Resistance Suppression for P. Aeruginosa using Novel Combination Therapy Modeling

Summary

Principal Investigator: GEORGE LOUIS DRUSANO
Affiliation: Ordway Research Institute
Country: USA
Abstract: Pseudomonas aeruginosa is a major cause of morbidity and mortality in the ICU, particularly among patients with Ventilator-Associated Pneumonia. Many isolates are multi-drug resistant and some isolates are resistant to all currently extant anti-infective agents. There are currently no new antibiotics in clinical development (in man) with novel mechanisms of action against Pseudomonas. Given the cycle time associated with new drug development, it is likely that no antibiotics with new mechanisms of action for this pathogen will arise for 5 - 7 years. Thus, we must generate new knowledge about how best to suppress antibiotic resistance for this pathogen. This will help preserve our current drugs while we await new agents. Also, when agents with new mechanisms of action become available they can be developed in an optimal fashion for resistance suppression, both as monotherapy and in combination. In this application (Specific Aim #1), we hypothesize that we can identify optimal doses and schedules of administration for monotherapy for resistance suppression by studying this pathogen in our Hollow Fiber Infection Model (HFIM) and fitting a large mathematical model to the HFIM data to identify these doses and schedules. We further hypothesize that different resistance mechanisms will alter optimal doses and schedules. We propose to study isogenic mutants of the wild-type P. aeruginosa PAO-1 isolate, each containing a defined resistance mechanism. These findings will be bridged to man through use of Monte Carlo simulation (MCS). In Specific Aim #2, we propose to examine drugs in combination chemotherapy. We have developed a completely novel mathematical model that allows description of the impact of two drug combination chemotherapy on isolates of P. aeruginosa. This model is a mixture model and allows the fitting of the model to the concentration-time course of both agents as well as to fit the model to the disparate changes over time wrought by the combination of agents on the susceptible and less-susceptible populations of organisms present. Robust identification of the parameters of this system will allow calculation of optimal combination regimens for resistance suppression. Such regimens will be bridged to man through the use of MCS, as above. The HFIM is an in vitro system. In Specific Aim #3, we will also validate these optimal and non-optimal regimens in a neutropenic mouse pneumonia model, employing the same isolates studied in vitro in Aims #1 and #2. In examining this, we will use "humanized" dosing for the regimens, so that differences between mouse and human pharmacokinetics will not drive an improper inference. This will be done for both mono- and combination therapy. Prospective validation experiments will be designed and carried out. Results will be compared with the in vitro findings and also bridged to man. In so doing robust principles will be defined for drug regimens that will suppress amplification of resistant mutant populations. Pseudomonas aeruginosa is a pathogen of major importance in the Intensive Care Unit and is often resistant to many or even all of the drugs in our therapeutic armamentarium. As no agents with a unique mechanism of action active against Pseudomonas are expected for at least 7 years, it is imperative to learn how to use our currently available agents in a way that suppresses emergence of resistance and keeps these agents active for our patients. We plan to do this by 1) understanding the optimal way to dose Pseudomonas-active drugs in our hollow fiber infection model (HFIM) to suppress resistance and delineate the impact of different resistance mechanisms on this process 2) understand how to administer these drugs in combination in the HFIM to optimally suppress resistance emergence 3) validate the in vitro findings from the HFIM in a mouse model of Pseudomonas aeruginosa pneumonia.
Funding Period: ----------------2008 - ---------------2012-
more information: NIH RePORT

