An extended course of low-dose azithromycin (multiple brands) may significantly reduce treatment failure in patients hospitalized for acute exacerbation of chronic obstructive pulmonary disease (COPD), new data suggest.
Although the clinical benefits of the strategy appear to wane over time after discontinuation of the antibiotic, "our proposed intervention may help to address the highest risk period for readmission and provide a new treatment strategy for severe infectious AECOPD [acute exacerbation of COPD] requiring hospitalization," Kristina Vermeersch of the Department of Respiratory Diseases at University Hospitals Leuven in Belgium, and colleagues write in an article published online in the American Journal of Respiratory and Critical Care Medicine.
In previous studies, the addition of long-term azithromycin therapy to standard care has been associated with a reduced risk for COPD exacerbations in patients frequently hospitalized for the respiratory disorder, but this is the first study to investigate the strategy when the drug is initiated at hospital admission, the authors write.
The multicenter trial analyzed outcomes of 301 COPD patients hospitalized with an acute exacerbation. The patients were randomly assigned to treatment with azithromycin (n = 147) or placebo (n = 154) within 48 hours of admission. The treatment group received azithromycin 500 mg for 3 days, followed by azithromycin 250 mg every second day for 90 days. The primary outcome was time to treatment failure, defined as the occurrence any one of three outcomes: the need for treatment intensification, the need for step-up hospital care, or death by any cause.
Overall, 69 patients in the azithromycin group (49%) and 86 in the placebo group (60%) experienced treatment failure (hazard ratio [HR], 0.73; 95% confidence interval [CI], .53 – 1.01; P = .0526) during the treatment phase, the authors report.
Although the 18% difference in treatment failure rates was not statistically significant, the results point to a strong trend in favor of the intervention, the authors say. The trial, they note, was underpowered because the enrollment target was reduced, owing to slow recruitment, according to the authors. This could have led to the lack of statistical significance.
However, when analyzed individually, two of the three components of treatment failure showed statistically significant reductions with azithromycin in comparison with placebo. Specifically, within 3 months of randomization, 47% of patients in the azithromycin group required treatment intensification, vs 60% in the placebo group (HR, 0.70; 95% CI, .51 – .97, P = .0272), and 13% of patients in the azithromycin group required step-up care or readmission, vs 28% in the placebo group (HR, .43; 95% CI, .25 – .75; P = .0024). There was no significant difference in mortality among the two groups, at 2% vs 4% (HR, 0.62; 95% CI, .15 – 2.59; P = .5075).
Azithromycin treatment was beneficial regarding to several measures during hospitalization. Length of hospital stay during the 3-month period was reduced from an average of 14 days to 11 days, and the average number of days in the intensive care unit was reduced from 11 days to 3 days, the authors report.
During the course of the study, three events involving QTc prolongation occurred, two in the treatment group and one in the placebo group. Neither this difference nor that observed for any other adverse event was significant, the authors note.
The maximum between-group differences in treatment failure rates were observed 30 days following drug discontinuation. After discontinuation, the treatment failure rates for both groups converged and overlapped. "Clear convergence of the time-to-event curves 6 months after withdrawal demonstrates that prolonged treatment appears to be needed to sustain its clinical benefits," the authors write. It's possible, they add, that more than 3 months of treatment might be needed to "sufficiently interrupt the vicious circle of inflammation to alter the phenotype of 'frequent exacerbator,' " they write.
By bridging the in-hospital treatment of severe COPD exacerbation and post-discharge ambulatory care, the proposed intervention addresses a gap in the acute treatment of these patients during which an active inflammatory process may still be "smoldering," the authors write. Apart from recent trials that reported reductions in hospital admissions with inhaled corticosteroids and phosphodiesterase-4 inhibitors, "no other evidence-based chronic intervention has demonstrated such a large potential on top of maintenance therapy with long-acting bronchodilators," they continue.
The intervention strategy proposed by the authors has important clinical implications, according to James F. Donahue, MD, professor of medicine in the Division of Pulmonary and Critical Care Medicine at the University of North Carolina at Chapel Hill School of Medicine. "Treatment failure and relapse is a major issue in COPD," he said in an interview with Medscape Medical News. "Reducing the rates of these outcomes could reduce the burden of the disease and improve the management of these patients."
Azithromycin is widely used in pulmonary medicine to treat such conditions as bronchiolitis obliterans organizing pneumonia, panbronchiolitis, and small airway disease, among others. Besides its antibiotic effects, it also has important nonantibiotic effects that may contribute to its efficacy in these patients, Donahue said. "Macrolides have an effect on the function of goblet cells and submucosal glands. Reducing airway mucus hypersecretion, such as in chronic bronchitis, they affect goblet cells and mucus glands," he explained.
Donahue stressed that the intervention strategy should be considered carefully, particularly with respect to antibiotic stewardship. He noted that the potential for antibiotic overuse "in an already overused environment" could change microbial resistance patterns.
The authors acknowledge that bacterial resistance is the main risk of long-term azithromycin use. In the study, the investigators monitored for resistance, but the limited number of sputum samples precluded thorough evaluation of azithromycin-induced resistance.
Given the potential for antibiotic resistance, as well as the possibility of proarrhythmic effects, the researchers recommend a "careful and individualized approach" to the selection of patients who might benefit the most from this treatment.
The study was funded by the Flemish Government Agency for Innovation by Science and Technology (FWO Vlaanderen), the Belgium Respiratory Society, and TEVA, Belgium. The study authors report financial relationships with multiple companies, including Boehringer-Ingelheim, AstraZeneca, Novartis, Chiesi, GlaxoSmithKline, UCB Pharma, MSD, Pfizer, Teva, Zambon, and Sanofi/Regeneron. Donahue has disclosed no relevant financial relationships.
Am J Respir Crit Care Med. Published online May 3, 2019.