Azithromycin in Patients With Cystic Fibrosis Chronically Infected With Pseudomonas aeruginosa

A Randomized Controlled Trial

Saiman, Lisa MD, MPH
Marshall, Bruce C. MD
Mayer-Hamblett, Nicole PhD
Burns, Jane L. MD
Quittner, Alexandra L. PhD
Cibene, Debra A. CCRA
Coquillette, Sarah
Fieberg, Ann Yunker MS
Accurso, Frank J. MD
Campbell, Preston W. III MD

Department of Pediatrics, Columbia University, New York, NY (Dr Saiman); Department of Internal Medicine, University of Utah, Salt Lake City (Dr Marshall); Departments of Biostatistics (Dr Mayer-Hamblett) and Pediatrics (Drs Mayer-Hamblett and Burns), University of Washington, Seattle; Cystic Fibrosis Therapeutics Development Network Coordinating Center, Seattle, Wash (Dr Mayer-Hamblett and Mss Cibene, Coquillette, and Fieberg); Cystic Fibrosis Therapeutic Development Network Resource Center for CF Microbiology, Seattle, Wash (Dr Burns); Department of Clinical and Health Psychology, Department of Pediatrics, University of Florida, Gainesville (Dr Quittner); Department of Pediatrics, University of Colorado, and Cystic Fibrosis Therapeutic Development Network Resource Center for Inflammatory Markers (Dr Accurso), Denver, Colo; and Cystic Fibrosis Foundation, Bethesda, Md (Drs Marshall and Campbell).

Corresponding Author and Reprints: Lisa Saiman, MD, MPH, Department of Pediatrics, Columbia University College of Physicians and Surgeons, 650 W 168th St, BB4-427, New York, NY 10032-3784 (e-mail: [email protected]).

Author Contributions: Drs Saiman and Marshall were co-principal investigators and contributed equally to this study. Dr Saiman had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Saiman, Marshall, Mayer-Hamblett, Burns, Quittner, Campbell.

Acquisition of data: Saiman, Marshall, Mayer-Hamblett, Burns, Quittner, Cibene, Coquillette.

Analysis and interpretation of data: Saiman, Marshall, Mayer-Hamblett, Burns, Fieberg, Accurso, Campbell.

Drafting of the manuscript: Saiman, Marshall, Mayer-Hamblett, Burns, Quittner, Campbell.

Critical revision of the manuscript for important intellectual content: Saiman, Marshall, Mayer-Hamblett, Burns, Cibene, Coquillette, Fieberg, Accurso, Campbell.

Statistical expertise: Mayer-Hamblett, Quittner, Fieberg.

Obtained funding: Saiman, Marshall, Campbell.

Administrative, technical, or material support: Saiman, Burns, Cibene, Coquillette, Accurso.

Study supervision: Saiman, Marshall, Burns, Cibene, Coquillette, Campbell.