Top Publications

  1. pmc Impact of meropenem in combination with tobramycin in a murine model of Pseudomonas aeruginosa pneumonia
    Arnold Louie
    Department of Medicine, Institute for Therapeutic Innovation, College of Medicine, University of Florida, Gainesville, Florida, USA
    Antimicrob Agents Chemother 57:2788-92. 2013
  2. pmc Resistance emergence mechanism and mechanism of resistance suppression by tobramycin for cefepime for Pseudomonas aeruginosa
    G L Drusano
    Ordway Research Institute, Albany, New York, USA
    Antimicrob Agents Chemother 56:231-42. 2012
  3. pmc Meropenem penetration into epithelial lining fluid in mice and humans and delineation of exposure targets
    G L Drusano
    Ordway Research Institute, Albany, New York 12208, USA
    Antimicrob Agents Chemother 55:3406-12. 2011
  4. pmc Saturability of granulocyte kill of Pseudomonas aeruginosa in a murine model of pneumonia
    G L Drusano
    Ordway Research Institute, 150 New Scotland Ave, Albany, NY 12208, USA
    Antimicrob Agents Chemother 55:2693-5. 2011
  5. pmc Optimization of aminoglycoside therapy
    G L Drusano
    Ordway Research Institute, 150 New Scotland Ave, Albany, NY 12208, USA
    Antimicrob Agents Chemother 55:2528-31. 2011
  6. pmc Penetration of meropenem into epithelial lining fluid of patients with ventilator-associated pneumonia
    T P Lodise
    Ordway Research Institute, Albany, NY 12208, USA
    Antimicrob Agents Chemother 55:1606-10. 2011
  7. pmc Impact of burden on granulocyte clearance of bacteria in a mouse thigh infection model
    G L Drusano
    Ordway Research Institute, Albany, NY 12208, USA
    Antimicrob Agents Chemother 54:4368-72. 2010
  8. pmc The combination of meropenem and levofloxacin is synergistic with respect to both Pseudomonas aeruginosa kill rate and resistance suppression
    Arnold Louie
    Ordway Research Institute, Albany, NY 12208, USA
    Antimicrob Agents Chemother 54:2646-54. 2010
  9. pmc Impact of different carbapenems and regimens of administration on resistance emergence for three isogenic Pseudomonas aeruginosa strains with differing mechanisms of resistance
    Arnold Louie
    Ordway Research Institute, Albany, NY 12208, USA
    Antimicrob Agents Chemother 54:2638-45. 2010
  10. pmc Pharmacodynamics of levofloxacin in a murine pneumonia model of Pseudomonas aeruginosa infection: determination of epithelial lining fluid targets
    Arnold Louie
    Emerging Infections and Pharmacodynamics Laboratory, Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208, USA
    Antimicrob Agents Chemother 53:3325-30. 2009

Scientific Experts

  • G L Drusano
  • Arnold Louie
  • Weiguo Liu
  • Robert Kulawy
  • David Brown
  • T P Lodise
  • Brian Van Scoy
  • Christine Fregeau
  • Steven Fikes
  • D Melnick
  • F Sorgel
  • B Mason
  • M Kinzig
  • Nadzeya Bahniuk
  • Mohammed Khashab
  • Karen Bush
  • Susan Nicholson
  • Brian Morrow
  • James B Kahn
  • Adam Bied
  • Caroline Grasso
  • David L Brown
  • Anne Marie Queenan

