Azithromycin MDA did not reduce mortality, hospitalization rates

Photo of Daniel Chandramohan
Daniel Chandramohan

Results of a randomized trial published in The New England Journal of Medicine suggest that including azithromycin in a mass drug administration, or MDA, to prevent malaria did not reduce mortality or hospitalizations among children aged 5 years and younger. However, azithromycin modestly reduced the burden of infectious diseases like respiratory and gastrointestinal infections.

The researchers noted that mass administration of azithromycin “has been a highly effective approach to trachoma control,” leading to “reductions in the incidences of skin, gastrointestinal and respiratory infections.” However, Daniel Chandramohan, PhD, professor of public health at the London School of Hygiene & Tropical Medicine, told Infectious Diseases in Children these most recent results suggest that adding azithromycin to antimalarial agents is not warranted as a child survival strategy in areas of Africa where seasonal malaria chemoprevention is provided.

In the study, almost 20,000 children aged 3 to 59 months received either azithromycin or placebo alongside the antimalarial drugs sulfadoxine-pyrimethamine and amodiaquine. The drugs were administered during 3 malaria transmission seasons in Burkina Faso and Mali. According to the researchers 9,735 children received azithromycin and 9,843 received placebo.

In the intention-to-treat analysis, the overall number of deaths and hospital admissions were comparable between the azithromycin and placebo groups — 250 vs. 238 (events per 1,000 child-years at risk = 24.8 vs. 23.5; incidence risk ratio [IRR] = 1.1; 95% CI, 0.88-1.3).

However, when azithromycin was added to malaria chemoprevention, children experienced a reduced disease burden, including gastrointestinal infections (1,647 vs. 1,985 episodes; IRR = 0.85; 95% CI, 0.79-0.91), upper respiratory tract infections (4,893 vs. 5,763 episodes; IRR = 0.85; 95% CI, 0.81-0.9) and nonmalarial febrile illness (1,122 vs. 1,424 episodes; IRR = 0.79; 95% CI, 0.73-0.87).

The researchers said the prevalence of malaria parasitemia and the incidence of adverse events was similar in the two groups.

Chandramohan and colleagues noted that their findings contrast with those from the MORDOR (Mortality Reduction after Oral Azithromycin) trial, which was conducted in sub-Saharan Africa. MORDOR showed that azithromycin given to children aged younger than 5 years twice a year for 2 years was associated with a 13.5% (95% CI, 6.7-19.8) reduction in overall all-cause mortality compared with placebo. The researchers noted that children who were assigned to azithromycin in the latest trial had even greater exposure to the drug — four courses a year for up to 3 years — so the effect on mortality should be at least equal to that seen in MORDOR, “but this was not the case,” they said.

“In malaria-endemic areas where seasonal malaria chemoprevention with sulfadoxine-pyrimethamine and amodiaquine is implemented, adding azithromycin should not be recommended,” Chandramohan said. “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.”

WHO’s Guidelines Development Group is currently meeting to determine whether azithromycin should be added to MDAs. A spokesman told Infectious Diseases in Children that they expect to come to a decision soon. – by Katherine Bortz

References:

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

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

Disclosures: Chandramohan reports no relevant financial disclosures. Please see the study for a list of all other authors’ relevant financial disclosures.

Photo of Daniel Chandramohan
Daniel Chandramohan

Results of a randomized trial published in The New England Journal of Medicine suggest that including azithromycin in a mass drug administration, or MDA, to prevent malaria did not reduce mortality or hospitalizations among children aged 5 years and younger. However, azithromycin modestly reduced the burden of infectious diseases like respiratory and gastrointestinal infections.

The researchers noted that mass administration of azithromycin “has been a highly effective approach to trachoma control,” leading to “reductions in the incidences of skin, gastrointestinal and respiratory infections.” However, Daniel Chandramohan, PhD, professor of public health at the London School of Hygiene & Tropical Medicine, told Infectious Diseases in Children these most recent results suggest that adding azithromycin to antimalarial agents is not warranted as a child survival strategy in areas of Africa where seasonal malaria chemoprevention is provided.

In the study, almost 20,000 children aged 3 to 59 months received either azithromycin or placebo alongside the antimalarial drugs sulfadoxine-pyrimethamine and amodiaquine. The drugs were administered during 3 malaria transmission seasons in Burkina Faso and Mali. According to the researchers 9,735 children received azithromycin and 9,843 received placebo.

In the intention-to-treat analysis, the overall number of deaths and hospital admissions were comparable between the azithromycin and placebo groups — 250 vs. 238 (events per 1,000 child-years at risk = 24.8 vs. 23.5; incidence risk ratio [IRR] = 1.1; 95% CI, 0.88-1.3).

However, when azithromycin was added to malaria chemoprevention, children experienced a reduced disease burden, including gastrointestinal infections (1,647 vs. 1,985 episodes; IRR = 0.85; 95% CI, 0.79-0.91), upper respiratory tract infections (4,893 vs. 5,763 episodes; IRR = 0.85; 95% CI, 0.81-0.9) and nonmalarial febrile illness (1,122 vs. 1,424 episodes; IRR = 0.79; 95% CI, 0.73-0.87).

The researchers said the prevalence of malaria parasitemia and the incidence of adverse events was similar in the two groups.

Chandramohan and colleagues noted that their findings contrast with those from the MORDOR (Mortality Reduction after Oral Azithromycin) trial, which was conducted in sub-Saharan Africa. MORDOR showed that azithromycin given to children aged younger than 5 years twice a year for 2 years was associated with a 13.5% (95% CI, 6.7-19.8) reduction in overall all-cause mortality compared with placebo. The researchers noted that children who were assigned to azithromycin in the latest trial had even greater exposure to the drug — four courses a year for up to 3 years — so the effect on mortality should be at least equal to that seen in MORDOR, “but this was not the case,” they said.

“In malaria-endemic areas where seasonal malaria chemoprevention with sulfadoxine-pyrimethamine and amodiaquine is implemented, adding azithromycin should not be recommended,” Chandramohan said. “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.”

WHO’s Guidelines Development Group is currently meeting to determine whether azithromycin should be added to MDAs. A spokesman told Infectious Diseases in Children that they expect to come to a decision soon. – by Katherine Bortz

References:

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

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

Disclosures: Chandramohan reports no relevant financial disclosures. Please see the study for a list of all other authors’ relevant financial disclosures.