Twice-Yearly Azithromycin for Preschoolers May Spark Resistance to Other Drugs

By Gene Emery

November 12, 2020

NEW YORK (Reuters Health) - Four years of treating all preschool children with azithromycin every six months may have reduced childhood mortality, but it appears to be generating resistance to that antibiotic and others, according to a study of 29 Nigerian villages.

"Mass azithromycin distributions twice yearly for 4 years were associated with an increase in both macrolide- and non-macrolide-resistance genes," Dr. Thuy Doan of the University of California, San Francisco, and colleagues report in the New England Journal of Medicine.

During the first two years of distribution to children age 1 to 59 months, childhood mortality declined by 18% compared to those who received a placebo.

During that period, some macrolide resistance was seen in Streptococcus pneumoniae populating the nasopharynx. There also appeared to be some resistance in gut bacteria. Genetic resistance determinants for macrolides were 7.5 times higher than in the villages where the children received placebo, a significant difference.

However, no non-macrolide resistance was seen.

During the subsequent two years, when more than 2,000 rectal swabs were analyzed, a broader resistance pattern appeared in the communities with mass preschool administration of the drug, compared to control communities.

At the three-year mark, macrolide resistance was 7.4 times higher in the antibiotic group and "a notable increase in resistance determinants to several non-macrolide antibiotics was seen," including a doubling of beta-lactam-resistance determinants, the researchers report. Beta-lactams are widely used in sub-Saharan Africa.

Six months after the eighth treatment, traces of macrolide resistance were 7.5 times higher among the children who received the antibiotic. Resistance was nearly twice as high for beta-lactams, 3.6 times higher for metronidazole, and 1.8 times higher for tetracyclines - all significant differences.

Other antibiotics or antibiotic classes also showed increased resistance, including aminoglycosides and trimethoprim, but not at levels that met the unadjusted 95% confidence interval.

Senior author Dr. Thomas Lietman who, like Dr. Doan, is with the Proctor Foundation at UCSF, told Reuters Health in a telephone interview that there's no evidence that the resistance has become clinically relevant and it's gratifying that regular antibiotic therapy continues to show benefit in a region where 10% of children don't make it to their 5th birthday.

"If there's more mortality because of azithromycin resistance, we're not seeing that. Or if azithromycin's reduction in mortality is being mitigated by resistance, we're not seeing that either," he said.

A greater driver of resistance - although not one that has caused a major problem - is the long-term and widespread use of azithromycin to treat the infectious eye disease trachoma. More than 860 million doses have been given out worldwide for that purpose during a 20-year program.

Giving the drug to reduce preschool mortality may be generating less resistance than the trachoma program, Dr. Lietman said,

"With trachoma, we saw the resistance just march up with every year you treat it," he said. "We're going to have to look longer but there's the possibility that 48 (months of childhood therapy to reduce preschool mortality) is not worse than 36."

The balance between maximizing the benefit of regular azithromycin therapy while minimizing drug resistance "is the sweet spot we're still trying to find," Dr. Lietman said.

The researchers also noted that "the prevalence of antibiotic resistance has been shown to predictably decline when mass drug distributions are discontinued, at least for certain antibiotics, such as azithromycin."

"For these mass drug distributions, we have to be quite aware of the potential for multidrug resistance," Dr. Doan told Reuters by phone. "We have to have a surveillance program associated with that, and our goal is to have this surveillance done within countries."

Fortunately, "one of the exciting things here is that we can test for hundreds of different types of resistance using a now-relatively-common technology, deep sequencing or next-generation sequencing" that doesn't require refrigeration, she said.

The study was funded by the Bill and Melinda Gates Foundation and others.

SOURCE: The New England Journal of Medicine, online November 11, 2020.