Optimization of antimicrobial therapy for Gram-positive bacterial infections in children using a translational pharmacological approach

Nosocomial bloodstream infection (BSI) is the most common type of hospital-acquired infection in paediatric patients and a major cause of morbidity and mortality worldwide. Methicillin-resistant staphylococci (CoNS and MRSA) are a leading cause of hospital-acquired neonatal sepsis and BSI. Glycopeptides (vancomycin and teicoplanin) constitute the current mainstay of therapy. There is limited antimicrobial PK-PD data available for neonates and children and optimal drug exposures resulting in maximal efficacy and suppression of resistance are not known. A translational pharmacological approach can be used to build the evidence required to optimize the current use of antimicrobial therapy in children. Pre-clinical experimental (in vitro and in vivo) and clinical PK-PD work was conducted throughout this thesis to improve our understanding of the PK-PD relationships of vancomycin and teicoplanin against CoNS and MRSA. The in vitro HFIM defined the relevant PD indexes and free drug exposures associated with maximal bacterial killing and suppression of resistance. The in vivo models (a rabbit central-line associated BSI and a mouse neutropenic thigh infection model) validated the in vitro findings. CRP concentrations were incorporated as an in vivo PD input. A clinical PK study of teicoplanin in 57 patients (neonates, infants and older children) was conducted and the population PK parameters estimated. PK-PD modelling techniques were used to analyse the PK-PD data and bridge the experimental results to human patients by means of Monte Carlo (MC) simulations. Vancomycin and teicoplanin displayed a concentration-dependent pattern of activity. An AUC:MIC ratio was associated with maximal antibacterial activity and suppression of resistance. Based on MC simulations, the probability of the in vivo target attainment with currently used teicoplanin dosage regimens results insufficient to treat a majority of patients with MRSA infection. High teicoplanin PK variability was identified in children. Weight, age and renal function were the best explanatory covariates of PK variability. Wider drug exposure distribution is observed in the paediatric population with respect to adults. A patient-tailored TDM approach with the aid of a Bayesian feedback adaptive control tool is required to ensure individual patients achieve optimal drug exposures in a precise and safe manner. The defined pre-clinical optimal targets of exposure for vancomycin-CoNS and teicoplanin-MRSA now need to be prospectively evaluated in patients. Currently used teicoplanin dosage regimens in both, adults and children, may be insufficient to treat a high proportion of patients with serious MRSA infection. Current EUCAST clinical breakpoint may need to be revised for teicoplanin against MRSA. The current strategy of using teicoplanin fixed population-based antibiotic regimens results in a wide range of drug exposures in neonates and children. An individualised dosing and TDM approach can ensure optimal target attainment at the individual level and in real-time.