Prophylactic azithromycin may reduce exacerbations in primary antibody deficiencies

Antibiotic prophylaxis with azithromycin in individuals with primary antibody deficiencies (PAD) may lead to a reduced risk of respiratory exacerbations, according to a phase II trial presented at ERS 2019.

“In PAD with chronic infection-related pulmonary diseases, long-term prophylaxis with low-dose oral azithromycin reduces respiratory exacerbation rate, additional courses of antibiotics, and hospitalization,” said Dr Cinzia Milito from Sapienza University of Rome in Rome, Italy.

Study participants were 89 adults (mean age 45 years) with PAD (X-linked agammaglobulinemia or common variable immunodeficiency) and chronic pulmonary disease (eg, asthma, bronchiectasis, chronic obstructive pulmonary disease) who were randomized to receive once-daily azithromycin (250 mg; n=44) or placebo (n=45) on three consecutive days/week for 24 months. Throughout the study period, all patients completed diary cards noting symptoms, antibiotic treatments, and adverse events experienced on a monthly basis. Health-related quality of life (HRQoL) questionnaires were collected once a year and blood and sputum samples once every 4 months.

Patients who received azithromycin had a significant reduction in the rate of respiratory exacerbations compared with placebo recipients (mean 3.6 vs 5.2 per patient-year; p=0.02; hazard ratio [HR], 0.5, 95 percent confidence interval [CI], 0.3–0.9; p=0.03). [ERS 2019, abstract RCT 5100; J Allergy Clin Immunol 2019;144:584-593.e7]

There was a 16.1 percent absolute risk reduction in exacerbations among azithromycin recipients, with 10 patients free from exacerbations compared with three in the placebo group (p=0.039).

There was no significant difference between azithromycin and placebo recipients in terms of time to first exacerbation (134.0 vs 104.3 days; p=0.236). However, azithromycin recipients had a reduced likelihood of hospitalization compared with placebo recipients (0.1 vs 0.3 episodes; p=0.014; HR, 0.5, 95 percent CI, 0.2–1.1; p=0.04). They were also less likely to require additional antibiotics to treat respiratory exacerbations than placebo recipients (2.3 vs 3.6 per patient-year; p=0.004; HR, 0.6, 95 percent CI, 0.4–1.0; p=0.02). A greater proportion of azithromycin than placebo recipients did not require additional courses of antibiotics (21 percent vs 5 percent; p=0.030). There was no significant between-group difference pertaining to the change in percentage of predicted FEV₁ over time (p=0.231).

Mean scores in mental-related scales of the short-form 36 (SF-36) questionnaire improved at 1 year in azithromycin recipients, while symptoms based on the St George’s Respiratory Questionnaire were improved at 1 and 2 years among azithromycin recipients (p=0.03 and p=0.04, respectively) as well as placebo recipients.

Sputum swabs obtained from 29 and 30 azithromycin and placebo recipients, respectively, showed that Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa were the most commonly isolated pathogens. The rate of macrolide-resistant bacteria carriers was comparable between groups (p=0.221).

“Azithromycin does not increase the risk of developing bacteria strains not susceptible to macrolides,” said Milito.

However, the rising rates of macrolide resistance must be taken into account, said the authors. Physicians should consider the balance between the risk of driving bacterial resistance and the possible benefits on overall bacterial resistance due to the reduction in antibiotic courses, Milito added.

There were no serious drug-related adverse events or discontinuations in the azithromycin group. All-cause mortality incidence was comparable between azithromycin and placebo recipients (6.8 percent vs 4.4 percent; p=0.489). Patients on azithromycin had a lower risk of diarrhoea (p<0.0001), otitis (p=0.05), rhinitis (p=0.02), and acute sinusitis (p=0.04).

“Despite IgG replacement therapy, patients affected by PAD have a high incidence of infections of the respiratory tract leading over time to chronic lung disease and consequently a decline of lung function,” Milito noted.

“The efficacy of a low-dose macrolide therapy on PAD-related respiratory exacerbation might be explained by the antimicrobial and anti-inflammatory action of the new macrolides, especially on neutrophil chemotaxis, neutrophil-derived elastolytic-like activity, and concentrations of IL-8 and leukotriene B₄,” said the authors.

“In addition to antimicrobial effect, the efficacy on reducing respiratory exacerbations could be empowered by the immunomodulatory effect of azithromycin on the vicious cycle of infection-inflammation,” Milito explained.