TY - JOUR
T1 - Model-informed dose optimisation of polymyxin-rifampicin combination therapy against multidrug-resistant Acinetobacter baumannii
AU - Zhao, Jinxin
AU - Zhu, Yan
AU - Han, Mei-Ling
AU - Lu, Jing
AU - Yu, Heidi H.
AU - Wickremasinghe, Hasini
AU - Zhou, Qi Tony
AU - Bergen, Phillip
AU - Rao, Gauri
AU - Velkov, Tony
AU - Lin, Yu-Wei
AU - Li, Jian
N1 - Funding Information:
Funding: J.L., T.V. and Q.T.Z. are supported by a research grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (R01 AI132681, USA). J.L. is an Australian National Health Medical Research Council (NHMRC) Principal Research Fellow and T.V. is an Australian NHMRC Industry Career Development Level 2 Research Fellow. Y.W.L. is currently an employee of Certara, Australia and Co-Director of the Malaya Translational and Clinical Pharmacometrics Group, University of Malaya, Malaysia. J.Z. is a recipient of the 2022 Faculty of Medicine, Nursing and Health Sciences Bridging Fellowship, Monash University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.
Funding Information:
Funding: J.L. T.V. and Q.T.Z. are supported by a research grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (R01 AI132681, USA). J.L. is an Australian National Health Medical Research Council (NHMRC) Principal Research Fellow and T.V. is an Australian NHMRC Industry Career Development Level 2 Research Fellow. Y.W.L. is currently an employee of Certara, Australia and Co-Director of the Malaya Translational and Clinical Pharmacometrics Group, University of Malaya, Malaysia. J.Z. is a recipient of the 2022 Faculty of Medicine, Nursing and Health Sciences Bridging Fellowship, Monash University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. , Ethical approval: Animal experiments were approved by the Monash University Animal Ethics Committee and conducted in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purpose. Acknowledgements: We thank Professor John Turnidge and Associate Professor Denis Spelman for sharing the clinical isolates A. baumannii 248–01-C and #9, respectively.
Publisher Copyright:
© 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy
PY - 2023/9
Y1 - 2023/9
N2 - Objectives: Antimicrobial resistance is a major global threat. Because of the stagnant antibiotic pipeline, synergistic antibiotic combination therapy has been proposed to treat rapidly emerging multidrug-resistant (MDR) pathogens. We investigated antimicrobial synergy of polymyxin/rifampicin combination against MDR Acinetobacter baumannii. Methods: In vitro static time-kill studies were performed over 48 h at an initial inoculum of ∼107 CFU/mL against three polymyxin-susceptible but MDR A. baumannii isolates. Membrane integrity was examined at 1 and 4 h post-treatment to elucidate the mechanism of synergy. Finally, a semi-mechanistic PK/PD model was developed to simultaneously describe the time course of bacterial killing and prevention of regrowth by mono- and combination therapies. Results: Polymyxin B and rifampicin alone produced initial killing against MDR A. baumannii but were associated with extensive regrowth. Notably, the combination showed synergistic killing across all three A. baumannii isolates with bacterial loads below the limit of quantification for up to 48 h. Membrane integrity assays confirmed the role of polymyxin-driven outer membrane remodelling in the observed synergy. Subsequently, the mechanism of synergy was incorporated into a PK/PD model to describe the enhanced uptake of rifampicin due to polymyxin-induced membrane permeabilisation. Simulations with clinically utilised dosing regimens confirmed the therapeutic potential of this combination, particularly in the prevention of bacterial regrowth. Finally, results from a neutropenic mouse thigh infection model confirmed the in vivo synergistic killing of the combination against A. baumannii AB5075. Conclusion: Our results showed that polymyxin B combined with rifampicin is a promising option to treat bloodstream and tissue infection caused by MDR A. baumannii and warrants clinical evaluations.
AB - Objectives: Antimicrobial resistance is a major global threat. Because of the stagnant antibiotic pipeline, synergistic antibiotic combination therapy has been proposed to treat rapidly emerging multidrug-resistant (MDR) pathogens. We investigated antimicrobial synergy of polymyxin/rifampicin combination against MDR Acinetobacter baumannii. Methods: In vitro static time-kill studies were performed over 48 h at an initial inoculum of ∼107 CFU/mL against three polymyxin-susceptible but MDR A. baumannii isolates. Membrane integrity was examined at 1 and 4 h post-treatment to elucidate the mechanism of synergy. Finally, a semi-mechanistic PK/PD model was developed to simultaneously describe the time course of bacterial killing and prevention of regrowth by mono- and combination therapies. Results: Polymyxin B and rifampicin alone produced initial killing against MDR A. baumannii but were associated with extensive regrowth. Notably, the combination showed synergistic killing across all three A. baumannii isolates with bacterial loads below the limit of quantification for up to 48 h. Membrane integrity assays confirmed the role of polymyxin-driven outer membrane remodelling in the observed synergy. Subsequently, the mechanism of synergy was incorporated into a PK/PD model to describe the enhanced uptake of rifampicin due to polymyxin-induced membrane permeabilisation. Simulations with clinically utilised dosing regimens confirmed the therapeutic potential of this combination, particularly in the prevention of bacterial regrowth. Finally, results from a neutropenic mouse thigh infection model confirmed the in vivo synergistic killing of the combination against A. baumannii AB5075. Conclusion: Our results showed that polymyxin B combined with rifampicin is a promising option to treat bloodstream and tissue infection caused by MDR A. baumannii and warrants clinical evaluations.
KW - Model-informed dose optimisation
KW - Multidrug-resistant Acinetobacter baumannii
KW - Pharmacokinetics/pharmacodynamics
KW - Polymyxin
KW - Rifampicin
KW - Semi-mechanistic PK/PD model
UR - https://www.scopus.com/pages/publications/85168799644
U2 - 10.1016/j.ijantimicag.2023.106902
DO - 10.1016/j.ijantimicag.2023.106902
M3 - Article
C2 - 37380093
AN - SCOPUS:85168799644
SN - 0924-8579
VL - 62
JO - International Journal of Antimicrobial Agents
JF - International Journal of Antimicrobial Agents
IS - 3
M1 - 106902
ER -
SDG 3 Good Health and Well-being