New Approach Against Antibiotic-resistant Bacteria in CF Patients Shows Promise in Phase 1 Trial
In a preliminary Phase 1 trial, a single five-day infusion with the potential treatment, called gallium nitrate, improved the lung function of CF patients with a chronic P. aeruginosa infection, showing no signs of toxicity.
Trial results were published in the study, “Gallium disrupts bacterial iron metabolism and has therapeutic effects in mice and humans with lung infections,” in the journal Science Translational Medicine.
Research looking for new treatments against difficult-to-treat and antibiotic-resistant bacteria has focused mostly on discovering new therapies that can enter bacteria and stop their proliferation, disrupt their cell wall or cell membrane, or interfere with their protein production.
But a team of researchers University of Washington School of Medicine came up with a different strategy to treat these infections: “cheating” bacteria into taking up a metal called gallium as if it were iron, which is a critical nutrient for bacteria to survive and grow.
Gallium disrupts iron-dependent processes, so gallium uptake by bacteria would work as a “Trojan horse” leading to their death.
“The body goes to great lengths to keep iron away from bacteria, and infecting organisms crank up special systems to import iron and steal it from the host,” Pradeep Singh, MD, UW professor of microbiology and medicine and the senior author of the study, said in a press release.
“Gallium disrupts machinery that bacteria use to make new DNA, and without this the bacteria can’t multiply. This and other essential processes require iron, and gallium is a monkey wrench that shuts the system down,” said study co-author Bradley Britigan, MD, a professor of internal medicine at the University of Nebraska Medical Center.
In earlier lab studies by the team and others, gallium was seen to exert antibacterial activity against several human disease-causing strains of bacteria, including Pseudomonas aeruginosa and Klebsiella pneumoniae.
This evidence prompted researchers to test gallium in mouse models and in humans. The study focused on chronic infections with P. aeruginosa, which are particularly harmful and difficult to treat in people unable to properly fight infections due to diseases such as CF, cancer, or AIDS.
In lab tests, P. aeruginosa bacteria were found to develop a resistance to gallium at low rates, comparable to the pace at which the same bacteria become resistant to antibiotics that are able to kill them through multiple mechanisms.
In mouse models of airway infection, a single dose of gallium nitrate cured lethal lung P. aeruginosa infections.
Based on the positive results in mice, researchers set up a Phase 1 clinical trial (NCT01093521) to evaluate the efficacy and safety of gallium nitrate in 20 CF patients with chronic lung infections caused by antibiotic-resistant Pseudomonas bacteria.
Patients were treated with intravenous infusions of gallium nitrate for five days. Of note, gallium nitrate is a medication marketed under the brand name Ganite, approved for the treatment of hypercalcemia, or too much calcium in the blood, a condition that can occur in cancer patients.
Results showed that patients’ lung function got significantly better 14 and 28 days after treatment with gallium nitrate. No serious adverse events or signs of toxicity were noted.
“Our preliminary study in a small group of people with CF suggests that gallium is safe and improves patients’ lung function,” said Christopher Goss, MD, a UW professor of medicine and pediatrics and the study’s first author. “These are exciting results, but we need to do more studies to determine if gallium can be developed into a routine, safe treatment.”
Although the results may open new avenues for treating lung infections in CF patients, the researchers emphasized in the study that “the promising safety and efficacy results need to be confirmed in a larger placebo-controlled study.”
“It will also be important to study the safety of repeated administration, investigate combined use with antibiotics in humans, and determine whether oral or inhaled treatment is feasible,” they added.