PROMISe of inhaled antibiotics for treating bronchiectasis and P. aeruginosa infection

medwireNews: Inhaled colistimethate sodium could help prevent exacerbations in patients with bronchiectasis and Pseudomonas aeruginosa infection, suggest findings from the phase 3 PROMIS-I trial. The annual rate of exacerbation was reduced by a significant 39% in the patients randomly assigned to receive colistimethate sodium (1 million IU; delivered dose 0.3 million IU) twice a day via the I-neb adaptive aerosol delivery device (Xellia Pharmaceuticals Aps, Copenhagen, Denmark) for up to 12 months, compared with those assigned to receive placebo. The findings were not replicated in the phase 3 PROMIS-II trial; however, say James Chalmers (University of Dundee, UK) and colleagues, although they point out that PROMIS-II was “prematurely terminated due to the COVID-19 pandemic and after the positive results of PROMIS-I,” and add that a post-hoc analysis identified beneficial treatment effects consistent with PROMIS-I during the prepandemic phase. The patients in both trials had CT-confirmed bronchiestasis, a history of P. aeruginosa respiratory infection, and a sputum culture positive for P. aeruginosa at study entry. They had either at least two pulmonary exacerbations in the preceding 12 months that required oral antibiotic treatment, or one exacerbation that was treated with intravenous antibiotics. The mean age of the study participants was 64 years in PROMIS-I and 60 years in PROMIS-II. In PROMIS-I, 34% of the 176 patients given colistimethate sodium experienced a total of 89 pulmonary exacerbations over 12 months of treatment, compared with a total of 163 exacerbations in 48% of the 197 patients given placebo. An exacerbation was defined as the presence of at least three symptoms for at least 24 hours that required antibiotic treatment, namely increased cough, sputum volume and/or consistency; increased sputum purulence; a new or increased hemoptysis; increased wheezing; increased dyspnea; increased fatigue and/or malaise; and episodes of fever. The annual pulmonary exacerbation rate was estimated to be 0.58 for patients given colistimethate sodium versus 0.95 for those given placebo, a significant difference with a rate ratio of 0.61. In PROMIS-II, there was no significant difference in the rate of exacerbations between the 152 patients given colistimethate sodium and the 135 given placebo. There was a total of 111 exacerbations in 47% of patients in the former group and 98 in 47% of patients in the latter group. The annual exacerbation rate was 0.89 in both groups. However, when evaluating data accrued for 89 patients in the colistimethate sodium group and 83 in the placebo group in the prepandemic phase (before March 2020), the annual exacerbation rate was 0.92 and 1.26, respectively, giving an exacerbation rate ratio of 0.73 in favor of colistimethate sodium that was of borderline significance. During the pandemic period, the annual exacerbation rate fell sharply by 50.8% in the placebo group, compared with 5.4% in the colistimethate sodium group, giving a nonsignificant exacerbation rate ratio of 1.40. PROMIS-I also showed “statistically and clinically significant benefits” with colistimethate sodium versus placebo across multiple secondary endpoints, say the investigators. These included a significant delay in the median time to first exacerbation (not reached vs 208 days), a significant 59% reduction in the annual rate of severe exacerbations requiring intravenous antibiotics, hospitalization, or associated with pneumonia, and a significant 4.55-point greater reduction from baseline in total scores on the 50-item St George’s Respiratory Questionnaire, where higher scores indicate poorer quality of life. In terms of safety, the profile of colistimethate sodium was “very similar” to that of placebo, Chalmers and co-workers point out, and bronchospasm was reported in just 3–5% of patients receiving the treatment in PROMIS I and II versus 1–2% of placebo-treated patients. Any treatment-emergent adverse event (TEAE) occurred in 81% of patients given colistimethate sodium in both studies and in 77–81% of patients given placebo. The corresponding serious TEAE rates were 18% versus 13–23%. TEAEs leading to study discontinuation were reported for 11–13% of patients in the colistimethate sodium group and 6–15% of those in the placebo group. There were seven deaths in total, four of which occurred in patients given colistimethate sodium, but none were considered related to treatment. Discussing the findings in The Lancet Respiratory Medicine, Marta María García Clemente (University of Ovideo, Spain) and Guillermo Suárez Cuartín (University of Barcelona, Spain) say that the results “represent a positive milestone in the search for effective management strategies for patients with bronchiectasis,” and support “the recommendation to use inhaled antibiotics in patients with bronchiectasis and chronic bronchial infection with P aeruginosa.” But the commenters caution that further study is needed to determine the effectiveness of inhaled antibiotics for patients whose chronic bronchial infection is caused by potentially pathogenic microorganisms other than P. aeruginosa and the optimal timing for initiating inhaled antibiotics, adding that “considering bacterial density stratification in future bronchiectasis trials might be beneficial.” The results of the two studies were also presented at the ERS Congress in Vienna, Austria. medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group Lancet Respir Med 2024; doi:10.1016/S2213-2600(24)00225-X Lancet Respir Med 2024; doi:10.1016/S2213-2600(24)00256-X ERS Congress 2024; Vienna, Austria: 7–11 September

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PROMISe of inhaled antibiotics for treating bronchiectasis and P. aeruginosa infection

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