A novel anti-infective approach is to exploit stresses already imposed on invading organisms in vivo. Iron (Fe) metabolism is a key vulnerability of infecting bacteria because organisms require Fe for growth. We have shown that a strategy that uses the metal gallium (Ga) to disrupt bacterial Fe metabolism holds promise as an antimicrobial approach. Due to its chemical similarity to Fe, Ga can substitute for Fe in many biologic systems and inhibit Fe-dependent processes. Our data shows that Ga kills the opportunistic pathogen Pseudomonas aeruginosa (including antibiotic resistant strains), is active against biofilms, and treats 3 different models of P. aeruginosa infections. These data, the fact that gallium nitrate (trade name, Ganite"""""""") is Food and Drug Administration (FDA) approved for intravenous (IV) administration, and the dearth of new antibiotics in development make Ga a promising new therapeutic for P. aeruginosa infections. We have shown in our initial phase 1b study in patient with cystic fibrosis chronically infected with P. aeruginosa that IV Ga is safe, well tolerated, has a good pharmacokinetic profile and is associated with a clinically meaningful improvement in lung function 14 days and 28 days after the start of a 5 day infusion of IV Ga. Here we propose a proof of concept phase 2 clinical trial to confirm our prior findings of efficacy and provide further data regarding the safety and pharmacokinetics of IV Ga in CF subjects infected with P. aeruginosa. Chronic P. aeruginosa airway infections are the major cause of death in these patients and few treatments exist.

Public Health Relevance

Our data shows that gallium (Ga) kills the opportunistic pathogen Pseudomonas aeruginosa (including antibiotic resistant strains), is active against biofilms, and treats 3 different model P. aeruginosa infections. We have also shown that Ga is safe and well tolerated in our phase 1b study in cystic fibrosis (CF) with preliminary evidence of clinical efficacy. We propose to assess efficacy of Ga in a proof of concept randomized controlled trial in this patient population which if successful, could provide a novel agent to fight chronic infections with P. aeruginosa in other disease settings beyond CF.

Agency
National Institute of Health (NIH)
Institute
Food and Drug Administration (FDA)
Type
Research Project (R01)
Project #
2R01FD003704-03A1
Application #
8565239
Study Section
Special Emphasis Panel (ZFD1-OPD-N (S1))
Project Start
2009-09-23
Project End
2017-06-30
Budget Start
2013-09-16
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Goss, Christopher H; Sykes, Jenna; Stanojevic, Sanja et al. (2018) Comparison of Nutrition and Lung Function Outcomes in Patients with Cystic Fibrosis Living in Canada and the United States. Am J Respir Crit Care Med 197:768-775
Ramos, Kathleen J; Somayaji, Ranjani; Nichols, David P et al. (2018) Comparative Effectiveness Research in Pediatric Respiratory Disease: Promise and Pitfalls. Paediatr Drugs 20:1-7
West, Natalie E; Goss, Christopher H; Nichols, David P (2018) The Long and the Short of It in Cystic Fibrosis Clinical Research Outcomes. Ann Am Thorac Soc 15:430-431
Lechtzin, Noah; Mayer-Hamblett, Nicole; West, Natalie E et al. (2017) Home Monitoring of Patients with Cystic Fibrosis to Identify and Treat Acute Pulmonary Exacerbations. eICE Study Results. Am J Respir Crit Care Med 196:1144-1151
Sack, Cora S; Goss, Christopher H (2017) Yet Again, Air Pollution Impacts Lung Health. Ann Am Thorac Soc 14:1761-1762
Stephenson, Anne L; Sykes, Jenna; Stanojevic, Sanja et al. (2017) Survival Comparison of Patients With Cystic Fibrosis in Canada and the United States: A Population-Based Cohort Study. Ann Intern Med 166:537-546
Muhlebach, Marianne Sponer; Beckett, Valeria; Popowitch, Elena et al. (2017) Microbiological efficacy of early MRSA treatment in cystic fibrosis in a randomised controlled trial. Thorax 72:318-326
Heltshe, Sonya L; Cogen, Jonathan; Ramos, Kathleen J et al. (2017) Cystic Fibrosis: The Dawn of a New Therapeutic Era. Am J Respir Crit Care Med 195:979-984
Ramos, Kathleen J; Quon, Bradley S; Heltshe, Sonya L et al. (2017) Heterogeneity in Survival in Adult Patients With Cystic Fibrosis With FEV1 < 30% of Predicted in the United States. Chest 151:1320-1328
Ramos, Kathleen J; Sack, Coralynn S; Mitchell, Kristina H et al. (2017) Cystic Fibrosis is Associated with Adverse Neonatal Outcomes in Washington State, 1996-2013. J Pediatr 180:206-211.e1

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