Targeting MDR hetero-resistant Gram-negatives: PK/PD for rational combinations

Summary

Principal Investigator: Francesca Incardona
Abstract: DESCRIPTION (provided by applicant): The Gram-negative bacteria Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae are causing significant problems in the USA and other parts of the world. These bacteria are opportunistic pathogens that cause pneumonia and other serious infections in critically-ill patients and those with impaired immune systems. Because these bacteria are increasingly displaying high levels of resistance to almost all currently available antibiotics and because of the shortage of new antibiotics coming into clinical use, clinicians are often left with little option but to use colistin, which is an antibiotic of the polymyxin class. Colistin first came onto the market nearly 50 years ago and has been used relatively rarely, until recent times. Unfortunately, although the resistance rates to colistin are much lower than for other antibiotics, there is mounting evidence that resistance to colistin is increasing. Since colistin is, in essence, the 'last-line'antibiotic for treatment of many infections, resistance to it implies resistance to virtually all antibiotics. It has become clear that even bacteria that seem to be susceptible to colistin harbor a highly colistin-resistant sub-population. Exposure to colistin leads to death of the susceptible bacteria in the total population, but unfortunately this leads to a situation where the highly colistin-resistant bacteria multiply to much larger numbers. Although two or more antibiotics are often prescribed in an attempt to overcome antibiotic resistance, this has been an empiric clinical practice, based on little or no evidence. The central aim of the present project is to use a series of very systematic studies to identify antibiotics that can be prescribed together with colistin to kill all members of the total bacterial population. The research strategy starts with the novel approach of identifying other antibiotics that are most active against the colistin-resistant sub-population of bacteria, as there is good evidence that the sub-population may be much more susceptible than previously thought to other antibiotics. These experiments are followed by screening of combinations, involving colistin and many other antibiotics, to determine which combinations and relative concentrations result in the highest activity. Then, a systematic series of in vitro studies will be conducted to simulate the conditions of infection and drug concentrations in the human body to devise regimens that optimize the combination regimens (each involving colistin plus another antibiotic) that most effectively kill both the colistin-susceptible and the colistin-resistant bacteria. Finally, once an optimal regimen is determined in vitro, animal studies will be performed to provide proof of concept. Each progressive stage in the research plan provides key information to develop understanding of the combinations and is driven by the development of mathematical mechanistic models to guide the optimization process. The outcome will be identification and optimization of colistin combination regimens to prevent amplification of resistant sub- populations in the very troublesome Gram-negative bacteria above. The world is facing an enormous and growing threat from the emergence of bacteria that are resistant to almost all available antibiotics and in the past two decades there has been a marked decline in discovery of novel antibiotics. As described in the 'Bad Bugs, No Drugs'paper published by the Infectious Diseases Society of America, "as antibiotic discovery stagnates, a public health crisis brews". This highlights the relevance of the current project which aims to preserve the usefulness of colistin through the study of novel approaches in the fight against very difficult to treat infections caused by Gram-negative bacteria to minimize the emergence of resistance.
Funding Period: ----------------2008 - ---------------2012-
more information: NIH RePORT