The Macrolide Study Group:CF Foundation Therapeutics Development Network Coordinating Center: University of Washington, Seattle: Christopher Goss, MD, MPH, Bonnie Ramsey, MD, Richard A. Kronmal, PhD, Judy Williams, MPH, RN; Children's Hospital and Regional Medical Center, Seattle, Wash: Morty Cohen, RPh, Jean Kirihara, BS, Jenny Stapp, BS; Axio Research Corporation, Seattle, Wash: Craig Johnson, MS, Brian Ingersoll, BS, Sandi Tennyson, BS; The University of Alabama at Birmingham/Children's Health System: Raymond Lyrene, MD, Valerie Eubanks, MS, RD; University of Arkansas for Medical Sciences, Little Rock: Paula Anderson, MD, Larry P. Gann, BS, Cynthia Spinks, MSE, April Stewart, BS; University of Arizona Health Sciences Center, Tucson: Mark Brown, MD, Betty-Pauline Polanco, RRT, Pat Cunningham, CRT; Children's Hospital, Phoenix, Ariz: Peggy Radford, MD, Natalia Argel, BSN, RNC, Annette Szpiszar, MS, RN; Childrens Hospital, Los Angeles, Calif: Marlyn S. Woo, MD, Antoniette Ziolkowski, RN, BSN, MSN, Daisy B. Bolduc, RPFT, MBA; University of Colorado, Denver: Iris Osberg, MT; Emory University, Atlanta, Ga: Daniel Caplan, MD, Gerald Teague, MD, Jacqueline Geter, MS, RN, CPNP, Diane Morrison, RN, BSN; Children's Memorial Hospital, Northwestern University, Chicago, Ill: Steven Boas, MD, Manu Jain, MD, Eileen Potter, MS, RD, Catherine Powers, CCRC, RD; Riley Hospital for Children, Indianapolis, Ind: Michelle Howenstine, MD, Mary Blagburn, RN, BSN, CCRC, Delana Terrill, RRT, RPFT, CCRC; University of Kentucky Medical Center, Lexington, Ky: Michael Anstead, MD, Jamshed Kanga, MD, Lois Craigmyle, RN; Tulane University School of Medicine, New Orleans, La: Scott Davis, MD, Robert Beckerman, MD, Annette Broussard, RRT; The Floating Hospital for Children, Tufts-New England Medical Center, Boston, Mass: William Yee, MD, Monica Ulles, RN, MS, PNP; University of Michigan Health Systems, Ann Arbor: Samya Nasr, MD, Julie Konkle, RN, Ermee Sakmar, RN; University of Nebraska Medical Center, Omaha: John Colombo, MD, Dee Acquazzino, BS; The Children's Hospital of Buffalo, Buffalo, NY: Jack K. Sharp, MD, Mary Kontos, PNP; Columbia University, New York: NY: Lynne Quittell, MD, Benay Johnson, RN, MSN, CPNP; The Children's Hospital, Columbus, Ohio: Karen McCoy, MD, Terri Johnson, RN, BSN; Oregon Health and Science University, Portland: Mark Chesnutt, MD, Lynn Oveson, RN, MN, ANP, Svetlana Sheinkman, RN, BSN; Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pa: Jonathan D. Finder, MD, Elizabeth Hartigan, RN, MPH; Vanderbilt University Medical Center, Nashville, Tenn: Christopher Harris, MD, Stefanie F. Rushing, RN, MSN, Judy Marciel, RN, MSN, CPNP; Cook Children's Medical Center, Fort Worth, Tex: Maynard Dyson, MD, Janet Garbarz, RN, CPNP; Baylor College of Medicine, Texas Children's Hospital, Houston: Peter Hiatt, MD, Charlene Hallmark, RN, Charles Sellers, BBA, RRT; University of Utah, Salt Lake City: Barbara Chatfield, MD, Carmen Henshaw, RN, BSN, Deanna Allred, RN, BSN; Children's Hospital, University of Wisconsin, Madison: Michael Rock, MD, Tim Wolf, PharmD.

Funding/Support: This study was supported by the Cystic Fibrosis Foundation.

Acknowledgment: We acknowledge Pfizer Pharmaceuticals for helpful discussions regarding study drug regimens and toxicity, supplying active drug and placebo, and measuring sputum concentrations of azithromycin. Pfizer Pharmaceuticals did not participate in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript. We gratefully thank the study participants.

JAMA: The Journal of the American Medical Association 290(13):p 1749-1756, October 1, 2003.

Context

Treatment strategies for cystic fibrosis (CF) lung disease include antibiotics, mucolytics, and anti-inflammatory therapies. Increasing evidence suggests that macrolide antibiotics might be beneficial in patients with CF.

Objective

To determine if an association between azithromycin use and pulmonary function exists in patients with CF.

Design and Setting

A multicenter, randomized, double-blind, placebo-controlled trial conducted from December 15, 2000, to May 2, 2002, at 23 CF care centers in the United States.

Participants

Of the 251 screened participants with a diagnosis of CF, 185 (74%) were randomized. Eligibility criteria included age 6 years or older, infection with Pseudomonas aeruginosa for 1 or more years, and a forced expiratory volume in 1 second (FEV₁) of 30% or more. Participants were stratified by FEV₁ (≥60% predicted vs <60% predicted), weight of less than 40 kg vs 40 kg or more, and CF center.

Intervention

The active group (n = 87) received 250 mg (weight <40 kg) or 500 mg (weight ≥40 kg) of oral azithromycin 3 days a week for 168 days; placebo group (n = 98) received identically packaged tablets.

Main Outcome Measures

Change in FEV₁ from day 0 to completion of therapy at day 168 and determination of safety. Secondary outcomes included pulmonary exacerbations and weight gain.

Results

The azithromycin group had a mean 0.097-L (SD, 0.26) increase in FEV₁ at day 168 compared with 0.003 L (SD, 0.23) in the placebo group (mean difference, 0.094 L; 95% confidence interval [CI], 0.023–0.165; P = .009). Nausea occurred in 17% more participatns in the azithromycin group (P = .01), diarrhea in 15% more (P = .009), and wheezing in 13% more (P = .007). Participants in the azithromycin group had less risk of experiencing an exacerbation than participants in the placebo group (hazard ratio, 0.65; 95% CI, 0.44–0.95; P = .03) and weighed at the end of the study an average 0.7 kg more than participants receiving placebo (95% CI, 0.1–1.4 kg; P = .02).

Conclusion

Azithromycin treatment was associated with improvement in clinically relevant end points and should be considered for patients with CF who are 6 years or older and chronically infected with P aeruginosa.