V Ramos-Martín1,2, A Johnson1, L McEntee1, N Farrington1, K Padmore2, P Cojutti3,4, F Pea3,4, M N Neely5, W W Hope1. 1. Antimicrobial Pharmacodynamics and Therapeutics, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 2. Alder Hey Children's NHS Foundation Trust, Liverpool, UK. 3. Institute of Clinical Pharmacology, Santa Maria della Misericordia University Hospital, ASUIUD, Udine, Italy. 4. Department of Medicine, University of Udine, Udine, Italy. 5. Laboratory of Applied Pharmacokinetics and Bioinformatics, The Saban Research Institute and The Division of Paediatric Infectious Diseases, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA.
Abstract
OBJECTIVES: The overall study aim was to identify the relevant preclinical teicoplanin pharmacokinetic (PK)/pharmacodynamic (PD) indices to predict efficacy and suppression of resistance in MRSA infection. METHODS: A hollow-fibre infection model and a neutropenic murine thigh infection model were developed. The PK/PD data generated were modelled using a non-parametric population modelling approach with Pmetrics. The posterior Bayesian estimates derived were used to study the exposure-effect relationships. Monte Carlo simulations from previously developed population PK models in adults and children were conducted to explore the probability of target attainment (PTA) for teicoplanin dosage regimens against the current EUCAST WT susceptibility range. RESULTS: There was a concentration-dependent activity of teicoplanin in both the in vitro and in vivo models. A total in vivo AUC/MIC of 610.4 (total AUC of 305.2 mg·h/L) for an MRSA strain with an MIC of 0.5 mg/L was needed for efficacy (2 log10 cell kill) against a total bacterial population. A total AUC/MIC ratio of ∼1500 (total AUC of ∼750 mg·h/L) was needed to suppress the emergence of resistance. The PTA analyses showed that adult and paediatric patients receiving a standard regimen were only successfully treated for the in vivo bactericidal target if the MIC was ≤0.125 mg/L in adults and ≤0.064 mg/L in children. CONCLUSIONS: This study improves our understanding of teicoplanin PD against MRSA and defines an in vivo AUC/MIC target for efficacy and suppression of resistance. Additional studies are needed to further corroborate the PK/PD index in a variety of infection models and in patients.
OBJECTIVES: The overall study aim was to identify the relevant preclinical teicoplanin pharmacokinetic (PK)/pharmacodynamic (PD) indices to predict efficacy and suppression of resistance in MRSA infection. METHODS: A hollow-fibre infection model and a neutropenic murine thigh infection model were developed. The PK/PD data generated were modelled using a non-parametric population modelling approach with Pmetrics. The posterior Bayesian estimates derived were used to study the exposure-effect relationships. Monte Carlo simulations from previously developed population PK models in adults and children were conducted to explore the probability of target attainment (PTA) for teicoplanin dosage regimens against the current EUCAST WT susceptibility range. RESULTS: There was a concentration-dependent activity of teicoplanin in both the in vitro and in vivo models. A total in vivo AUC/MIC of 610.4 (total AUC of 305.2 mg·h/L) for an MRSA strain with an MIC of 0.5 mg/L was needed for efficacy (2 log10 cell kill) against a total bacterial population. A total AUC/MIC ratio of ∼1500 (total AUC of ∼750 mg·h/L) was needed to suppress the emergence of resistance. The PTA analyses showed that adult and paediatric patients receiving a standard regimen were only successfully treated for the in vivo bactericidal target if the MIC was ≤0.125 mg/L in adults and ≤0.064 mg/L in children. CONCLUSIONS: This study improves our understanding of teicoplanin PD against MRSA and defines an in vivo AUC/MIC target for efficacy and suppression of resistance. Additional studies are needed to further corroborate the PK/PD index in a variety of infection models and in patients.
Authors: A Kontou; K Sarafidis; O Begou; H G Gika; A Tsiligiannis; K Ogungbenro; A Dokoumetzidis; E Agakidou; E Roilides Journal: Antimicrob Agents Chemother Date: 2020-03-24 Impact factor: 5.191
Authors: Christopher A Darlow; Fernando Docobo-Perez; Nicola Farrington; Adam Johnson; Laura McEntee; Jennifer Unsworth; Ana Jimenez-Valverde; Silke Gastine; Ruwanthi Kolamunnage-Dona; Renata M A de Costa; Sally Ellis; François Franceschi; Joseph F Standing; Mike Sharland; Michael Neely; Laura Piddock; Shampa Das; William Hope Journal: Antimicrob Agents Chemother Date: 2021-06-17 Impact factor: 5.191
Authors: Mohd H Abdul-Aziz; Jan-Willem C Alffenaar; Matteo Bassetti; Hendrik Bracht; George Dimopoulos; Deborah Marriott; Michael N Neely; Jose-Artur Paiva; Federico Pea; Fredrik Sjovall; Jean F Timsit; Andrew A Udy; Sebastian G Wicha; Markus Zeitlinger; Jan J De Waele; Jason A Roberts Journal: Intensive Care Med Date: 2020-05-07 Impact factor: 17.440
Authors: Christopher A Darlow; Nicola Farrington; Adam Johnson; Laura McEntee; Jennifer Unsworth; Ana Jimenez-Valverde; Ruwanthi Kolamunnage-Dona; Renata M A Da Costa; Sally Ellis; François Franceschi; Mike Sharland; Michael Neely; Laura J V Piddock; Shampa Das; William Hope Journal: J Antimicrob Chemother Date: 2022-04-27 Impact factor: 5.758
Authors: V Ramos-Martín; M N Neely; K Padmore; M Peak; M W Beresford; M A Turner; S Paulus; J López-Herce; W W Hope Journal: Antimicrob Agents Chemother Date: 2017-09-22 Impact factor: 5.191