Determination of the pharmacodynamics of vancomycin in young infants via time-to-event analysis

Posted on by Xiao Zhu

Introduction: Coagulase-negative staphylococci (CoNS) are a leading cause of late-onset sepsis in young infants. Vancomycin is commonly used for the empirical treatment of CoNS. However, the therapeutic target for these bacteria is poorly defined and is currently extrapolated from data for methicillin-resistant Staphylococcus aureus (MRSA) in adults and older children (1). Further understanding of the vancomycin pharmacokinetic / pharmacodynamic relationship for Staphylococcal infections in young infants is warranted.

Aims: (i) To develop a parametric time-to-event (TTE) model describing the clearance of staphylococcal bacteraemia in young infants, (ii) To determine the therapeutic target for vancomycin for the treatment of staphylococcal bacteraemia in young infants.

Methods: This study included young infants (aged 0-90 days) who had either an MRSA bacteraemia or two positive blood cultures with CoNS and received vancomycin at the Royal Children’s Hospital Melbourne between 2016 and 2019. A parametric TTE model was developed in NONMEM to describe the time to clearance of staphylococcal bacteraemia (2). Vancomycin exposure metrics (i.e. predicted first 24-hour area under the curve (AUC0-24), time above minimum inhibitory concentration (fT>MIC) and peak concentration (Cmax)) were evaluated to determine the influence on infection clearance in addition to patients’ characteristics. The exposure metrics used were determined from a published population pharmacokinetic model via maximum a posteriori method (3). Model performance was evaluated with a visual predictive check (VPC).

Results: Data from 30 infants were analysed, 28 with CoNS and 2 with MRSA bacteraemia. Bacterial MIC was determined in 26 isolates via Etest, 24 with an MIC of 2 mg/L and 2 with an MIC of 1 mg/L. The baseline hazard function was best described by log-normal distribution. All model parameters were precisely estimated (<30% relative standard error). Overall, the Turnbull estimator (4) (as nonparametric survival curve for interval-censored data) was well overlapped with the 90% predicted intervals by VPC. Vancomycin exposure metrics significantly influenced the time to clearance of infection. Specifically, an AUC0-24 ≥ 300 mg/L·h was associated with a 7.8-fold increase in infection clearance hazard at any time point compared to AUC0-24 < 300 mg/L·h (hazard ratio 95% CI: 3.21 – 18.8). In contrast, the removal of a central venous catheter had little influence on clearance of infection.

Conclusion: A parametric TTE model was developed to quantify the clearance of staphylococcal bacteraemia in young infants. An AUC0-24 ≥ 300 mg/L·h was determined as the therapeutic target for vancomycin in the treatment of staphylococcal bacteraemia in young infants.

References:

  1. Rybak MJ, Le J, Lodise TP, et al. Am J Health Syst Pharm, 2020, 77(11): 835-864.
  2. Holford N. CPT: Pharmacomet Syst Pharmacol, 2013, 2(5): 1-8
  3. Gwee A, Cranswick N, McMullan B, et al. JAMA Pediatr, 2019, 173(8): 791-793.
  4. Turnbull BW. J R Stat Soc Series B Stat Methodol, 1976, 38(3): 290-295.
2021