Detail Information

Publications12

  1. pmc Impact of meropenem in combination with tobramycin in a murine model of Pseudomonas aeruginosa pneumonia
    Arnold Louie
    Department of Medicine, Institute for Therapeutic Innovation, College of Medicine, University of Florida, Gainesville, Florida, USA
    Antimicrob Agents Chemother 57:2788-92. 2013
    ..Combination therapy produced additive drug interaction and suppressed all resistance amplification. It is likely that optimal therapy for Pseudomonas aeruginosa pneumonia will involve a combination of agents...
  2. pmc Resistance emergence mechanism and mechanism of resistance suppression by tobramycin for cefepime for Pseudomonas aeruginosa
    G L Drusano
    Ordway Research Institute, Albany, New York, USA
    Antimicrob Agents Chemother 56:231-42. 2012
    ..For P. aeruginosa resistance suppression, combination therapy is critical...
  3. pmc Meropenem penetration into epithelial lining fluid in mice and humans and delineation of exposure targets
    G L Drusano
    Ordway Research Institute, Albany, New York 12208, USA
    Antimicrob Agents Chemother 55:3406-12. 2011
    ..Combination chemotherapy is likely required in humans if we are to minimize resistance emergence in Pseudomonas aeruginosa pneumonia. This combination needs evaluation both in the murine pneumonia model and in humans...
  4. pmc Saturability of granulocyte kill of Pseudomonas aeruginosa in a murine model of pneumonia
    G L Drusano
    Ordway Research Institute, 150 New Scotland Ave, Albany, NY 12208, USA
    Antimicrob Agents Chemother 55:2693-5. 2011
    ..These findings suggest the need for aggressive chemotherapy early in the treatment of VAP to keep the burden from saturating the granulocytes. This should optimize the outcome for these seriously infected patients...
  5. pmc Optimization of aminoglycoside therapy
    G L Drusano
    Ordway Research Institute, 150 New Scotland Ave, Albany, NY 12208, USA
    Antimicrob Agents Chemother 55:2528-31. 2011
    ..Furthermore, daily administration is much preferred, and stopping therapy as quickly as possible (a week or less may be optimal) will contribute to the ability to optimize therapy...
  6. pmc Penetration of meropenem into epithelial lining fluid of patients with ventilator-associated pneumonia
    T P Lodise
    Ordway Research Institute, Albany, NY 12208, USA
    Antimicrob Agents Chemother 55:1606-10. 2011
    ....
  7. pmc Impact of burden on granulocyte clearance of bacteria in a mouse thigh infection model
    G L Drusano
    Ordway Research Institute, Albany, NY 12208, USA
    Antimicrob Agents Chemother 54:4368-72. 2010
    ..aureus. Bacterial kill by granulocytes is saturable. No difference between saturation points of different isolates was seen. A higher bacterial burden means an increasing reliance on chemotherapy to drive bacterial clearance...
  8. pmc The combination of meropenem and levofloxacin is synergistic with respect to both Pseudomonas aeruginosa kill rate and resistance suppression
    Arnold Louie
    Ordway Research Institute, Albany, NY 12208, USA
    Antimicrob Agents Chemother 54:2646-54. 2010
    ..This combination should be evaluated in a clinical trial...
  9. pmc Impact of different carbapenems and regimens of administration on resistance emergence for three isogenic Pseudomonas aeruginosa strains with differing mechanisms of resistance
    Arnold Louie
    Ordway Research Institute, Albany, NY 12208, USA
    Antimicrob Agents Chemother 54:2638-45. 2010
    ..For the wild-type organism, the 1-g, 4-h infusion regimen is preferred. For organisms with resistance mutations, larger doses or addition of a second drug should be studied...
  10. pmc Pharmacodynamics of levofloxacin in a murine pneumonia model of Pseudomonas aeruginosa infection: determination of epithelial lining fluid targets
    Arnold Louie
    Emerging Infections and Pharmacodynamics Laboratory, Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208, USA
    Antimicrob Agents Chemother 53:3325-30. 2009
    ..More isolates need to be studied to make these observations more robust...
  11. pmc Differing effects of combination chemotherapy with meropenem and tobramycin on cell kill and suppression of resistance of wild-type Pseudomonas aeruginosa PAO1 and its isogenic MexAB efflux pump-overexpressed mutant
    G L Drusano
    Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208, USA
    Antimicrob Agents Chemother 53:2266-73. 2009
    ..When resistance suppression is explored by combination chemotherapy, it is important to examine the impacts of differing resistance mechanisms for both agents...
  12. doi Impact of short-course quinolone therapy on susceptible and resistant populations of Staphylococcus aureus
    G L Drusano
    Emerging Infections and Host Defense Laboratory, Ordway Research Institute, Albany, New York 12208, USA
    J Infect Dis 199:219-26. 2009
    ..Ultimately, the susceptible population became dominant by day 13. Modeling demonstrated that the resistant isolates grew more slowly and had a higher natural death rate...