Top Publications

  1. pmc Development and validation of a liquid chromatography-mass spectrometry assay for polymyxin B in bacterial growth media
    Soon Ee Cheah
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University Parkville Campus, 381 Royal Parade, Parkville, Victoria 3052, Australia
    J Pharm Biomed Anal 92:177-82. 2014
  2. pmc Structure-activity relationships for the binding of polymyxins with human α-1-acid glycoprotein
    Mohammad A K Azad
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia
    Biochem Pharmacol 84:278-91. 2012
  3. pmc Interaction of colistin and colistin methanesulfonate with liposomes: colloidal aspects and implications for formulation
    Stephanie J Wallace
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
    J Pharm Sci 101:3347-59. 2012
  4. pmc The combination of colistin and doripenem is synergistic against Klebsiella pneumoniae at multiple inocula and suppresses colistin resistance in an in vitro pharmacokinetic/pharmacodynamic model
    Zakuan Z Deris
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
    Antimicrob Agents Chemother 56:5103-12. 2012
  5. pmc Pharmacokinetics and pharmacodynamics of 'old' polymyxins: what is new?
    Phillip J Bergen
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
    Diagn Microbiol Infect Dis 74:213-23. 2012
  6. doi Molecular basis for the increased polymyxin susceptibility of Klebsiella pneumoniae strains with under-acylated lipid A
    Tony Velkov
    Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
    Innate Immun 19:265-77. 2013
  7. doi 'Old' antibiotics for emerging multidrug-resistant bacteria
    Phillip J Bergen
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Melbourne, Australia
    Curr Opin Infect Dis 25:626-33. 2012
  8. pmc Drug-binding energetics of human α-1-acid glycoprotein assessed by isothermal titration calorimetry and molecular docking simulations
    Johnny X Huang
    Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
    J Mol Recognit 25:642-56. 2012
  9. pmc Pharmacology of polymyxins: new insights into an 'old' class of antibiotics
    Tony Velkov
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, 381 Royal Parade Parkville 3052, Victoria, Australia
    Future Microbiol 8:711-24. 2013
  10. pmc Synergistic activity of colistin and rifampin combination against multidrug-resistant Acinetobacter baumannii in an in vitro pharmacokinetic/pharmacodynamic model
    Hee Ji Lee
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
    Antimicrob Agents Chemother 57:3738-45. 2013

Scientific Experts

  • Roger L Nation
  • Jian Li
  • Phillip J Bergen
  • Tony Velkov
  • Jurgen B Bulitta
  • Rachel L Soon
  • Alan Forrest
  • Brian T Tsuji
  • Rajesh V Dudhani
  • Johnny X Huang
  • Mohammad A K Azad
  • Matthew A Cooper
  • Hee Ji Lee
  • Philip E Thompson
  • Neang S Ly
  • Jumana M Yousef
  • Stephanie J Wallace
  • Ian Larson
  • Mark A Baker
  • Zakuan Z Deris
  • David L Paterson
  • Soon Ee Cheah
  • Gauri G Rao
  • Kade D Roberts
  • Kade Roberts
  • Cornelia B Landersdorfer
  • Gong Chen
  • Prue A Hill
  • Jovan Jacob
  • Richard J Prankerd
  • Hanna E Sidjabat
  • Marina Harper
  • Ben J Boyd
  • Ben Adler
  • John D Boyce
  • Jenny C Yang
  • Lauren M Lim
  • John D Turnidge
  • Ben Boyd
  • Patricia N Holden
  • Lisa M Kaminskas
  • Mark Butler
  • Curtis E Haas
  • Yao Da Dong
  • Pamela A Kelchlin
  • Samira Garonzik
  • Sivashangarie Sivanesan
  • Brian Tsuji
  • Richard A Strugnell
  • Abigail Clements
  • Pei L Chong
  • Caron K Ku
  • Heidi H Yu
  • Anima Poudyal
  • Kathryn Davis
  • Miao Zhao
  • Jing Zhang
  • Jenny Yang
  • Chun Hong Tan
  • Rashmi Kancharla
  • Francis Chiu
  • Stewart Cockram
  • Jennifer H Moffatt
  • Craig R Rayner
  • Neang Ly
  • Dana Anderson
  • Liliana Yohonn
  • Laurie Macander
  • Robert W Milne
  • Silvia V Brown
  • Rebecca E D'Hondt
  • Kingsley Coulthard
  • William J Jusko
  • Anthony Jarkowski
  • Patrick G Hartley

