Multidrug-resistant Gram-negative 'superbugs' are causing a global health crisis. Due to a marked decline in the discovery of antibiotics and the current shortage of new antibiotics, clinicians are often left with little option but to use the polymyxins (polymyxin B and colistin, i.e. polymyxin E). Polymyxins first came onto the market more than 50 years ago and have been used rarely, until recent times. Unfortunately, there is mounting evidence that resistance to polymyxins is increasing. A major factor promoting resistance is that plasma concentrations of polymyxins at recommended daily doses are sub-optimal in a significant proportion of critically-ill patients. Unfortunately, simply increasing th polymyxin daily dose is not an option because kidney toxicity (up to 60% incidence with current regimens) is the major dose-limiting adverse effect. Emergence of resistance to polymyxins is a significant risk with monotherapy and, because of the 'last-line' status, implies resistance to all current antibiotics. This highlights the urgent need to explore novel, highly active dosing strategies with polymyxin combinations. The central aim of the present project is to evaluate novel dosing regimens for polymyxin combinations to maximize antibacterial activity and minimize emergence of resistance and toxicity. Our research strategy involves a systematic evaluation of the effectiveness of novel 'burst', 'front-loading' (e.g. high dose, short duration dosing at the beginning of therapy) and 'sequential' polymyxin combination dosing strategies. The research plan incorporates a multi-tiered approach across a range of in vitro and rabbit infection models. First, in vitro models will be used to simulate the conditions of infection and drug concentration-time profiles in the human body to devise combination dosing strategies that most effectively kill both polymyxin-susceptible and polymyxin-resistant bacteria. Next, promising dosing strategies for the polymyxin combinations will be tested for resistance suppression against clinical isolates in a hollow-fiber infection model. Cutting-edge genomics/transcriptomics/metabolomics studies will guide selection of optimal regimens by characterizing the global bacterial responses (including emergence of resistance) to the novel combination dosing strategies. Finally, prospective validation studies for our superior regimens will be conducted in 10-day immune-compromised and -competent rabbit infection models for prospective evaluation of resistance suppression and toxicity. Each progressive stage will provide key information to uniquely inform the development of innovative mechanism-based mathematical models that will be used to translate across all experimental tiers. The final translation will be performed by mechanism-based Monte Carlo Simulations to propose novel dosing strategies for polymyxin combinations that maximize antibacterial activity and minimize resistance and toxicity for future testing in humans.

Public Health Relevance

Gram-negative 'superbugs' resistant to all current antibiotics except the polymyxins are presenting a global health crisis. As highlighted in the 'Bad Bugs, No Drugs' paper by the Infectious Diseases Society of America, no new antibiotics will be available for these pathogens for many years to come. This highlights the significance of the current project which aims to preserve the usefulness of polymyxins through the study of novel dosing strategies for polymyxin combinations which optimally suppress resistance emergence and minimize nephrotoxicity against the Gram-negative 'superbugs'

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI111990-03
Application #
9034546
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Ernst, Nancy Lewis
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
038633251
City
Amherst
State
NY
Country
United States
Zip Code
14228
Landersdorfer, Cornelia B; Wang, Jiping; Wirth, Veronika et al. (2018) Pharmacokinetics/pharmacodynamics of systemically administered polymyxin B against Klebsiella pneumoniae in mouse thigh and lung infection models. J Antimicrob Chemother 73:462-468
Bulman, Zackery P; Ly, Neang S; Lenhard, Justin R et al. (2017) Influence of rhlR and lasR on Polymyxin Pharmacodynamics in Pseudomonas aeruginosa and Implications for Quorum Sensing Inhibition with Azithromycin. Antimicrob Agents Chemother 61:
Zhao, Miao; Bulman, Zackery P; Lenhard, Justin R et al. (2017) Pharmacodynamics of colistin and fosfomycin: a 'treasure trove' combination combats KPC-producing Klebsiella pneumoniae. J Antimicrob Chemother 72:1985-1990
Lenhard, Justin R; Bulitta, Jürgen B; Connell, Terry D et al. (2017) High-intensity meropenem combinations with polymyxin B: new strategies to overcome carbapenem resistance in Acinetobacter baumannii. J Antimicrob Chemother 72:153-165
Bulman, Zackery P; Satlin, Michael J; Chen, Liang et al. (2017) New Polymyxin B Dosing Strategies To Fortify Old Allies in the War against KPC-2-Producing Klebsiella pneumoniae. Antimicrob Agents Chemother 61:
Maifiah, Mohd Hafidz Mahamad; Creek, Darren J; Nation, Roger L et al. (2017) Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii. Sci Rep 7:45527
Smith, Nicholas M; Bulman, Zackery P; Sieron, Arthur O et al. (2017) Pharmacodynamics of dose-escalated 'front-loading' polymyxin B regimens against polymyxin-resistant mcr-1-harbouring Escherichia coli. J Antimicrob Chemother 72:2297-2303
Lenhard, Justin R; Thamlikitkul, Visanu; Silveira, Fernanda P et al. (2017) Polymyxin-resistant, carbapenem-resistant Acinetobacter baumannii is eradicated by a triple combination of agents that lack individual activity. J Antimicrob Chemother 72:1415-1420
Bulman, Zackery P; Chen, Liang; Walsh, Thomas J et al. (2017) Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and blaNDM-5: Preparation for a Postantibiotic Era. MBio 8:
Lenhard, Justin R; Smith, Nicholas M; Bulman, Zackery P et al. (2017) High-Dose Ampicillin-Sulbactam Combinations Combat Polymyxin-Resistant Acinetobacter baumannii in a Hollow-Fiber Infection Model. Antimicrob Agents Chemother 61:

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