The Emerging Infections and Host Defense Theme is currently organized into two laboratories:

• The Emerging Infections and Pharmacodynamics Laboratory
• Virology Therapeutics and Pharmacodynamics Laboratory

Each laboratory has several sections
(see Figure 1 below).

The Emerging Infections and Pharmacodynamics Laboratory is nationally and internationally recognized for its work in applying cutting-edge, novel hollow fiber pharmacodynamic and animal infection models and mathematical methods to design dosing strategies for antibiotics that optimize their efficacies and minimize the probability that the infecting pathogens will become resistant to the antimicrobial agents during therapy. Much of the laboratory's work involves antibacterial and antifungal drugs for the treatment of hospital-acquired infections due to the bacteria Pseudomonas aeruginosa, Klebsiella pneumoniae, and multi-antibiotic resistant Staphylococcus aureus (MRSA) and the fungi Candida albicans, Candida glabrata, and Aspergillus species. Both commercially available and investigational antimicrobial agents are examined.

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. 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 recently embarked on 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 this combination may improve outcomes for infections due to S. pneumoniae 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.

The laboratory has completed studies examining the use of glucan synthase inhibitors and beta-cyclic amino acids in the treatment of disseminated candidemia in neutropenic animals. The dosing strategies that ere developed are currently being evaluated for use in the clinical arena. In the near future, the Emerging Infections and Host Defense Theme 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 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 recently awarded a 5 year $9.1 million program project grant (1 P01 AI060908-01A1) from the National Institutes of Health 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-investigators 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" throughout worldwide.

Under the guidance of Drs. Tawanda Gumbo and George Drusano, the laboratory has just 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. 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. Active collaboration is with Dr. Max Salfinger of the Wadsworth Center for Laboratories and Research (New York State Department of Health), and Dr G. Kadzirange and Professor I. Gangaidzo of the Department of Medicine at the University of Zimbabwe .

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. Additionally, Dr. McSharry has conducted studies with vaccinia virus (the surrogate for the potential bioterror agent smallpox); cytomegalovirus; influenza virus; and herpes simplex virus. Studies with influenza virus are timely given the rapid spread of the avian flu across the globe.

Figure 1

Principal Investigators for the Emerging Infections and Host Defense Theme

George L. Drusano, M.D.
Arnold Louie, M.D.
James J. McSharry, Ph.D.

Back to top