Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis. The OPTIMIZE Randomized Trial.

Creator(s)

Nicole Mayer-Hamblett
George Retsch-Bogart
Margaret Kloster
Frank Accurso
Margaret Rosenfeld
Gary Albers
Philip Black, Children's Mercy Hospital
Perry Brown
AnneMarie Cairns
Stephanie D. Davis
Gavin R. Graff
Gwendolyn S. Kerby
David Orenstein
Rachael Buckingham
Bonnie W. Ramsey
OPTIMIZE Study Group

Document Type

Article

Publication Date

11-1-2018

Identifier

PMCID: PMC6221579 DOI: 10.1164/rccm.201802-0215OC

Abstract

RATIONALE: New isolation of Pseudomonas aeruginosa (Pa) is generally treated with inhaled antipseudomonal antibiotics such as tobramycin inhalation solution (TIS). A therapeutic approach that complements traditional antimicrobial therapy by reducing the risk of pulmonary exacerbation and inflammation may ultimately prolong the time to Pa recurrence.

OBJECTIVES: To test the hypothesis that the addition of azithromycin to TIS in children with cystic fibrosis and early Pa decreases the risk of pulmonary exacerbation and prolongs the time to Pa recurrence.

METHODS: The OPTIMIZE (Optimizing Treatment for Early Pseudomonas aeruginosa Infection in Cystic Fibrosis) trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial in children with CF, 6 months to 18 years of age, with early Pa. Azithromycin or placebo was given 3× weekly with standardized TIS.

MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the time to pulmonary exacerbation requiring antibiotics and the secondary endpoint was the time to Pa recurrence, in addition to other clinical and safety outcomes. A total of 221 participants (111 placebo, 110 azithromycin) out of a planned 274 were enrolled. Enrollment was stopped early by the NHLBI because the trial had reached the prespecified interim boundary for efficacy. The risk of pulmonary exacerbation was reduced by 44% in the azithromycin group as compared with the placebo group (hazard ratio, 0.56; 95% confidence interval, 0.37-0.83; P = 0.004). Weight increased by 1.27 kg in the azithromycin group compared with the placebo group (95% confidence interval, 0.01-2.52; P = 0.046). No significant differences were seen in microbiological or other clinical or safety endpoints.

CONCLUSIONS: Azithromycin was associated with a significant reduction in the risk of pulmonary exacerbation and a sustained improvement in weight, but had no impact on microbiological outcomes in children with early Pa. Clinical trial registered with clinicaltrials.gov (NCT02054156).

Journal Title

American journal of respiratory and critical care medicine

Volume

198

Issue

9

First Page

1177

Last Page

1187

MeSH Keywords

Administration, Inhalation; Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Cystic Fibrosis; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Infant; Male; Pseudomonas Infections; Pseudomonas aeruginosa; Recurrence; Time Factors; Tobramycin; Treatment Outcome

Keywords

Pseudomonas aeruginosa; clinical trial; eradication; pulmonary exacerbation

Comments

Comment in

• Preservation of Lung Function in Cystic Fibrosis: Are Macrolides the Answer? [Am J Respir Crit Care Med. 2018]

• Reply to Shanthikumar et al.: Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis: Do the Benefits Outweigh the Harms? [Am J Respir Crit Care Med. 2018]

• Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis: Do the Benefits Outweigh the Harms? [Am J Respir Crit Care Med. 2018]

Secondary source ID

• ClinicalTrials.gov/NCT02054156

Grant support

• P30 DK089507/DK/NIDDK NIH HHS/United States

• U01 HL114623/HL/NHLBI NIH HHS/United States

Recommended Citation

Mayer-Hamblett N, Retsch-Bogart G, Kloster M, et al. Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis. The OPTIMIZE Randomized Trial [published correction appears in Am J Respir Crit Care Med. 2019 Mar 15;199(6):809]. Am J Respir Crit Care Med. 2018;198(9):1177-1187. doi:10.1164/rccm.201802-0215OC