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In a pair of identical randomized trials, an old antibiotic in a novel nebulized formulation showed mixed results on benefits for patients with bronchiectasis and Pseudomonas aeruginosa infections, but investigators say they identified the culprit behind negative results in the one trial.

In the PROMIS-I trial, the mean annual exacerbation rate for these patients declined from 0.95 with placebo to 0.58 with colistimethate sodium administered via the I-neb adaptive aerosol delivery system (rate ratio [RR] 0.61, 95% CI 0.46-0.82, P=0.0010). Yet in PROMIS-II, these rates were an identical 0.89 in both groups (RR 1.00, 95% CI 0.75-1.35, P=0.98).

Why the stark difference? "PROMIS-II was heavily disrupted by the COVID-19 pandemic and was terminated prematurely," according to investigator Charles Haworth, MD, of the University of Cambridge in England, who presented the findings of the phase III trials at the annual European Respiratory Society (ERS) congress in Vienna. Both were published simultaneously in .

Pre-pandemic data from PROMIS-II showed mean exacerbation rates of 0.92 with twice-daily use of the antibiotic and 1.26 with placebo (RR 0.73, 95% CI 0.49-1.08), with rates flipping during the pandemic period (0.87 vs 0.62; RR 1.40, 95% CI 0.93-2.13).

"We recognize the issues with post-hoc analysis, but the impact of the pandemic in our view cannot be ignored, and the totality of the evidence supports a consistent and clinically meaningful treatment effect of CMS [colistimethate sodium] I-neb outside of pandemic conditions," Haworth concluded.

The investigators also ran a meta-analysis involving 689 patients from PROMIS-I, the pre-pandemic period of PROMIS-II, and an , which together supported colistimethate sodium's reduction in exacerbation rates (RR 0.65, 95% CI 0.52-0.81).

"COVID-19 fundamentally changed the experimental conditions," said Haworth. "Lockdowns, social distancing, and mask wearing resulted in a reduction in circulating respiratory pathogens, and real-world data -- both in Europe and in the U.S. -- showed that bronchiectasis ."

Amid mixed evidence, the use of inhaled antibiotics for bronchiectasis has been considered controversial, but the approach has nonetheless received conditional endorsement in and in other international guidelines. A of randomized trials found that inhaled antibiotics were associated with a 21% decrease in exacerbations among adults with bronchiectasis, along with a 52% decrease in severe exacerbations.

In Europe, colistimethate sodium has become the go-to option for inhaled antibiotics for bronchiectasis. A pro-drug of colistin, the polymyxin antibiotic is active against P. aeruginosa, an aerobic gram-negative pathogen that is associated with increased exacerbations and mortality in patients with bronchiectasis.

"In the last three decades, inhaled antibiotics have been used more frequently in clinical practice, given their ability to achieve high local concentrations directly to the site of infection with a lower risk of toxicity and bacterial resistance," noted authors of an .

But as noted, randomized trials so far have shown , and many patients' infections are caused by other microorganisms for which inhaled antibiotics have not proven effective, according to Marta María García Clemente, PhD, of the University of Oviedo, and Guillermo Suárez Cuartín, MD, of the University of Barcelona, both in Spain.

"Another contentious issue in bronchiectasis is identifying when to initiate inhaled antibiotics," they wrote. "European recommendations propose starting inhaled antibiotics in patients with chronic P. aeruginosa infection after three or more exacerbations despite appropriate treatment, whereas Spanish guidelines consider inhaled antibiotics in patients with chronic P. aeruginosa infection and those with chronic bronchial infection from other microorganisms with two or more exacerbations."

Data from the PROMIS trials, which enrolled patients with at least two exacerbations, make it "reasonable to consider that inhaled antibiotic treatment might be beneficial before a third exacerbation occurs," the editorialists said.

In , developer Zambon said it was "continuing to work with regulatory authorities" to bring the inhaled colistimethate sodium product to the market for patients with bronchiectasis and P. aeruginosa infections.

and included adults with a CT-confirmed diagnosis of bronchiectasis enrolled at hospitals across 17 nations, including the U.S. Participants were randomized 1:1 to either inhaled colistimethate sodium (delivered dose of 0.3 million IU) or placebo, with both administered twice daily via the I-neb device for 12 months.

Participants were required to have two or more exacerbations in the prior 12 months or one that required oral antibiotics; a documented history of P. aeruginosa, as well as a positive culture for the infection at screening; and a forced expiratory volume (FEV) at least 25% of the predicted value.

PROMIS-I randomized 377 patients from June 6, 2017, to April 8, 2020, while PROMIS-II randomized 287 patients from Feb. 12, 2018, to Oct. 22, 2021.

Across the two trials, participants had a mean age of 60-64 years, more than 95% were white, and about two-thirds were women. They averaged an FEV roughly 60% of the predicted value, and a majority had three or more affected lobes. The underlying cause of bronchiectasis was idiopathic or unknown in most cases, with about one-fourth a result of infection.

Approximately a third of patients were on macrolides, and the average rate of exacerbation requiring oral antibiotics prior to enrollment was 1.9 to 2.3 per year, with 0.5 exacerbations requiring IV antibiotics.

Beyond meeting the primary endpoint, PROMIS-I also demonstrated a significant reduction in severe exacerbations with inhaled colistimethate sodium (RR 0.41, 95% CI 0.23-0.74, P=0.003) and significant improvements in quality of life on the St. George's Respiratory Questionnaire that exceeded the minimum clinically important difference, neither of which were replicated in PROMIS-II.

In terms of resistance, 2.5% and 9% of patients on colistimethate sodium in the two trials, respectively, developed evidence of resistance over the 12-month treatment period.

The safety profile of colistimethate sodium was similar to placebo, said Haworth, with treatment-emergent adverse event (TEAE) rates of 81% for both groups in PROMIS-I and 81% with colistimethate sodium versus 77% with placebo in PROMIS-II. Most TEAEs were mild or moderate in severity. Of note, bronchospasm was reported in fewer than 5% across groups.

TEAEs considered possibly related to study treatment were slightly higher with colistimethate sodium in each trial (16-20% vs 7-18% with placebo), but the differences were not significant. No deaths were considered related to treatment.