Impact of azithromycin on the clinical and antimicrobial effectiveness of tobramycin in the treatment of cystic fibrosis

Abstract

Background Concomitant use of oral azithromycin and inhaled tobramycin occurs in approximately half of US cystic fibrosis (CF) patients. Recent data suggest that this combination may be antagonistic. Methods Test the hypothesis that azithromycin reduces the clinical benefits of tobramycin by analyses of clinical trial data, in vitro modeling of P. aeruginosa antibiotic killing, and regulation of the MexXY efflux pump. Results Ongoing administration of azithromycin associates with reduced ability of inhaled tobramycin, as compared with aztreonam, to improve lung function and quality of life in a completed clinical trial. In users of azithromycin FEV1 (L) increased 0.8% during a 4-week period of inhaled tobramycin and an additional 6.4% during a subsequent 4-week period of inhaled aztreonam (P < 0.005). CFQ-R respiratory symptom score decreased 1.8 points during inhaled tobramycin and increased 8.3 points during subsequent inhaled aztreonam (P < 0.001). A smaller number of trial participants not using azithromycin had similar improvement in lung function and quality of life scores during inhaled tobramycin and inhaled aztreonam. In vitro, azithromycin selectively reduced the bactericidal effects tobramycin in cultures of clinical strains of P. aeruginosa, while up regulating antibiotic resistance through MexXY efflux. Conclusions Azithromycin appears capable of reducing the antimicrobial benefits of tobramycin by inducing adaptive bacterial stress responses in P. aeruginosa, suggesting that these medications together may not be optimal chronic therapy for at least some patients.

Inflammation in cystic fibrosis: An update

“…Azithromycin is remarkably able to concentrate and persist in the airway—particularly within airway leukocytes . More recent laboratory research shows that azithromycin, when tested in media environments more similar to the mammalian airway, can inhibit growth or even kill relevant bacteria such as P aeruginosa or other Gram‐negative pathogens at physiologically relevant concentrations . Others report that azithromycin primes the host immune response to better resist viral infection .…”

“…Investigators, including those who led the pivotal clinical trials of azithromycin in CF, recognize a need to study the impact of this therapy when used beyond several months. Others, including our group, raise concerns about a potential for azithromycin to inhibit the antimicrobial effects of other antibiotics—namely tobramycin . This concern has led to an ongoing clinical trial (NCT02677701) that hopes to better clarify this potential risk.…”

“…[169][170][171][172][173][174] More recent laboratory research shows that azithromycin, when tested in media environments more similar to the mammalian airway, can inhibit growth or even kill relevant bacteria such as P aeruginosa or other Gram-negative pathogens at physiologically relevant concentrations. [175][176][177] Others report that azithromycin primes the host immune response to better resist viral infection. [178][179][180] If true, then this mechanism may help to explain how chronic macrolide therapy reduces the risk of or improves recovery from acute pulmonary exacerbations for people with a variety of lung diseases, ranging from CF with or without P aeruginosa infection to COPD in older populations and bronchiolitis in young children.…”

“…Others, including our group, raise concerns about a potential for azithromycin to inhibit the antimicrobial effects of other antibiotics-namely tobramycin. 177,[184][185][186] This concern has led to an ongoing clinical trial (NCT02677701) that hopes to better clarify this potential risk. Studies to understand if azithromycin remains beneficial to CF patients over several years of chronic use may only be possible through careful retrospective analyses of large patient populations, such as the CFFPR.…”

Infection prevention and chronic disease management in cystic fibrosis and noncystic fibrosis bronchiectasis

“…Interestingly there was an increase in ppFEV 1 and QOL in patients using azithromycin with inhaled aztreonam. 73 To further study the relationship between inhaled tobramycin and enteral azithromycin, Seattle Children's Hospital is sponsoring a phase IV prospective, randomized, double-blinded, placebo-controlled trial of the addition of thrice weekly azithromycin 500 mg to chronic inhaled tobramycin in adolescents and adults with CF (NCT02677701).…”