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CENTER FOR BIODEFENSE & EMERGING INFECTIONS |
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PRINCIPAL INVESTIGATORS
Each laboratory has several sections (see Organizational Chart located at the end of this section).
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Using animal and in-vitro hollow fiber infection models, the group has also worked extensively to design antibiotic regimens to optimize outcomes and minimize emergence of resistance to therapies for the bacterium Streptococcus pneumoniae (S. pneumoniae). This bacterium is the most common cause of bacterial meningitis, community-acquired pneumonia, acute middle ear infection, and acute sinus infection. Worldwide, S. pneumoniae is becoming increasingly resistant to standard antibiotics including penicillin, erythromycin, tetracycline, and the sulfa drugs. Work has been done with new antibiotics before they become available to physicians. The laboratory has also developed hollow fiber infection models to examine the activity of established and novel agents for the treatment of community-acquired MRSA, Salmonella species, and Haemophilus influenzae.
The laboratory has completed studies examining the use of glucan synthase inhibitors and beta-lactam dosing strategies that were developed and are currently being evaluated for use in the clinical arena. In the near future, the Center for Biodefense and Emerging Infections will be evaluating the role of agents that augment the immune system as an adjunct to antibiotics as a means of improving outcomes of infections due to various pathogens, including the fungi Candida albicans and Candida glabrata. The Bacterial and Fungal Emerging Infections and Pharmacodynamics Laboratory is also interested in Biodefense. With Dr. Louie as project leader, the laboratory completed work using a novel in-vitro hollow fiber pharmacodynamic infection model to expand the available antibiotic armamentarium for the treatment of Bacillus anthracis, the bacterium that causes anthrax. Dr. Louie conducted similar studies with Yersinia pestis, the bacterium that causes plague. With these data, Dr. Louie and Dr. George Drusano were awarded a 5-year $9.1 million program project grant (1 P01 AI060908-01A1) from the National Institutes of Health in 2005 to use hollow fiber and animal infections systems together with mathematical modeling to identify and optimize candidate drugs for the treatment of anthrax and plague. Design of dosing regimens that minimize toxicity and minimize emergence of resistance during therapy are also emphasized. It should be noted that the Bacillus anthracis and Yersinia pestis bacterial strains that are used in the research conducted at Ordway Research Institute have been genetically altered such that they cannot cause disease in humans and other mammalian species. Studies using murine models of inhalational anthrax and plague pneumonia are being conducted by our co-investigator, Dr. Henry (Hank) Heine at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID, Maryland ). Hollow fiber infection models of Francisella tularensis and Salmonella infections have also been developed by the laboratory for evaluation and optimization of candidate therapeutics. These pathogens are potential agents of bioterrorism and biowarfare. Salmonella species are also important causes of “food poisoning” worldwide. One branch of our center focuses on optimal therapy and prevention of resistance in critically-ill patients with serious Pseudomonas aeruginosa or multidrug-resistant Staphylococcus aureus (MRSA) infections. While these patients are frequently immunocompromised, such infections often carry a high bacterial density, are difficult to treat due to an attenuated effect of many antibiotics at high bacterial densities, and pose a significant challenge to the immune system. Therefore, this patient group vitally needs optimal antibacterial therapy to achieve cure and to prevent emergence of resistance. As strongly emphasized by the ‘Bad Bugs, No Drugs’ and ‘Bad Bugs Need Drugs’ campaign of the Infectious Diseases Society of America (IDSA), new treatment options against multidrug-resistant pathogens such as P. aeruginosa are urgently needed. Dr Jürgen Bulitta has recently performed a series of studies to optimize bacterial killing for infections with high (and low) initial inocula of Pseudomonas aeruginosa and multidrug-resistant S. aureus (MRSA). These studies aim at identifying the mechanism why certain antibiotic combinations are able to achieve ‘synergistic killing’ and suppress re-growth of genotypically resistant or phenotypically tolerant sub-populations. Such regimens should be able to eradicate cells in log-growth phase, early and late stationary phase, as well as non-replicating persisters (NRPs). These studies included both antibiotics with small molecular weight and larger peptide antibiotics which may offer unique advantages in combination therapy. All these data are then combined to develop and prospectively ‘validate’ mechanism-based mathematical models within our Mathematical Modeling Core that can describe and predict the time course of bacterial killing, and emergence of phenotypically or genotypically distinct sub-populations. Ultimately, these models aim at designing and ‘validating’ optimized antibiotic regimens for mono- and combination therapy in patients based on a mechanistic understanding of antibiotic synergy in vitro and may greatly support and accelerate translation from in vitro infection models to animal and clinical trials. Under the guidance of Drs. Arnold Louie, Tawanda Gumbo (currently at Univ. of Texas Southwestern) and George Drusano, the laboratory has recently completed studies that identify antibiotic dosing strategies that optimize therapeutic outcome and minimize emergence of drug resistance in Mycobacterium tuberculosis, the organism that causes tuberculosis. Research has also been completed in the arena of re-examination of some of the dogmas that have been the cornerstone of anti-tuberculosis therapy for the last half a century. In 2007, Dr. George Drusano and colleagues received a two year grant from the Bill and Melinda Gates Foundation to apply pharmacodynamic principles to hollow fiber technology to identify treatment strategies that would optimize the rate of kill of M. tuberculosis that are in a non-replicating persister state and that would prevent emergence of resistance during therapy. These findings may have a profound impact on how anti-TB drugs are given in the future. These findings are currently being taken into the clinic. Dr. McSharry (Head of the Virology Therapeutics and Pharmacodynamics Laboratory ) and Dr. Drusano are also using a novel in-vitro hollow fiber infection model to evaluate new compounds as candidate agents for the treatment of Human Immunodeficiency Virus (HIV). Results from earlier studies demonstrated that this novel in-vitro infection model accurately predicts the efficacies of HIV drugs in man. These include the relative potential that various drug dosing regimens will select for drug-resistant viral populations. The virology team is actively developing a novel in vitro pharmacodynamic method for examining the antimicrobial activity of investigational compounds against Hepatitis C virus. Additionally, Dr. McSharry has conducted studies with vaccinia virus (the surrogate for the potential bioterror agent smallpox); cytomegalovirus; influenza virus; and herpes simplex virus. In 2008, the team was awarded a 4-year NIH grant to develop mono- and combination drug treatment strategies that would effectively treat influenza viral infections and would prevent the virus from becoming resistant to drug during the course of therapy. Studies with influenza virus are timely given the rapid spread of the avian flu across the globe. Organizational Chart for the Center for Biodefense and Emerging Infections
The Center for Biodefense and Emerging Infections team:
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The Bacterial and Fungal Emerging Infections and Pharmacodynamics Laboratory is nationally and internationally recognized for its work in applying cutting-edge, novel 
The laboratory conducted studies to evaluate the role of using agents that neutralize the effect of some resistance mechanisms in combination with antibiotics. The studies focus on how these combinations may improve outcomes for infections due to S. pneumoniae, Klebsiella pneumoniae, Pseudomonas aeruginosa, and S. aureus isolates that are resistant to certain classes of antibiotics and as an additional means for preventing emergence of drug resistance during therapy. In 2008 Drs. Drusano and Louie were awarded a 4-year NIH grant to use in vitro hollow fiber systems and mouse infection models in combination with mathematical modeling to examine the role and to develop combination therapies that would effectively kill P. aeruginosa and to prevent emergence of resistance during therapy.
