In the Journals

AMAZES: Azithromycin may increase antibiotic resistance in severe asthma

In a substudy of the AMAZES trial, azithromycin, when used as a treatment for exacerbations in patients with severe asthma, reduced Haemophilus influenzae load but also increased resistance to antibiotics, researchers reported in the American Journal of Respiratory and Critical Care Medicine.

“Acquired macrolide resistance is a global health concern, particularly relating to the treatment of infections where macrolides are routinely prescribed, such as in nontuberculous Mycobacterium infections and atypical infections in community-acquired pneumonia and sexually transmitted infections,” they wrote. “Identifying reservoirs of transmissible resistance genes is a global health strategy to limit the dissemination of antibiotic resistance to the wider community; however, this has not been investigated in patients receiving azithromycin in asthma.”

The 48-week, double-blind, placebo-controlled AMAZES trial evaluated the use of oral azithromycin 500 mg administered three times per week in adults with persistent, uncontrolled asthma. In this analysis, the investigators performed 16S rRNA sequencing and quantitative polymerase chain reaction to assess the effect of azithromycin on sputum microbiology in the trial participants.

Effects on bacterial load, antibiotic resistance

Of the 420 patients enrolled in the trial, paired sputum samples from 61 patients, including 34 in the placebo group and 27 in the azithromycin group, were included in the analysis.

After 48 weeks of treatment, azithromycin did not appear to affect total bacterial load, but it was associated with a significant decrease in bacterial diversity (P = .026), which was not observed with placebo. Results also denoted a significant difference in microbiome composition among patients assigned azithromycin (P = .014) that was also seen in higher unweighted UniFrac distance with azithromycin vs. placebo (P = .022).

“Together, these results demonstrate that, in the lower airways, azithromycin therapy reduces bacterial diversity while total bacterial levels remain unchanged,” the researchers wrote.

Azithromycin was also linked to a significant reduction in H. influenzae load (P < .0001), but the treatment appeared to have no effect on Streptococcus pneumonia, Staphylococcus aureus, Pseudomonas aeruginosa or Moraxella catarrhalis loads.

The investigators identified 89 antibiotic resistance genes across the sputum samples. Of these, they noted significant increases in five macrolide resistance genes and two tetracycline resistance genes.

“These results highlighted the need for studies assessing the efficacy of nonantibiotic macrolides as a long-term therapy for patients with persistent uncontrolled asthma,” the researchers wrote.

Major concerns

In an accompanying editorial, Tobias Welte, MD, from the department of respiratory medicine and infectious diseases at Medizinische Hochschule Hannover and a member of the German Center of Lung Research in Germany, highlighted his concerns regarding the findings.

“The study has a number of strengths. It is a prospective randomized controlled study, and the microbiome workup had been performed according to established and worldwide accepted standards. Nevertheless, the study results leave me helpless,” he wrote. “The decrease in microbiome diversity has been shown to be detrimental with regard to the long-term prognosis in different diseases.”

He also noted that the increase in macrolide resistance is “not good news.”

The respiratory microbiome appeared to play an important role in preventing exacerbations in chronic respiratory diseases and these findings should give clinicians pause, according to Welte.

“There is no doubt that antibiotics affect both the gastrointestinal and respiratory microbiome. However, in the age of a worldwide increase in antibiotic resistance, it is questionable whether the broad use of antibiotics as maintenance treatment for chronic diseases is a wise decision, as antibiotic resistance is closely correlated to infectious disease-related mortality,” he wrote. “King Arthur and the Knights of the Round Table died, and the Holy Grail was lost forever. Even though this is only a Welsh tale, it should be a lesson.” – by Melissa Foster

Disclosure s: One author reports personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Menarini and Novartis and nonfinancial support from GlaxoSmithKline. A second author reports grants from GSK Australia and grants and other support from AstraZeneca Australia. A third author reports grants and personal fees from AstraZeneca and GSK, personal fees and other support from Novartis and Boehringer Ingelheim and other support from Menarini. A third author reports grants from the National Health and Medical Research Council, grants and fees from AstraZeneca, GlaxoSmithKline and Novartis. A fourth author reports grants from the National Health and Medical Research Council and other forms of support from Boehringer Ingelheim. All other authors report no relevant financial disclosures. Welte reports personal fees from AstraZeneca, Boehringer Ingelheim, Berlin Chemie, GSK, Novartis and Teva.