Detail Information

Publications31

  1. pmc Development and validation of a liquid chromatography-mass spectrometry assay for polymyxin B in bacterial growth media
    Soon Ee Cheah
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University Parkville Campus, 381 Royal Parade, Parkville, Victoria 3052, Australia
    J Pharm Biomed Anal 92:177-82. 2014
    ..The accuracy, precision and cost-efficiency of the assay make it ideally suited to quantifying polymyxin B in samples from in vitro pharmacodynamic models. ..
  2. pmc Structure-activity relationships for the binding of polymyxins with human α-1-acid glycoprotein
    Mohammad A K Azad
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia
    Biochem Pharmacol 84:278-91. 2012
    ..Collectively, the data are consistent with a role of this acute-phase reactant protein in the transport of polymyxins in plasma...
  3. pmc Interaction of colistin and colistin methanesulfonate with liposomes: colloidal aspects and implications for formulation
    Stephanie J Wallace
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
    J Pharm Sci 101:3347-59. 2012
    ....
  4. pmc The combination of colistin and doripenem is synergistic against Klebsiella pneumoniae at multiple inocula and suppresses colistin resistance in an in vitro pharmacokinetic/pharmacodynamic model
    Zakuan Z Deris
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
    Antimicrob Agents Chemother 56:5103-12. 2012
    ..This investigation provides important information for optimization of colistin-doripenem combinations...
  5. pmc Pharmacokinetics and pharmacodynamics of 'old' polymyxins: what is new?
    Phillip J Bergen
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
    Diagn Microbiol Infect Dis 74:213-23. 2012
    ..We must pursue rational approaches to the use of polymyxins and other existing antibiotics through the application of PK/PD principles...
  6. doi Molecular basis for the increased polymyxin susceptibility of Klebsiella pneumoniae strains with under-acylated lipid A
    Tony Velkov
    Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
    Innate Immun 19:265-77. 2013
    ..Under-acylation appears to facilitate the integration of the N-terminal fatty-acyl chain of polymyxin into the OM resulting in an increased susceptibility to its antimicrobial activity/activities...
  7. doi 'Old' antibiotics for emerging multidrug-resistant bacteria
    Phillip J Bergen
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Melbourne, Australia
    Curr Opin Infect Dis 25:626-33. 2012
    ..This review focuses on colistin as an exemplar of a successful redevelopment process and briefly discusses two other old antibiotics, fusidic acid and fosfomycin...
  8. pmc Drug-binding energetics of human α-1-acid glycoprotein assessed by isothermal titration calorimetry and molecular docking simulations
    Johnny X Huang
    Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
    J Mol Recognit 25:642-56. 2012
    ....
  9. pmc Pharmacology of polymyxins: new insights into an 'old' class of antibiotics
    Tony Velkov
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, 381 Royal Parade Parkville 3052, Victoria, Australia
    Future Microbiol 8:711-24. 2013
    ..Before new antibiotics become available, we must optimize the clinical use of polymyxins through the application of pharmacokinetic/pharmacodynamic principles, thereby minimizing the development of resistance...
  10. pmc Synergistic activity of colistin and rifampin combination against multidrug-resistant Acinetobacter baumannii in an in vitro pharmacokinetic/pharmacodynamic model
    Hee Ji Lee
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
    Antimicrob Agents Chemother 57:3738-45. 2013
    ..Our study provides important information for optimizing colistin-rifampin combinations against colistin-susceptible and -resistant MDR A. baumannii...
  11. ncbi Surface changes and polymyxin interactions with a resistant strain of Klebsiella pneumoniae
    Tony Velkov
    1Drug Development and Innovation, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Vic, Australia
    Innate Immun 20:350-63. 2014
    ..pneumoniae can block the electrostatically driven first stage of polymyxin action, which thereby renders the hydrophobically driven second tier of polymyxin action on the outer membrane inconsequential. ..
  12. pmc New dosing strategies for an old antibiotic: pharmacodynamics of front-loaded regimens of colistin at simulated pharmacokinetics in patients with kidney or liver disease
