Investigators find increased treatment regimen is effective and long-lasting for patients.
Reviewed by Thuy Doan, MD, PhD
The potential mechanisms by which mass distribution of azithromycin improves health and childhood mortality and its effects on both human microbiomes and antimicrobial resistance were discussed recently by Thuy Doan, MD, PhD.
“As of 2020, approximately 1 billion doses of azithromycin [have been] distributed worldwide for trachoma elimination,” Doan said. “It is now proven that mass distribution of azithromycin to preschool children improves childhood mortality [rates]. Furthermore, azithromycin is one of the most-prescribed oral antibiotics in the United States, and it was the No. 1 prescribed antibiotic worldwide to patients with SARS-CoV-2 [severe acute respiratory syndrome coronavirus 2] infection at one point during the pandemic.”
Doan is director of the Ralph and Sophie Heintz Laboratory, Francis I. Proctor Foundation, at the University of California, San Francisco.
Doan pointed out that the effects of mass distribution of azithromycin are long-lasting.
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“In a series of studies, we have shown that mass drug distribution affects the microbiomes of the ocular surface, nasopharynx, and gut,” Doan said. “It decreases the pathogen load in the gut, particularly Campylobacter species, and the alpha and beta coronaviruses in the nasopharynx.”
Doan noted that azithromycin alters the structure of the ocular surface microbiome and the bacterial community diversity of the ocular surface.
“Not surprisingly, we found that mass distribution of azithromycin for 2 years increases macrolide resistance determinants in the gut, but it does not affect the resistance determinants of other classes of antibiotics in the gut,” Doan said.
Benefits and risks
The first evidence that mass distribution of oral azithromycin in a trachoma-endemic area reduced mortality in children came from a randomized study conducted in Ethiopia led by Thomas M. Lietman, MD.
The benefit was confirmed in the MORDOR study, which was a larger scale investigation run by the Proctor Foundation, sponsored by the Bill and Melinda Gates Foundation. It involved communities in 3 sub-Saharan African countries.
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According to Doan, the reduction in childhood mortality with mass azithromycin treatment could be partly attributed to the antimicrobial activity of the antibiotic, which led to reduced rates of malaria, dysentery, meningitis, and pneumonia.
Studies of the effects of mass distribution of azithromycin on the human microbiome were undertaken after analyses of conjunctival, nasopharyngeal, and rectal swabs from a subgroup of children in the MORDOR study identified microbiome changes.
The analyses focused on the top 15 genera of bacteria in the gut identified by RNA deep sequencing and evaluated changes after 4 biannual distributions of azithromycin and placebo.
The results showed no difference in Campylobacter load at baseline between treatment arms, but there was a reduction in Campylobacter at the genus level in the gut microbiome of children treated with azithromycin at 24 months.
In addition, at the species level, C upsaliensis was significantly more abundant in the control group compared with children who received azithromycin.
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The findings were replicated in an individual randomized controlled study conducted in another sub-Saharan country.
“These results make sense because we know Campylobacter infections could potentially result in mortality by causing dysentery and malnutrition,” Doan said. “Taken together, they suggest that Campylobacter spp likely play an important role in childhood health in sub-Saharan Africa.”
The investigators also evaluated the role of viral infections in childhood mortality by using RNA deep sequencing to interrogate the nasopharyngeal virome.
“In this study we were surprised to find a relative reduction in coronavirus both at the genus level and also at the species level in villages [where individuals] were treated with azithromycin,” Doan noted.
“The significance of these findings escaped us until the beginning of 2020 when we started to hear about outbreaks of respiratory distress syndrome in China that were associated with a novel coronavirus now known as SARS-CoV-2.”
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The coronaviruses isolated from the African children belong to the same genus as SARS-CoV-2 and are known human pathogens reported to cause respiratory tract infection, meningitis, and gastroenteritis in children.
“These particular viruses generally cause self-limiting diseases, although deaths have been reported in children and immunocompromised patients,” Doan said. “Although we do not know if clinical severity depends on viral load and our study was not designed to study the effect of the virus in childhood mortality, we do know that treatment with azithromycin was associated with a reduction in coronavirus levels. The change in the virome is intriguing, as we do not expect antibiotics to affect viruses. This may be a unique property of azithromycin.”
Evaluation of the biospecimens from conjunctival swabs showed that azithromycin treatment also altered the structure of the ocular surface microbiome, at least at the community level, Doan said.
Comparisons between the placebo- and azithromycin-treated children showed that the density distribution of the ocular surface microbiome was similar at baseline in the 2 groups but differed significantly after 24 months of treatment because of increased diversity in the azithromycin group.
“Generally, we associate an increase in diversity with health, whereas a decrease in diversity is associated with disease,” Doan said.
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Probing antibiotic resistance
Accompanying the practice of mass antibiotic distribution is the concern that it will promote selection of bacteria resistant to the specific class of antibiotic and to other classes.
This issue was addressed by evaluating resistance gene expression of Streptococcus pneumoniae isolated from the nasopharynx and of gut bacteria sequences from rectal swabs.
Focusing on the results for the gut, Doan reported that after 4 biannual distributions, the prevalence of macrolide resistance gene expression was increased significantly among children residing in villages who received azithromycin compared with placebo. However, coresistance of other classes of antibiotics was not detected.
Thuy Doan, MD, PhD
Doan delivered the Jones/Smolin Lecture at the American Academy of Ophthalmology’s virtual 2020 annual meeting. Doan has no relevant financial interests to disclose.