Pharmacodynamics of vancomycin for CoNS infection: experimental basis for optimal use of vancomycin in neonates

Abstract

Objectives: CoNS are the most common cause of neonatal late-onset sepsis. Information on the vancomycin pharmacokinetics/pharmacodynamics against CoNS is limited. The aim of this study was to characterize vancomycin pharmacokinetic/pharmacodynamic relationships for CoNS and investigate neonatal optimal dosage regimens.

Methods: A hollow fibre and a novel rabbit model of neonatal central line-associated bloodstream CoNS infections were developed. The results were then bridged to neonates by use of population pharmacokinetic techniques and Monte Carlo simulations.

Results: There was a dose-dependent reduction in the total bacterial population and C-reactive protein levels. The AUC/MIC and Cmax/MIC ratios were strongly linked with total and mutant resistant cell kill. Maximal amplification of resistance was observed in vitro at an fAUC/MIC of 200 mg · h/L. Simulations predicted that neonates <29 weeks post-menstrual age are underdosed with standard regimens with respect to older age groups.

Conclusions: The AUC/MIC and Cmax/MIC ratios are the pharmacodynamic indices that best explain total and resistant cell kill in CoNS infection. This suggests that less-fractionated regimens are appropriate for clinical use and continuous infusions may be associated with increased risk of emergence of antimicrobial resistance. This study has provided the pharmacodynamic evidence to inform an optimized neonatal dosage regimen to take into a randomized controlled trial.

© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Schematic representation of neonatal CLABSI models. (a) In vitro, HFIM: MH broth was pumped from a central compartment through an HF cartridge (FiberCell Systems, Frederick, MD, USA). Vancomycin was injected into the central compartment using a programmable syringe driver (Aladdin pump, World Precision Instruments, UK). Two peristaltic pumps (205U, Watson-Marlow, UK) were used. Fresh medium was pumped from a reservoir into the central compartment and the same volume removed as waste. The first pump had a speed rate that represented the neonatal simulated vancomycin elimination t1/2. (b) In vivo, rabbit model: central venous access was established with a rabbit jugular vein catheter with a Smiths P.A.S. Port® Elite (SAI Infusion Technologies, IL, USA) under general anaesthesia, to enable CoNS infection through the central line and biofilm formation.

Figure 2.

PD of vancomycin against five CoNS neonatal strains in the HFIM. (a) The total bacterial density (log10 cfu/mL) decline along the different fAUC/MIC reached at steady-state (96–120 h) in all the experiments. A sigmoid Emax model was fitted to the data (r2 = 0.62). (b) The resistant bacterial population decline along the same PD index. (c) The probability of emergence of resistance compared with control with each 100 range of fAUC/MIC ratios at steady-state.

Figure 3.

(a) Dose-fractionation studies (15 mg/kg/day) with (a) S. epidermidis 121164, the strain with the lowest mutational frequency to resistance, (b) S. capitis 062012 and (c) S. capitis 122828. Regimens consisted of 15 mg/kg q24h (1), q12h (2) and 24 h continuous infusion (3) in the HFIM. Filled symbols show the data points (bacterial density count in drug-free plates) for the total bacterial population. Open symbols represent data points (bacterial density count in 4 mg/L vancomycin drug-containing plates) for the resistant subpopulation. Dotted lines represent the lower limit of quantification (LOQ) of 1 log10 cfu/mL.

Figure 4.

PD of vancomycin against CoNS (S. capitis 122828), the strain with the highest mutational frequency to vancomycin resistance, in the HFIM. The endpoint is the bacterial density count (log10 cfu/mL) at the end of 9 days in the HFIM. An inhibitory sigmoid Emax model was fitted to the total bacterial population versus the PD index and a non-linear regression model was fitted to the resistant subpopulation versus the PD index. (a) fAUC/MIC. (b) fCmax/MIC. (c) fCmin/MIC.

Figure 5.

Concentration–time profile of CRP for the control rabbits (a) and for the rabbits receiving the lowest (c) and highest (d) dose of vancomycin along the 4 days of the experiment in the CLABSI rabbit model. (b) The CRP profile in neonates at 0, 24 (first day of treatment) and 96 h of therapy with teicoplanin for comparison.

Figure 6.

Tip of the central catheter cultures (log10 cfu/mL) at autopsy from the CLABSI rabbit model (pooled data means and standard error of means) for each of the dosage regimens and the strains investigated (S. epidermidis 122648 and S. capitis 122828).

Figure 7.

PD total AUC/MIC ratio relationship of vancomycin against CoNS (S. epidermidis and S. capitis) in the rabbit CLABSI model.

Figure 8.

Bridging study. Predicted CRP-AUC linked histograms showing the distribution of simulated neonates per PMA group [(a) 35 weeks] receiving currently recommended dosage regimens and a proposed optimized vancomycin regimen [(b) 15 mg/kg q12h for PMA