In the JournalsPerspective

MORDOR 2: Azithromycin MDA remains effective at 3 years in Niger

A mass drug administration, or MDA, of azithromycin remained effective at reducing child mortality in the 3rd year of its implementation in Niger, according to a cluster-randomized trial published in The New England Journal of Medicine.

The second phase of the Mortality Reduction after Oral Azithromycin (MORDOR) trial builds upon the first, in which researchers administered azithromycin to more than 1,500 communities across Niger, Malawi and Tanzania with the hopes of reducing mortality in children aged 1 to 59 months. Children were given four, twice-yearly doses of approximately 20 mg/kg of body weight. The researchers reported that child mortality rates were significantly reduced by 18.1% in communities in Niger where azithromycin was administered. Malawi experienced a 5.7% reduction, and Tanzania a decrease of 3.4%, both of which were deemed nonsignificant differences by the researchers.

To address the possibility of a waning effect on treatment in the recent MORDOR 2 trial, the researchers provided two additional open-label azithromycin distributions to communities in Niger from MORDOR 1 (n = 594). Azithromycin was administered in both the communities that had originally received placebo and those that had received the drug, the researchers wrote. This allowed researchers to compare the 1st and 3rd years of the MDA program. Census workers, who were unaware of participants’ original assignments, assessed all-cause mortality rates twice yearly.

“We found no evidence that the benefit of azithromycin waned in the third year,” Jeremy Keenan, MD, director of international programs at the Francis I. Proctor Foundation for Research Ophthalmology at the University of California, San Francisco, and colleagues wrote. “Some experts had hypothesized that there would be a decrease in efficacy of azithromycin with more distributions owing to the selection of antibiotic-resistant bacteria.”

Infographic about reduction in mortality after azithromycin mass drug administration in Niger 

In previous studies, researchers found that azithromycin MDAs in trachoma programs have selected for macrolide-resistant strains of Streptococcus pneumoniae and Escherichia coli. Resistance was noted in nasopharynx and stool samples in children in Niger during MORDOR 1, but this development does not appear to have reversed any gains the researchers made in reducing mortality rates.

In a related editorial, Naor Bar-Zeev, PhD, MBBS(Hons), MPH, an associate professor of international health at Johns Hopkins Bloomberg School of Public Health, and colleagues said the findings in these studies raised more questions than they answered.

“What mechanism explains these observations?” they wrote. “Which groups would it be best to target with azithromycin? And what of the thorny issue of antimicrobial resistance? Even if benefits are confirmed for some, will antimicrobial resistance cause harm to others? Perhaps our hopes for azithromycin should be more modest.”

A 2018 analysis of MORDOR 1 found that the MDA in Niger resulted in significant changes in the bacterial gut microbiome composition in children. Rather than suggesting the presence of disease, these changes were instead associated with improvements in childhood mortality, researchers said.

A separate secondary analysis concluded that the protective effect from azithromycin came in the first 3 months after distribution, and the researchers suggested that distributing the antibiotic more frequently than twice a year might be feasible. However, the MORDOR 2 findings did not confirm this because Keenan and colleagues “found no evidence that the effect of azithromycin was enhanced with additional distributions.” Rather than increasing or decreasing, its effect was sustained, according to the study.

Results from MDAs have been inconsistent. Findings from a randomized trial published in The New England Journal of Medicine suggested that including azithromycin in an MDA to prevent malaria did not reduce mortality or hospitalizations among children aged 5 years and younger.

A WHO spokesman told Infectious Diseases in Children that WHO’s Guidelines Development Group is still developing guidelines for an azithromycin MDA and the organization will make an announcement once they are finalized. – by Joe Gramigna

References:

Bar-Zeev N, et al. N Engl J Med. 2019;doi:10.1056/NEJMe1906459.

Chandramohan D, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1811400.

Doan T, et al. Open Forum Infect Dis. 2018;doi:10.1093/ofid/ofy182.

Keenan JD, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1715474.

Keenan JD, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1817213.

Porco TC, et al. Clin Infect Dis. 2018;doi:10.1093/cid/ciy973.

Disclosures: Bar-Zeev and colleagues report no relevant financial disclosures. Keenan and colleagues report funding from the Bill and Melinda Gates Foundation.

A mass drug administration, or MDA, of azithromycin remained effective at reducing child mortality in the 3rd year of its implementation in Niger, according to a cluster-randomized trial published in The New England Journal of Medicine.

