In two identical randomized trials, inhaled colistimethate sodium showed mixed results in patients with bronchiectasis and Pseudomonas aeruginosa infections. The PROMIS-I trial demonstrated a significant reduction in exacerbation rates, while PROMIS-II did not, due to disruptions caused by the COVID-19 pandemic. These Phase III trial findings were presented at the European Respiratory Society (ERS) congress in Vienna and simultaneously published in Lancet Respiratory Medicine.
PROMIS Trial Results
In PROMIS-I, the mean annual exacerbation rate decreased from 0.95 with placebo to 0.58 with colistimethate sodium (rate ratio [RR] 0.61, 95% CI 0.46-0.82, P = 0.0010). However, PROMIS-II showed identical rates of 0.89 in both groups (RR 1.00, 95% CI 0.75-1.35, P = 0.98).
Charles Haworth, MD, of the University of Cambridge, explained that PROMIS-II was significantly affected by the COVID-19 pandemic and was terminated prematurely. Pre-pandemic data from PROMIS-II showed exacerbation rates of 0.92 with colistimethate sodium and 1.26 with placebo (RR 0.73, 95% CI 0.49-1.08), but these rates flipped during the pandemic (0.87 vs 0.62; RR 1.40, 95% CI 0.93-2.13).
Meta-Analysis and Pandemic Impact
A meta-analysis involving 689 patients from PROMIS-I, the pre-pandemic period of PROMIS-II, and an earlier phase II study supported the reduction in exacerbation rates with colistimethate sodium (RR 0.65, 95% CI 0.52-0.81).
"COVID-19 fundamentally changed the experimental conditions," Haworth stated. "Lockdowns, social distancing, and mask wearing resulted in a reduction in circulating respiratory pathogens, and real-world data showed that bronchiectasis exacerbation rates were reduced by approximately 50%."
Context of Inhaled Antibiotics for Bronchiectasis
The use of inhaled antibiotics for bronchiectasis has been controversial, but it has received conditional endorsement in ERS guidelines from 2017 and other international guidelines. A recent meta-analysis found that inhaled antibiotics were associated with a 21% decrease in exacerbations and a 52% decrease in severe exacerbations among adults with bronchiectasis.
Colistimethate sodium, a pro-drug of colistin, is active against P. aeruginosa, a pathogen associated with increased exacerbations and mortality in bronchiectasis patients. Inhaled antibiotics are favored for their ability to achieve high local concentrations at the site of infection with a lower risk of toxicity and bacterial resistance.
Considerations for Treatment Initiation
Marta María García Clemente, PhD, and Guillermo Suárez Cuartín, MD, noted the ongoing debate about when to initiate inhaled antibiotics. European recommendations suggest starting in patients with chronic P. aeruginosa infection after three or more exacerbations, while Spanish guidelines consider it after two or more exacerbations.
The PROMIS trials, which enrolled patients with at least two exacerbations, suggest that inhaled antibiotic treatment might be beneficial before a third exacerbation occurs.
Trial Details
PROMIS-I and PROMIS-II included adults with CT-confirmed bronchiectasis across 17 nations. Participants were randomized 1:1 to inhaled colistimethate sodium (0.3 million IU) or placebo, administered twice daily via the I-neb device for 12 months. Patients were required to have at least two exacerbations in the prior year or one requiring oral antibiotics, a history of P. aeruginosa, and a forced expiratory volume (FEV) at least 25% of the predicted value.
PROMIS-I randomized 377 patients from June 2017 to April 2020, while PROMIS-II randomized 287 patients from February 2018 to October 2021. Participants had a mean age of 60-64 years, were predominantly white (over 95%), and mostly women (about two-thirds). They averaged an FEV roughly 60% of the predicted value.
Additional Outcomes and Safety
PROMIS-I also showed a significant reduction in severe exacerbations (RR 0.41, 95% CI 0.23-0.74, P = 0.003) and improvements in quality of life, which were not replicated in PROMIS-II. Resistance to colistimethate sodium developed in 2.5% and 9% of patients in the two trials, respectively.
The safety profile of colistimethate sodium was similar to placebo, 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. Bronchospasm was reported in fewer than 5% across groups.