    Gauri G Rao
    Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA
    Antimicrob Agents Chemother 58:1381-8. 2014
    ..Our findings may have important clinical implications, as front-loading polymyxins as a part of a combination regimen may be a viable strategy for aggressive treatment of high-bacterial-burden infections...
  13. pmc Effect of colistin exposure and growth phase on the surface properties of live Acinetobacter baumannii cells examined by atomic force microscopy
    Rachel L Soon
    Facility for Anti Infective Drug Development and Innovation, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
    Int J Antimicrob Agents 38:493-501. 2011
    ..These studies, conducted for the first time on live A. baumannii cells in liquid, have contributed to our understanding of the action of colistin in this problematic pathogen...
  14. pmc Synergistic killing of multidrug-resistant Pseudomonas aeruginosa at multiple inocula by colistin combined with doripenem in an in vitro pharmacokinetic/pharmacodynamic model
    Phillip J Bergen
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
    Antimicrob Agents Chemother 55:5685-95. 2011
    ..Emergence of colistin-resistant subpopulations of ATCC 27853 was substantially reduced and delayed with combination therapy. This investigation provides important information for optimization of colistin-doripenem combinations...
  15. pmc Colistin in the 21st century
    Roger L Nation
    Facility for Anti Infective Drug Development and Innovation, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
    Curr Opin Infect Dis 22:535-43. 2009
    ..Despite its age, or because of its age, there has been a dearth of knowledge on its pharmacological and microbiological properties. This review focuses on recent studies aimed at optimizing the clinical use of this old antibiotic...
  16. pmc Elucidation of the pharmacokinetic/pharmacodynamic determinant of colistin activity against Pseudomonas aeruginosa in murine thigh and lung infection models
    Rajesh V Dudhani
    Facility for Anti Infective Drug Development and Innovation, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
    Antimicrob Agents Chemother 54:1117-24. 2010
    ..The findings of this in vivo study indicate the importance of achieving adequate time-averaged exposure to colistin. The results will facilitate efforts to define the more rational design of dosage regimens for humans...
  17. pmc Attenuation of colistin bactericidal activity by high inoculum of Pseudomonas aeruginosa characterized by a new mechanism-based population pharmacodynamic model
    Jurgen B Bulitta
    School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260, USA
    Antimicrob Agents Chemother 54:2051-62. 2010
    ..aeruginosa by colistin were markedly decreased at high CFUo compared to those at low CFUo. This was well described by a mechanism-based mathematical model, which should be further validated using dynamic in vitro models...
  18. pmc Self-assembly behavior of colistin and its prodrug colistin methanesulfonate: implications for solution stability and solubilization
    Stephanie J Wallace
    Facility for Anti Infective Drug Development and Innovation, Monash Institute of Pharmaceutical Sciences, Parkville, Melbourne, Victoria 3052, Australia
    J Phys Chem B 114:4836-40. 2010
    ..The formation of colistin and CMS micelles demonstrated in this study is the proposed mechanism for solubilization of azithromycin and the concentration-dependent stability of CMS...
  19. pmc Evaluating the stability of colistin and colistin methanesulphonate in human plasma under different conditions of storage
    Rajesh V Dudhani
    Facility for Anti Infective Drug Development and Innovation, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
    J Antimicrob Chemother 65:1412-5. 2010
    ..The purpose of this study was to assess the stability of colistin and colistin methanesulphonate (CMS) in human plasma under storage conditions typically used in clinical pharmacokinetic (PK) and PK/pharmacodynamic (PD) investigations...
  20. pmc fAUC/MIC is the most predictive pharmacokinetic/pharmacodynamic index of colistin against Acinetobacter baumannii in murine thigh and lung infection models
    Rajesh V Dudhani
    Facility for Anti Infective Drug Development and Innovation, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
    J Antimicrob Chemother 65:1984-90. 2010
    ....
