Testing the effects of combining azithromycin with inhaled tobramycin for P. aeruginosa in cystic fibrosis: a randomised, controlled clinical trial

David P Nichols; Pradeep K Singh; Arthur Baines; Lindsay J Caverly; James F Chmiel; Ronald L GIbson; Jorge Lascano; Sarah J Morgan; George Retsch-Bogart; Lisa Saiman; Hossein Sadeghi; Joanne L Billings; Sonya L Heltshe; Shannon Kirby; Ada Kong; Jerry A Nick; Nicole Mayer-Hamblett; TEACH Study Group

doi:10.1136/thoraxjnl-2021-217782

Testing the effects of combining azithromycin with inhaled tobramycin for P. aeruginosa in cystic fibrosis: a randomised, controlled clinical trial

Thorax. 2022 Jun;77(6):581-588. doi: 10.1136/thoraxjnl-2021-217782. Epub 2021 Oct 27.

Authors

David P Nichols^{1

2}, Pradeep K Singh³, Arthur Baines², Lindsay J Caverly⁴, James F Chmiel⁵, Ronald L GIbson⁶, Jorge Lascano⁷, Sarah J Morgan³, George Retsch-Bogart⁸, Lisa Saiman⁹, Hossein Sadeghi⁹, Joanne L Billings¹⁰, Sonya L Heltshe^{6

2

11}, Shannon Kirby², Ada Kong¹², Jerry A Nick^#^{13

14}, Nicole Mayer-Hamblett^#^{6

2

11}; TEACH Study Group

Collaborators

TEACH Study Group:
Peter Mogayzel, Perry Brown, Gregory Sawicki, Manu Jain, Gary McPhail, Kimberly McBennett, Gary Mueller, Karen Schultz, Susan Millard, Gavin Graff, Clement Ren, Hugo Escobar, Robert Zanni, Thomas Keens, Nicholas Antos, Marie Egan, Patricia Walker, Floyd Livingston, Carlos Milla, Okan Elidemir, Subramanyam Chittivelu, Laurie Varlotta, Joseph Pilewski, Anne Marie Cairns, Kelvin MacDonald, Karen Voter, Fadi Asfour, Douglas Conrad, Christopher Goss, Gary Albers, Jessica Pittman, Ted Kremer, Irene Bondick, Maggie Brassil, Missy Cianciola, Laurel Couture, Jeannette Dingledine, Martha Doyle, Barbra Fogarty, Susan Jacobs, Miya Johnson, Barbara Mathewson, Peter McDonnell, Anna Mead, Matthew Myers, Jill VanDalfsen

Affiliations

¹ Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA David.Nichols@seattlechildrens.org.
² Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Centre, Seattle Children's Research Institute, Seattle, Washington, USA.
³ Department of Microbiology, University of Washington, Seattle, Washington, USA.
⁴ Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
⁵ Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁶ Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.
⁷ Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Florida Health, Gainesville, Florida, USA.
⁸ Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
⁹ Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
¹⁰ Department of Medicine, Pulmonary, Allergy and Critical Care Division, University of Minnesota Medical Center, Minneapolis, Minnesota, USA.
¹¹ Department of Biostatistics, University of Washington School of Public Health, Seattle, Washington, USA.
¹² Department of Pharmacy, Seattle Children's Hospital, Seattle, Washington, USA.
¹³ Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA.
¹⁴ Department of Medicine, National Jewish Health, Denver, Colorado, USA.

^# Contributed equally.

Abstract

Rationale: Inhaled tobramycin and oral azithromycin are common chronic therapies in people with cystic fibrosis and Pseudomonas aeruginosa airway infection. Some studies have shown that azithromycin can reduce the ability of tobramycin to kill P. aeruginosa. This trial was done to test the effects of combining azithromycin with inhaled tobramycin on clinical and microbiological outcomes in people already using inhaled tobramycin. We theorised that those randomised to placebo (no azithromycin) would have greater improvement in forced expiratory volume in one second (FEV₁) and greater reduction in P. aeruginosa sputum in response to tobramycin.

Methods: A 6-week prospective, randomised, placebo-controlled, double-blind trial testing oral azithromycin versus placebo combined with clinically prescribed inhaled tobramycin in individuals with cystic fibrosis and P. aeruginosa airway infection.

Results: Over a 6-week period, including 4 weeks of inhaled tobramycin, the relative change in FEV₁ did not statistically significantly differ between groups (azithromycin (n=56) minus placebo (n=52) difference: 3.44%; 95% CI: -0.48 to 7.35; p=0.085). Differences in secondary clinical outcomes, including patient-reported symptom scores, weight and need for additional antibiotics, did not significantly differ. Among the 29 azithromycin and 35 placebo participants providing paired sputum samples, the 6-week change in P. aeruginosa density differed in favour of the placebo group (difference: 0.75 log₁₀ CFU/mL; 95% CI: 0.03 to 1.47; p=0.043).

Conclusions: Despite having greater reduction in P. aeruginosa density in participants able to provide sputum samples, participants randomised to placebo with inhaled tobramycin did not experience significantly greater improvements in lung function or other clinical outcomes compared with those randomised to azithromycin with tobramycin.

Keywords: bacterial Infection; cystic fibrosis; respiratory Infection.

Publication types

Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Inhalation
Anti-Bacterial Agents / therapeutic use
Azithromycin
Cystic Fibrosis* / complications
Cystic Fibrosis* / drug therapy
Forced Expiratory Volume
Humans
Prospective Studies
Pseudomonas Infections* / drug therapy
Pseudomonas aeruginosa
Tobramycin

Substances

Anti-Bacterial Agents
Azithromycin
Tobramycin

Abstract

Publication types

MeSH terms

Substances

Grants and funding