The second phase of the Mortality Reduction after Oral Azithromycin (MORDOR) trial builds upon the first, in which researchers administered azithromycin to more than 1,500 communities across Niger, Malawi and Tanzania with the hopes of reducing mortality in children aged 1 to 59 months. Children were given four, twice-yearly doses of approximately 20 mg/kg of body weight. The researchers reported that child mortality rates were significantly reduced by 18.1% in communities in Niger where azithromycin was administered. Malawi experienced a 5.7% reduction, and Tanzania a decrease of 3.4%, both of which were deemed nonsignificant differences by the researchers.

To address the possibility of a waning effect on treatment in the recent MORDOR 2 trial, the researchers provided two additional open-label azithromycin distributions to communities in Niger from MORDOR 1 (n = 594). Azithromycin was administered in both the communities that had originally received placebo and those that had received the drug, the researchers wrote. This allowed researchers to compare the 1st and 3rd years of the MDA program. Census workers, who were unaware of participants’ original assignments, assessed all-cause mortality rates twice yearly.

“We found no evidence that the benefit of azithromycin waned in the third year,” Jeremy Keenan, MD, director of international programs at the Francis I. Proctor Foundation for Research Ophthalmology at the University of California, San Francisco, and colleagues wrote. “Some experts had hypothesized that there would be a decrease in efficacy of azithromycin with more distributions owing to the selection of antibiotic-resistant bacteria.”

Infographic about reduction in mortality after azithromycin mass drug administration in Niger 

In previous studies, researchers found that azithromycin MDAs in trachoma programs have selected for macrolide-resistant strains of Streptococcus pneumoniae and Escherichia coli. Resistance was noted in nasopharynx and stool samples in children in Niger during MORDOR 1, but this development does not appear to have reversed any gains the researchers made in reducing mortality rates.

In a related editorial, Naor Bar-Zeev, PhD, MBBS(Hons), MPH, an associate professor of international health at Johns Hopkins Bloomberg School of Public Health, and colleagues said the findings in these studies raised more questions than they answered.

“What mechanism explains these observations?” they wrote. “Which groups would it be best to target with azithromycin? And what of the thorny issue of antimicrobial resistance? Even if benefits are confirmed for some, will antimicrobial resistance cause harm to others? Perhaps our hopes for azithromycin should be more modest.”

PAGE BREAK

A 2018 analysis of MORDOR 1 found that the MDA in Niger resulted in significant changes in the bacterial gut microbiome composition in children. Rather than suggesting the presence of disease, these changes were instead associated with improvements in childhood mortality, researchers said.

A separate secondary analysis concluded that the protective effect from azithromycin came in the first 3 months after distribution, and the researchers suggested that distributing the antibiotic more frequently than twice a year might be feasible. However, the MORDOR 2 findings did not confirm this because Keenan and colleagues “found no evidence that the effect of azithromycin was enhanced with additional distributions.” Rather than increasing or decreasing, its effect was sustained, according to the study.

Results from MDAs have been inconsistent. Findings from a randomized trial published in The New England Journal of Medicine suggested that including azithromycin in an MDA to prevent malaria did not reduce mortality or hospitalizations among children aged 5 years and younger.

A WHO spokesman told Infectious Diseases in Children that WHO’s Guidelines Development Group is still developing guidelines for an azithromycin MDA and the organization will make an announcement once they are finalized. – by Joe Gramigna

References:

Bar-Zeev N, et al. N Engl J Med. 2019;doi:10.1056/NEJMe1906459.

Chandramohan D, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1811400.

Doan T, et al. Open Forum Infect Dis. 2018;doi:10.1093/ofid/ofy182.

Keenan JD, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1715474.

Keenan JD, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1817213.

Porco TC, et al. Clin Infect Dis. 2018;doi:10.1093/cid/ciy973.

Disclosures: Bar-Zeev and colleagues report no relevant financial disclosures. Keenan and colleagues report funding from the Bill and Melinda Gates Foundation.

    Perspective
    Amesh A. Adalja

    Amesh A. Adalja

    The MORDOR 2 trial provides further evidence of the benefit of azithromycin MDA in resource-poor settings. Prior studies have shown a mortality benefit with this practice but were tempered with the possibility that such a benefit would be diminished because such mass distributions would promote antimicrobial resistance. MORDOR 2 shows that this effect is durable through 3 years. Although it remains to be seen how durable this effect is after 3 years, MDA of azithromycin, which traditionally has been associated with trachoma reduction programs but has other antimicrobial and immune-modulating properties, may be an important tool to use in resource-poor countries in which childhood mortality is unacceptably high.

    • Amesh A. Adalja, MD
    • Senior scholar
      Johns Hopkins Center for Health Security

    Disclosures: Adalja reports no relevant financial disclosures.