-resistant Staphylococcus aureus (MRSA). Guidelines by the Infectious Diseases Society of America recommend vancomycin 24-hour area under the concentration-time curve to MIC ratio (AUC₂₄/MIC, hr) > 400 as the best predictor of successful treatment against MRSA infections when MIC (mg/L) is ≤ 1. The relationship between steady state vancomycin trough concentrations and AUC₂₄ (mg ⋅ hr/L) has not been studied in an Asian neonatal population. We conducted a retrospective chart review in Singapore hospitals, and collected patient characteristics and therapeutic drug monitoring data from neonates on vancomycin therapy over a 5-year period. A one-compartment population pharmacokinetic model was built from the collected data, internally validated, and then used to assess the relationship between steady state trough concentrations and AUC₂₄. A Monte Carlo simulation sensitivity analysis was also conducted. A total of 76 neonates with 429 vancomycin concentrations were included for analysis. Median (interquartile range) was 30 weeks (28-36 weeks) for postmenstrual age (PMA) and 1043 g (811-1919 g) for weight at initiation of treatment. Vancomycin clearance was predicted by weight, PMA, and serum creatinine. For MRSA isolates with MIC ≤ 1, our major finding was that the minimum steady state trough concentration range predictive of achieving AUC₂₄/MIC > 400 was 8 to 8.9 mg/L. Steady state troughs within 15 to 20 mg/L are unlikely to be necessary to achieve AUC₂₄/MIC > 400, while troughs within 10 to 14.9 mg/L may be more appropriate.

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