In a substudy of the AMAZES trial, azithromycin, when used as a treatment for exacerbations in patients with severe asthma, reduced Haemophilus influenzae load but also increased resistance to antibiotics, researchers reported in the American Journal of Respiratory and Critical Care Medicine.

“Acquired macrolide resistance is a global health concern, particularly relating to the treatment of infections where macrolides are routinely prescribed, such as in nontuberculous Mycobacterium infections and atypical infections in community-acquired pneumonia and sexually transmitted infections,” they wrote. “Identifying reservoirs of transmissible resistance genes is a global health strategy to limit the dissemination of antibiotic resistance to the wider community; however, this has not been investigated in patients receiving azithromycin in asthma.”

The 48-week, double-blind, placebo-controlled AMAZES trial evaluated the use of oral azithromycin 500 mg administered three times per week in adults with persistent, uncontrolled asthma. In this analysis, the investigators performed 16S rRNA sequencing and quantitative polymerase chain reaction to assess the effect of azithromycin on sputum microbiology in the trial participants.

Effects on bacterial load, antibiotic resistance

Of the 420 patients enrolled in the trial, paired sputum samples from 61 patients, including 34 in the placebo group and 27 in the azithromycin group, were included in the analysis.

After 48 weeks of treatment, azithromycin did not appear to affect total bacterial load, but it was associated with a significant decrease in bacterial diversity (P = .026), which was not observed with placebo. Results also denoted a significant difference in microbiome composition among patients assigned azithromycin (P = .014) that was also seen in higher unweighted UniFrac distance with azithromycin vs. placebo (P = .022).

“Together, these results demonstrate that, in the lower airways, azithromycin therapy reduces bacterial diversity while total bacterial levels remain unchanged,” the researchers wrote.

Azithromycin was also linked to a significant reduction in H. influenzae load (P < .0001), but the treatment appeared to have no effect on Streptococcus pneumonia, Staphylococcus aureus, Pseudomonas aeruginosa or Moraxella catarrhalis loads.

The investigators identified 89 antibiotic resistance genes across the sputum samples. Of these, they noted significant increases in five macrolide resistance genes and two tetracycline resistance genes.

“These results highlighted the need for studies assessing the efficacy of nonantibiotic macrolides as a long-term therapy for patients with persistent uncontrolled asthma,” the researchers wrote.

Major concerns

In an accompanying editorial, Tobias Welte, MD, from the department of respiratory medicine and infectious diseases at Medizinische Hochschule Hannover and a member of the German Center of Lung Research in Germany, highlighted his concerns regarding the findings.

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“The study has a number of strengths. It is a prospective randomized controlled study, and the microbiome workup had been performed according to established and worldwide accepted standards. Nevertheless, the study results leave me helpless,” he wrote. “The decrease in microbiome diversity has been shown to be detrimental with regard to the long-term prognosis in different diseases.”

He also noted that the increase in macrolide resistance is “not good news.”

The respiratory microbiome appeared to play an important role in preventing exacerbations in chronic respiratory diseases and these findings should give clinicians pause, according to Welte.

“There is no doubt that antibiotics affect both the gastrointestinal and respiratory microbiome. However, in the age of a worldwide increase in antibiotic resistance, it is questionable whether the broad use of antibiotics as maintenance treatment for chronic diseases is a wise decision, as antibiotic resistance is closely correlated to infectious disease-related mortality,” he wrote. “King Arthur and the Knights of the Round Table died, and the Holy Grail was lost forever. Even though this is only a Welsh tale, it should be a lesson.” – by Melissa Foster

Disclosure s: One author reports personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Menarini and Novartis and nonfinancial support from GlaxoSmithKline. A second author reports grants from GSK Australia and grants and other support from AstraZeneca Australia. A third author reports grants and personal fees from AstraZeneca and GSK, personal fees and other support from Novartis and Boehringer Ingelheim and other support from Menarini. A third author reports grants from the National Health and Medical Research Council, grants and fees from AstraZeneca, GlaxoSmithKline and Novartis. A fourth author reports grants from the National Health and Medical Research Council and other forms of support from Boehringer Ingelheim. All other authors report no relevant financial disclosures. Welte reports personal fees from AstraZeneca, Boehringer Ingelheim, Berlin Chemie, GSK, Novartis and Teva.