COM4S_M.TTF

Research Focus

The focus of the laboratory is to use cutting-edge, novel in-vitro hollow fiber pharmacodynamic and animal infection systems and mathematical models to define the dosage and frequency of administration of antibiotics that should be used clinically to optimize outcomes in human infections. While the members of the Emerging Infections and Pharmacodynamics Laboratory conduct studies using a diverse range of pathogens, Dr. Louie conducts studies primarily with the fungus Candida albicans and with the bacteria Streptococcus pneumoniae , Pseudomonas aeruginosa , Klebsiella pneumoniae , Mycobacterium tuberculosis , and multi-drug resistant Staphylococcus aureus. Candida albicans is associated with high morbidity and mortality in immunocompromised, hospitalized patients. The bacterial species of interest are increasingly resistant to an array of antibiotics.

Emergence of antibiotic resistance is a growing problem nationally and internationally. The laboratory is one of the few worldwide that uses infection and mathematical models to identify a minimum antibiotic exposure that should be used in order to prevent the selection of drug-resistant bacterial mutants during antibiotic therapy.

The laboratory is also actively conducting studies to expand the selection of antibiotics that may be useful for the treatment of infections due to potential agents of bioterrorism and biowarfare, including Bacillus anthracis and Yersinia pestis , the bacteria that cause anthrax and plague. Using novel in-vitro pharmacokinetic/pharmacodynamic and mathematical models, the laboratory has defined the dosage and dosing frequency of a fluoroquinolone antibiotic that should be used to maximize the efficacy of this drug, while preventing these bacteria from developing resistance to the antibiotic during therapy. The use of other agents for the treatment of anthrax and plague are actively being sought as part of a five year $9.1 million program project grant, funded by the National Institutes of Health.

Dr. Louie has also developed a hollow fiber model of F. tularensis infection, another potential agent of bioterrorism and biowarfare. The laboratory is evaluating and optimizing candidate drugs for the treatment of infections due to this pathogen.

The group is actively exploring the value of using two or more antibiotics in combination for the treatment of serious bacterial and fungal infections, as well as the potential benefit of administering antibiotics in combination with compounds that augment the effectiveness of the infected host’s own immune defenses as additional methods for improving treatment outcomes.

Selected Publications

• Louie A, Kaw P, Banerjee P, Liu W, Chen G, Miller MH. Impact of the Order of Initiation of Fluconazole and Amphotericin B in Sequential or Combination Therapies on Killing of Candida albicans In Vitro and in a Rabbit Model of Endocarditis and Pyelonephritis. Antimicrobial Agents and Chemotherapy 2001; 45: 485-494.
• Jumbe N, Louie A, Leary R, Liu W, Deziel M, Tam V, Bachhawat R, Freeman C, Kahn J, Bush K, Dudley M, Miller M, Drusano G. Application of a Mathematical Model to Prevent In-vivo Amplification of Antibiotic-Resistant Bacterial Populations during Therapy. Journal of Clinical Investigation 2003; 112: 275-285.
• Gumbo T, Louie A, Deziel MR, Parsons LM, Salfinger M, Drusano GL. Selection of a Moxifloxacin Dose that Suppresses Drug Resistance in Mycobacterium tuberculosis by Use of an In Vitro Pharmacodynamic Infection Model and Mathematical Modeling. Journal of Infectious Diseases 2004; 190: 1642-1651.
• Tam VH, Louie A, Deziel MR, Liu W, Leary R, Drusano GL. Bacterial–Population Responses to Drug-Selective Pressure: Examination of Garenoxacin’s Effect on Pseudomonas aeruginosa . Journal of Infectious Diseases 2005; 192: 420-428.
• Gumbo T, Louie A, Deziel MR, Drusano GL. Pharmacodynamic Evidence that Ciprofloxacin Failure against Tuberculosis Is Not due to Poor Microbial Kill But to Rapid Emergence of Resistance. Antimicrobial Agents and Chemotherapy 2005; 49: 3178-3181.
• Louie A, Deziel M, Liu W, Drusano MF, Gumbo T, Drusano GL. Pharmacodynamics of Caspofungin in a Murine Model of Systemic Candidiasis: Importance of Persistence of Caspofungin in Tissues to Understanding Drug Activity. Antimicrobial Agents and Chemotherapy 2005; 49: 5058-5068.
• Deziel MR, Heine H, Louie A, Kao M, Byrne WR, Basset J, Miller L, Bush K, Kelley M, Drusano GL. Effective Antimicrobial Regimens for Use in Humans for Therapy of Bacillus anthracis Infections and Postexposure Prophylaxis. Antimicrobial Agents and Chemotherapy 2005; 49: 5099-5106.
• Jumbe NL, Louie A, Miller MH, Liu W, Deziel MR, Tam VH, Bachhawat R, Drusano GL. Quinolone Efflux Pumps Play a Central Role in Emergence of Fluoroquinolone Resistance in Streptococcus pneumoniae . Antimicrobial Agents and Chemotherapy 2006; 50; 310-317.