Kalydeco reduces acute CF lung infections, not chronic ones: Study
Impact studied to understand why bacteria remain, affect on patients’ health
Treatment with Kalydeco (ivacaftor) reduces the number of Pseudomonas aeruginosa bacteria in the lungs during an acute infection, but not during a chronic infection, a study using a rat model of cystic fibrosis (CF) indicates.
Kalydeco led to better outcomes, including weight gain, increased CFTR protein function, and decreased mucus buildup in these animals, despite persistent lung infection and inflammation.
“These data suggest that [Kalydeco] improves tolerance of infection, rather than eradication, in this rat model,” the researchers wrote in the study, “Ivacaftor ameliorates mucus burden, bacterial load, and inflammation in acute but not chronic P. aeruginosa infection in hG551D rats,” published in Respiratory Research.
Genetic mutations that cause CF alter the production or function of CFTR, a protein channel that acts as a gate to control the flow of chloride salts into and out of cells. A lack of functional CFTR disrupts salt and water balance on cell surfaces, leading to the abnormal buildup of sticky mucus in organs.
Mucus building up in the lungs makes for a fertile breeding ground for many types of bacteria, including Pseudomonas aeruginosa, or P. aeruginosa, a major contributor to lung disease in CF.
Kalydeco is a type of CFTR modulator therapy that’s designed to address gating by mutations that affect the flow of salts through the CFTR protein. Approved to treat CF patients with certain mutations, it works by holding the CFTR gate open longer, allowing proper salt flow. The therapy significantly improves lung function and reduces acute worsening of symptoms, called exacerbations, but bacterial infections of the lung, including P. aeruginosa, can persist.
Kalydeco’s impact on lung infections in CF
Here, a research team at the University of Alabama at Birmingham tested the impact of Kalydeco on lung infections in a CF rat model with a gating mutation (G551D) to better understand “why the bacteria remain, or how impactful future infections will be to patients’ health.”
To mimic an acute infection, rats with CF and healthy rats received either Kalydeco or an innocuous substance daily for three days starting four days after an infection with P. aeruginosa. For a chronic infection, treatment was delayed until 21 days.
CF rats in the acute infection group treated with Kalydeco had significantly fewer P. aeruginosa bacteria in the lungs than the CF controls. No differences were observed in the chronic phase, however. As expected, healthy rats eliminated the infection.
Treating an infection with Kalydeco had no impact on the number of immune neutrophil cells in lung fluid, a marker for inflammation, compared with the controls in both acute and chronic infection groups. Still, neutrophils were significantly higher among CF rats with a chronic infection, regardless of their treatment status.
CF rats in both acute and chronic infection groups gained weight, starting within a day on Kalydeco, but it remained lower than healthy rats by the end of the study in the chronic infection group. While treatment did reduce muc5ac, a protein component of mucus, in CF rats with acute infection, there were no differences during the chronic phase.
Pre-treatment with Kalydeco
Because some newly diagnosed CF patients begin CFTR modulator treatment before being exposed to P. aeruginosa, the researchers also treated CF rats with Kalydeco seven days before an infection. The rats were assessed three days and a week after infection for the acute phase and after a month for a chronic infection.
Pre-treatment with Kalydeco also significantly reduced the bacterial burden during the acute phase in CF rats. However, after a month, it rose to levels that matched untreated CF rats. Unlike post-infection treatment, pre-treatment significantly lowered the numbers of neutrophils in the lungs of CF rats during an acute infection, but not a chronic one.
Pre-treatment also led to significant weight gain, but there were no differences in muc5ac levels regardless of treatment during the acute phase. After a month, muc5ac was higher in the Kalydeco-treated animals.
When the researchers assessed CFTR protein function in airway tissue, Kalydeco was seen to significantly enhance the flow of chloride salts to levels about half of those seen in healthy rats, as expected by its mechanism of action. Even so, Kalydeco-induced CFTR function remained intact throughout a month of a P. aeruginosa infection.
The researchers then tested the impact of Kalydeco pre-treatment on the mucociliary transport (MCT) rate, an assessment of airway mucus clearance. During the acute infection phase, Kalydeco didn’t restore MCT rates, but the therapy increased MCT rates compared with controls during a chronic infection. Still, MCT rates in healthy rats were markedly higher than in CF rats treated with Kalydeco, which suggests “a potential mechanism for retention of infection,” the researchers wrote.
Lastly, CF rats treated with Kalydeco had fewer airways with mucus plugs than untreated controls, despite a persistent infection.
“The data indicate that the [G551D] rats have better outcomes during infection when treated with [Kalydeco] compared to the vehicle group,” the researchers wrote. “Rats have increased weight gain, increased CFTR protein function, and decreased mucus accumulation, despite the persistence of infection and inflammation.”
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