It is easy to overlook the basic role antibiotics have for those without readily available supplies as we strategize methods to tackle antimicrobial resistance (AMR). Antibiotic stewardship, reduction of antibiotics in agriculture, and stringent infection control practices, are only handful of the control methods being utilized. In our quest for getting a handle on AMR, a recent study
has posed a unique dilemma for future efforts.
A research team from the University of California, San Francisco, that included Jeremy Keenan, MD, MPH, and Thomas Lietman, MD, and supported by a grant through the Bill and Melinda Gates Foundation, sought to evaluate the efficacy of mass-distribution of a broad-spectrum antibiotic to school-age children as a means of reducing mortality in Sub-Saharan Africa. The randomized trial distributed oral azithromycin (20mg per kilogram of body weight) or a placebo in twice-yearly mass distributions to children aged 1 to 59 months in communities within Malawi, Niger, and Tanzania. A total of 97,047 children were enrolled in the azithromycin group and 93,191 were enrolled in the placebo group. The trial took place over 4 years and ultimately revealed a lower mortality rate in those communities randomly assigned to mass distribution of azithromycin versus the placebo. The overall mortality rate was 14.6 deaths per 1000 person-years in azithromycin communities, while those given the placebo had 16.5 deaths per 1000 person-years. “Mortality was 13.5% lower overall in communities that received azithromycin than in communities that received placebo," the study authors wrote. The investigators reported that serious adverse health events were uncommon within 1 week following the mass distribution of either pill and that children aged 1 to 5 months had the greatest benefit in terms of decreased mortality.
What this study ultimately shows is the considerable impact that mass distribution of a broad-spectrum antibiotic can have against childhood mortality in Sub-Saharan Africa. Following the publication of the study, however, many have flagged the moral dilemma that follows such results. Although the authors make note of the need for policy implementation for future practices and the potential for antimicrobial resistance, the study has nonetheless posed unique ethical questions. The benefits of mass distribution were supported by their research; however, what sort of long-term costs will such communities pay?
On one hand, a closely monitored program could provide reduced mortality to millions of children; however, it could also result in irreversible antimicrobial resistance in regions that already struggle to access antibiotics.
Dr. Keenan was kind enough to answer some of the questions I had regarding their research:
Why Did You Choose to Use Azithromycin? Did You Consider Using Other Antibiotics?
: We have done many studies with mass azithromycin for trachoma. Trachoma is a neglected tropical disease caused by ocular chlamydia infection and the World Health Organization (WHO) recommends annual mass azithromycin distributions to clear ocular chlamydia, using just a single dose. In a prior cluster-randomized trial, Dr. Lietman designed a secondary analysis to compare the childhood mortality rate in communities given mass azithromycin (in several different frequencies) versus untreated communities. That study (JAMA 2009; 302:962) found 50% less reduction in mortality in the azithromycin-treated communities. We thought that was probably an overestimate of its efficacy, but that study formed the basis of trying to repeat this finding in an area non-endemic for trachoma. Azithromycin is donated by Pfizer in the millions of doses each year, and so there are established routes of getting the drug to countries, and existing mechanisms for storage/transport, etc. All individuals aged 6 months and up in a community are treated with a single dose of azithromycin for trachoma. It has proven to be extremely safe during these administrations. I am not an ID specialist but I am not aware of many other antibiotics that are effective when given as a single dose like azithromycin. The single dose makes it very amenable to mass treatment campaigns.
Did You Encounter Any Antibiotic-Resistant Infections?
We do not have any reports of antibiotic-resistant infections from the local health clinics. We actively collected data on a set of communities and will be reporting resistance data soon. We know that mass azithromycin distributions for trachoma do select for antibiotic resistance and that the more frequently antibiotics are given the more resistance is seen—though it is important to note that trachoma programs give antibiotics to everyone in the community, whereas the MORDOR intervention gave azithromycin only to children under 5 years of age, and so it is possible we will see less resistance in the community given the much lower volume of antibiotics. We also know from trachoma programs that once the antibiotic distributions are stopped (ie, the antibiotic selection pressure removed), the resistance decreases. Azithromycin is not frequently used as a medication in most areas where mass azithromycin distributions are undertaken, so the clinical importance may be less than expected.
Did You Experience Any Barriers to Getting People to Take the Medication?
In Niger and Malawi, we had very little resistance and little treatment fatigue. There were slightly more refusals in Tanzania, thought to be due to opposing political parties in a community telling people not to participate, but overall there were not many refusals in Tanzania either.
There Have Been Ethical Discussions Surrounding Your Publication Because Although Mortality Outcomes Improved, the Long-Term Costs May be Significant in Terms of AMR. What Is Your Response to These Concerns?
First of all, we think it is very important to monitor for antimicrobial resistance alongside any mass antibiotic program, and resistance should not be taken lightly. Having said that, I think that the global public health community has determined that the benefits of eliminating trachoma outweigh the possible harms of resistance. (Especially since there is little evidence that the resistance that appears is clinically meaningful.) It seems to me that the known benefit of preventing childhood mortality likely outweighs the possible harm of antibiotic resistance (again, this is a theoretical possibility that has not been shown to be clinically meaningful in areas where mass azithromycin distributions have been given). Moreover, we have already observed that the resistance will decrease if we stop antibiotic distributions, and so we would expect that if resistance did become a clinically meaningful issue, then stopping the mass treatments should effectively reverse this problem. We strongly endorse monitoring for resistance alongside mass antibiotic programs so that we can get more information and learn more about the true impact of resistance in treated communities.