LONDON—The Pseudomonas aeruginosa infection and inflammation associated with cystic fibrosis (CF) typically lead to lung damage and death. A macrolide antibiotic’s ability to enhance survival in a similar lung condition prompted researchers to test long-term azithromycin therapy in children with CF.[1] Compared with placebo, azithromycin (250 to 500 mg/d for four to six months) significantly improved forced expiratory volume in one second (FEV1) and reduced the number of additional antibiotics prescribed.

“Azithromycin, on a long-term basis, provides a significant benefit to a sufficiently large number of children to merit its use as a treatment in those who are not responding to conventional agents,” said Mark Rosenthal, FRCPCH, consultant in pediatric respiratory medicine at Royal Brompton Hospital, London. “You need multiple approaches; this just adds another to the list.”

Interest in long-term macrolide use for CF patients, Dr. Rosenthal explained, “came about from studies in Japanese men who suffer from a condition … called diffuse panbronchiolitis.” This disorder, like CF, involves chronic mucoid P aeruginosa infection. “They found … that using these antibiotics greatly improved survival,” he added.

The investigators enrolled 41 children with CF into a double-blind, placebo-controlled, six-month crossover trial of azithromycin. Patients weighing up to 40 kg with stable FEV1 were randomized to receive one 250-mg tablet azithromycin or placebo per day for six months; the dose was doubled for those heavier than 40 kg. After a two-month washout period, treatments were switched.

At all time points studied, mean FEV1 and forced vital capacity (FVC) levels were significantly higher with azithromycin than with placebo; median individual differences in FEV1 and FVC were 5.4% and 3.9%, respectively. A significantly greater proportion of patients received more prescriptions for additional oral antibiotics during placebo treatment than during azithromycin treatment. “For six months, it was effective in the majority of individuals,” said Dr. Rosenthal. He cautioned that azithromycin was not effective in all patients; in fact, he added, “We had one or two individuals who got worse.”

The data failed to explain azithromycin’s mode of action. Based on others’ in vitro work, azithromycin “may … work as an anti-inflammatory agent,” Dr. Rosenthal suggested. “But we looked for inflammatory markers, and we saw no difference, even in those who clinically did very well. It remains a mystery,” he admitted.

In addition, “there was an interaction between azithromycin and DNAse: If … DNAse [was given] at the same time, azithromycin appeared to be ineffectual,” said Dr. Rosenthal. Azithromycin treatment alone yielded improvement over placebo in FEV1, FVC, and mid-expiratory flow (median differences, 11.5% , 7.3%, and 21.9%, respectively), but azithromycin with simultaneous DNAse treatment did not (median differences, –3.6%, –4.5%, and –9.5%, respectively). Although the difference in efficacy is unexplained, Dr. Rosenthal noted, “There is some in vitro data suggesting that azithromycin stops the effects of DNAse.”

—Mimi Zucker, PhD

Reference
1. Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet. 2002;360:978-984.

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