  21. pmc Pharmacokinetic/pharmacodynamic investigation of colistin against Pseudomonas aeruginosa using an in vitro model
    Phillip J Bergen
    Facility for Anti Infective Drug Development and Innovation, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
    Antimicrob Agents Chemother 54:3783-9. 2010
    ..6 and 30.4, 27.1 and 35.7, and 5.04 and 6.81 for ATCC 27853, PAO1, and 19056 muc, respectively. The PK/PD targets identified will assist in designing optimal dosing strategies for colistin...
  22. pmc Design, synthesis, and evaluation of a new fluorescent probe for measuring polymyxin-lipopolysaccharide binding interactions
    Rachel L Soon
    Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
    Anal Biochem 409:273-83. 2011
    ..Dansyl[Lys]¹polymyxin B₃ may prove useful as a screening tool for drug development...
  23. pmc Different surface charge of colistin-susceptible and -resistant Acinetobacter baumannii cells measured with zeta potential as a function of growth phase and colistin treatment
    Rachel L Soon
    Facility for Anti Infective Drug Development and Innovation, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria, Australia
    J Antimicrob Chemother 66:126-33. 2011
    ..baumannii strains. Our aim was to determine the surface charge of colistin-susceptible and -resistant A. baumannii as a function of growth phase and in response to polymyxin treatment...
  24. doi Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing
    Lauren M Lim
    Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences Buffalo, and the New York State Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, Buffalo, New York 14260, USA
    Pharmacotherapy 30:1279-91. 2010
    ..Further research is needed to fully understand the impact that the two regulatory systems have on resistance, as well as the dosages of colistin needed to inhibit and overcome these developing patterns...
  25. pmc Melatonin attenuates colistin-induced nephrotoxicity in rats
    Jumana M Yousef
    Facility for Anti Infective Drug Development and Innovation, Drug Delivery, Disposition, and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
    Antimicrob Agents Chemother 55:4044-9. 2011
    ..It also highlights the potential of coadministering an antioxidant to widen the therapeutic window of this very important last-line antibiotic...
  26. pmc Dosing of colistin-back to basic PK/PD
    Phillip J Bergen
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
    Curr Opin Pharmacol 11:464-9. 2011
    ..Recent data suggest the current dosage regimens of CMS are suboptimal in many critically ill patients...
  27. pmc Impact of two-component regulatory systems PhoP-PhoQ and PmrA-PmrB on colistin pharmacodynamics in Pseudomonas aeruginosa
    Neang S Ly
    Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA
    Antimicrob Agents Chemother 56:3453-6. 2012
    ..718 mg/liter) (P < 0.05). An in vitro pharmacodynamic model simulating human colistin regimens displayed initial killing followed by regrowth in the phoP mutant and gradual regrowth in the pmrA mutant and wild type...
  28. pmc Ascorbic acid protects against the nephrotoxicity and apoptosis caused by colistin and affects its pharmacokinetics
    Jumana M Yousef
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
    J Antimicrob Chemother 67:452-9. 2012
    ..This study aimed to examine the nephroprotective effect of ascorbic acid against colistin-induced nephrotoxicity...
  29. pmc Clinically relevant plasma concentrations of colistin in combination with imipenem enhance pharmacodynamic activity against multidrug-resistant Pseudomonas aeruginosa at multiple inocula
    Phillip J Bergen
    Facility for Anti Infective Drug Development and Innovation, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
    Antimicrob Agents Chemother 55:5134-42. 2011
    ..This systematic study provides important information for optimization of colistin-imipenem combinations targeting both colistin-susceptible and colistin-resistant subpopulations...
  30. pmc Atomic force microscopy investigation of the morphology and topography of colistin-heteroresistant Acinetobacter baumannii strains as a function of growth phase and in response to colistin treatment
    Rachel L Soon
    Facility for Anti Infective Drug Development and Innovation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
    Antimicrob Agents Chemother 53:4979-86. 2009
    ..baumannii strains. These results contribute to an understanding of colistin action and resistance in regard to this problematic pathogen...