Azithromycin antibiotic not found to affect airway microbiome in CF

While adding azithromycin to another antibiotic, called tobramycin, showed benefits in children with cystic fibrosis (CF) and early Pseudomonas aeruginosa infections, these outcomes were not due to the medication’s effects on the community of microbes  — known as the microbiome — living in the airways.

That’s according to a new study that suggested that the improved outcomes seen with the use of azithromycin as an add-on treatment in a clinical trial might be linked to other mechanisms. Children in that trial, known as OPTIMIZE, saw a reduction in pulmonary exacerbations, or periods of acute symptom worsening, and increased body weight.

According to the researchers, “the mechanism of action for [azithromycin] is unlikely to be directly affecting the airway microbiome.”

The study, “Limited effects of azithromycin on the oropharyngeal microbiome in children with CF and early pseudomonas infection,” was published in the journal BMC Microbiology.

Understanding the mechanisms underlying the antibiotic azithromycin

Infections with the bacteria Pseudomonas aeruginosa, known as P. aeruginosa for short, are common among people with CF, and are associated with reduced lung function and worse outcomes. An antibiotic such as tobramycin or azithromycin, either alone or in combination, often is used to treat an initial infection and improve patient outcomes.

The Phase 3 OPTIMIZE trial (NCT02054156), completed in 2018, tested the use of azithromycin as an add-on to a tobramycin inhalation solution (TIS) in children with CF at the early stages of a P. aeruginosa infection. Data showed that the combination antibiotic treatment led to fewer pulmonary exacerbations and increased body weight among patients compared with TIS plus a placebo.

However, no differences were seen in P. aeruginosa eradication or recurrence, which suggested that the benefits shown in the trial might be linked with other mechanisms.

Now, a team led by researchers at the University of Colorado hypothesized that both TIS and azithromycin may modulate the airway microbiome.

To find out, they analyzed airway samples collected via oropharyngeal swabs during the OPTIMIZE trial, which had enrolled a total of 221 children. All participants were given TIS, and were randomly assigned to either azithromycin or the placebo. Azithromycin was given three times a week; TIS was administered twice daily.

Altogether, 110 patients, with a mean age of 6.7, received the azithromycin with TIS, while 111 patients, with a mean age of 6.9, were given the placebo in addition to the TIS solution.

Subsequently, depending on the presence or absence of P. aeruginosa, patients continued to receive their assigned treatment for up to 26 weeks, or about six months. A total of 42 patients received the combo of TIS and azithromycin, while 43 were given TIS and the placebo. Another 13 patients were given three series of TIS and azithromycin, and 10 children received three series of TIS and the placebo.

Airway samples were analyzed using a genetic sequencing method to determine their composition and diversity.

Streptococcus was the most abundant genus (type) at the study’s start, being dominant in 80 patients. However, in general, no single bacterial genus dominated the microbiome of 72 patients.

Investigating differences in bacteria such as P. aeruginosa

A first analysis comparing samples at the start of the study and after three weeks, showed that the bacterial communities changed regardless of receiving azithromycin.

After three weeks of treatment, both groups showed a significant decrease in total bacterial load and microbial diversity, as assessed by the Shannon Diversity Index. No significant differences were seen in the abundance of P. aeruginosa or Staphylococcus aureus, another bacteria linked with worse outcomes in CF patients.

In contrast, other bacteria not traditionally linked with CF showed marked decreases, including Veillonella, Lactobacillales, Streptococcus parasanguinis, Gemella, Neisseria subflava, and Leptotrichia. Also in both groups, Prevotella melaninogenica, Porphyromonas, Rothia and Erysipelotrichaceae were more abundant.

In general, the microbial changes detected after three weeks were no longer seen after nearly three months (13 weeks). The same was found at the end of the study, with the bacterial communities now being similar to results at the study’s start.

This study provides further evidence that the mechanism for [azithromycin’s] effect on clinical outcomes is not due solely to action on airway microbial composition.

The researchers then found that among children with large shifts in their bacterial communities at weeks three and 13, treatment with TIS plus azithromycin led to fewer pulmonary exacerbations compared with TIS plus a placebo (42% vs. 85%). The time to develop a first pulmonary exacerbation was increased with azithromycin. No such effects were seen in participants with more stable bacterial communities.

Overall, “this study provides further evidence that the mechanism for [azithromycin’s] effect on clinical outcomes is not due solely to action on airway microbial composition,” the researchers wrote.

“Our findings suggest that the impact on clinical outcomes observed during the OPTIMIZE trial was not due to antimicrobial effect by [azithromycin],” the team concluded.