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Azaithromycin MDA remains effective at 3 years in Niger
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A mass drug administration, or MDA, with azithromycin remained effective at reducing child mortality in the third 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 hope of reducing mortality in children aged 1 to 59 months. Between December 2014 and February 2017, children were given four twice-yearly doses of approximately 20 mg/kg of body weight of azithromycin. 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%, but both were deemed nonsignificant differences by the researchers.
Some experts have expressed concern that the development of antimicrobial resistance may reduce the treatment’s effect on mortality. To address this possibility, the researchers conducted MORDOR 2, extending the MDA program in communities in Niger from MORDOR 1 (n = 594) for another year. Azithromycin was administered in the communities that had originally received placebo, as well as those that had received the drug. This allowed researchers to compare the first and third years of the MDA program. Census workers who were unaware of patients’ original assignments assessed all-cause mortality rates twice a year, allowing researchers to compare the first and third years of mass azithromycin treatment.
Lietman
“We’ve shown that taking oral azithromycin twice a year for 2 years reduced childhood mortality in sub-Saharan Africa,” study researcher Thomas M. Lietman, MD, director of the Francis I. Proctor Foundation for Research in Ophthalmology at the University of California, San Francisco, told Infectious Diseases in Children. “Concern that resistance might quickly reduce efficacy led us to this study, where we demonstrated that the effect in the third year of treatment was just as effective as the first year.”
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 among preschool-aged children.
“We, like others, are quite concerned about antibiotic resistance,” Lietman said. “We know mass azithromycin selects for antibiotic-resistant strains of bacteria in the nasopharynx and the gut from trachoma programs and MORDOR 1, as Thuy Doan reported in The New England Journal of Medicine. We found it encouraging that we were unable to detect a decrease in efficacy against mortality in the third year.”
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.”
They did note, however, that it was “ingenious” of the research team to assess concurrent mortality rates among children who were newly exposed to azithromycin compared with those who had previously received azithromycin for 2 years, but in light of the uncertainties raised, the policy implications remain unclear.
A closer look at the results
A 2018 analysis of MORDOR 1 found that the MDA in Niger resulted in significant changes in the bacterial gut microbiome composition in children who were randomly assigned to receive azithromycin. Rather than suggesting the presence of disease, these changes were instead associated with improvements in childhood mortality, researchers explained.
A separate secondary analysis compared survival time after treatment in the azithromycin and placebo-treated communities. The researchers found that the protective effect from azithromycin came in the first 3 months after distribution, and they suggested that distributing the antibiotic more frequently than twice a year might offer further protection. However, MORDOR 2, which assessed biannual treatments for an additional year, did not confirm this because Lietman and colleagues said they “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.
Impact on health policy
Results from MDAs have been inconsistent. Findings from a randomized trial that were also published in The New England Journal of Medicine this year suggested that including azithromycin in an MDA to prevent malaria in Africa did not reduce mortality or hospitalizations among children aged 5 years and younger.
Study researcher Daniel Chandramohan, PhD, professor of public health at the London School of Hygiene & Tropical Medicine, told Infectious Diseases in Children that adding azithromycin to antimalarial agents is not warranted as a child survival strategy in areas of Africa where seasonal malaria chemoprevention is given.
“Although it reduces morbidity related to some infections by a modest amount, this needs to be balanced against the risks of enhancing resistance to this valuable antibiotic,” he said in a previous interview.
However, with the MORDOR studies demonstrating a sustained reduction in mortality in the context of a trachoma MDA program, the question remains as to whether MDAs should be incorporated into current health policy.
“If we were to implement these as policy, we’d need to continue to monitor for resistance and decreased efficacy for longer than 3 years,” Lietman said.
A WHO spokesman told Infectious Diseases in Children that WHO’s Guidelines Development Group is still putting together its recommendations for an azithromycin MDA, and that 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, including Lietman, report funding from the Bill and Melinda Gates Foundation.
Perspective
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Amesh A. Adalja, MD
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.
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