A Week With Antimicrobial Resistance on my mind

This one gets a bit technical in places. Bear with me – the next one will be less so. Pinky swear.

This month has been a pretty one big for me. Last week, a clinical trial I’m involved with kicked off in Mali. 10% of Malian children die before their fifth birthday and this trial aims to reduce the level of infant mortality. The study is called the Lakana Trial and aims to recruit 100,000 infants born in Mali over the next three years.

In a separate post, at some point, I’ll tell you the ‘Mali not Bali’ story, but I’ll need a double G&T in front of me first. (Or register for free for Stand up for Healthcare Science on 6th November.)

At this point you’re probably thinking what on earth does this have to do with antimicrobial resistance (AMR)?

The thing is, to save all these lives, we’re giving antibiotics to every child (some will get a placebo). Nothing special about that, you might be saying, we give antibiotics to children all the time.

This is different because we aren’t treating symptoms of a known infection. We are giving antibiotics in order to reduce infection risk/inflammatory response in asymptomatic (symptom free) children under one.

The antibiotic we’re giving is a drug called azithromycin and it’s from a class of antibiotics called the macrolides (see my A Starter for 10 on Antimicrobials post).

The LAKANA study follows on from the MORDOR study (the best study name in the world, in my personal opinion!) which gave two doses of Azithromycin/placebo to >190,000 children born in Malawi, Niger and Tanzania. The difference between that study and ours: they always gave two doses and the infants recruited were up to 59 months.

Mortality in the MORDOR study was 13.5% lower overall in communities receiving azithromycin vs those that were given the placebo (paper link here if you’d like more detail). Interestingly, there were differences in the survival increase by both country and by age group, with the highest mortality reduction seen in Niger. The greatest effects were seen in the one-to-five month age group which is why the under ones were selected for the LAKANA study.

To decide how many doses of azithromycin are needed to reduce infant mortality, the LAKANA study will gather evidence to answer three specific research questions:

  1. Does biannual azithromycin MDA (Mass Dosing of Azithromycin) to 1-11 month old infants reduce their mortality?
  2. Does quarterly azithromycin MDA to 1-11 month old infants reduce their mortality?
  3. Does quarterly azithromycin MDA result in a greater reduction in mortality than biannual MDA?

What has this got to do with antimicrobial resistance?

The AMR component of this study is the part that is being lead by UCL and the Institute of Child Health and so is sitting with me as a co-applicant. As we are giving antibiotics to children (and not treating a specific infection), it is crucial to understand whether this will impact on the level of antimicrobial resistance detected in them, their families and their communities.

Questions that we’re looking to answer (and that are currently running around my brain:)

  • If we do detect antimicrobial resistance is it stable? (I’ll explain this in a future post.)
  • Does detectable resistance return to baseline after a period of weeks, or does it lead to a permanent shift in their colonising bacteria?
  • Does any resistance detected make a difference to clinical treatment options? Macrolide resistance is usually due to accumulation of single nucleotide changes (single letters in the DNA code changing). This doesn’t necessarily mean the antibiotic will stop working.
  • Is resistance detected only in the Macrolide class of antibiotics, or does it lead to selective pressure that causes other resistance changes?
  • (Not AMR, but fascinating to me) How does azithromycin work? What is the mechanism? You would have thought this is well understood but, despite being available for decades, how it works as an anti-inflammatory is really not understood. Is the reduction in mortality because of its use as an antibiotic or because of this anti-inflammatory action.

What is incredibly important when doing this kind of work is that the first priority is to maintain the safety of participants. To that end we are working closely with the The World Health Organization who have recommended consideration of azithromycin MDA to under-one-year old infants, in areas with high childhood mortality.

Reducing infant mortality is so important: not just to survival but to quality of life and prosperity within these communities. These kinds of studies also need to be aware of their legacy. We are all incredibly keen to build laboratory capacity and infrastructure, not just in terms of equipment but also in terms of skills and skill infrastructure.

It’s early days and we won’t have any results from the AMR section for at least a year. I mostly wanted to record that this work is going on and the questions I have at the start. I also have some questions about balancing clinical outcomes which are pretty philosophical in my mind right now. If we see development of AMR, especially if it’s non-stable, but mortality is decreasing, where is the balance between those two things? How do you perform the risk assessment for the individual about short-term vs long-term outcomes? These thoughts convince me that this study is just the next step on a journey and that (as always) we have a lot to learn and a long way to go.

LAKANA team – Paris December 2019

All opinions in this blog are my own

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