Antibiotics for all?

Sometimes a paper is published that makes you stop dead in your tracks. In this post-truth era we are so used to reading headlines that sound too good to be true that we just skip over them. But this paper was published in the reputable New England Journal of Medicine.

The paper we are going to look at is this one.

Keenan JD, Bailey RL, West SK, Arzika AM, Hart J, Weaver J, Kalua K, Mrango Z, Ray KJ, Cook C, Lebas E, O’Brien KS, Emerson PM, Porco TC, Lietman TM; MORDOR Study Group. Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa. N Engl J Med. 2018 Apr 26;378(17):1583-1592. doi: 10.1056/NEJMoa1715474. PubMed PMID: 29694816

A little bit of background

Azithromycin is used to treat trachoma in many African countries. It has also been used to treat pneumonia, diarrhoeal illness and malaria (Plasmodium falciparum) to some degree. Given the burden of these diseases it has been posited that mass distribution to at-risk infants and children might reduce mortality.

Who conducted the study?

The study was funded by a grant from the Bill and Melinda Gates Foundation with trial drugs and placebos provided (free of charge) by Pfizer.

The basics

Africa is not one country but a continent of 54 disparate and different nations. According to the UN Development Fund, 46 of these are sub-Saharan. This was a cluster randomized trial that took place between 2014 and 2017 in three of them – Malawi, Niger and Tanzania. We all love a good trial acronym and this one is hard to beat – MORDOR (Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance).

Population

Small communities that were not previously eligible for macrolide-based trachoma eradication, and thus had not received azithromycin previously, were identified. Those that had a population of between 200 and 2000 were eligible and all children between 1 and 59 months of age enrolled.

Intervention

A single directly-observed dose of azithromycin (20mg/kg). Weight was estimated using a height stick.

Comparitor

The standard group were given an identically packaged placebo

Outcome

The pre-specified primary outcome measure was the community-level, three country aggregate mortality as measured by the twice yearly census.

So with the PICO out of the way, it is time to get a little nerdy (as Ken Milne would say). When I look at a paper I like to use a guide like that produced by the BEEM team, which is great for emergency medicine related topics. This trial doesn’t really fit into that remit as it is a massive multi-centre, multi-nation trial. So why not use the CASP tool instead?

 

Did the trial address a clearly focussed issue?

It certainly seems as if the trialists were rigid in their inclusion and exclusion criteria, using a simple intervention and a dichotomous outcome measure – dead or not dead.

Was the assignment of patients to treatments randomized?

Yes – there was central randomization using computer software. Participants, observers and investigators were unaware which trial arm a community was enrolled in.

Were patients, health workers and study personnel blinded?

The placebo arm received an oral suspension that was packaged identically to the study drug. It even contained a similar (drug-free) suspension so it would taste and smell the same as oral azithromycin.

Were the groups similar at the start of the trial?

Table 1 shows the basic data. The placebo and intervention groups appear similar in Malawi and Tanzania, though the number of children in the azithromycin-treated communities was larger in the Niger group. Both had equal numbers of boys and girls and the number in each age range were similar in placebo and intervention arms.

Aside from the intervention, were both groups treated equally?

Yes

Were all the patients that entered the trial accounted for at its conclusion?

No. Some children moved to different communities and so were not included in the final analysis.

How large was the treatment effect?

A 12-month interim analysis showed no difference between the groups. At the conclusion of the trial the aggregate mortality was 14.6 per 1000 person years in the azithromycin group and 16.5 per 1000 person years in the placebo group.

There was only a statistically significant decrease in mortality in the west African country of Niger. If you look at the confidence intervals above you could argue that there is another way to display this data.

As usual, it is the subgroup analyses that provide the headlines. Mortality was highest in the youngest age bracket (1 to 5 months) and it was in this cohort that the largest mortality difference between groups was detected. There was no difference at the first census period but by the time the 5th (and final) period came around two and a half years later there was a statistically significant result with a 22.1% reduction in mortality in the azithromycin group (16.1 per 1000 person-years to 13.1 deaths per 1000 person years).

After table 5 from the MORDOR study

If you look at the percentage lower mortality per age bracket data in Malawi and Tanzania then remove the youngest cohort of children (1 to 5 months) it would appear that there little difference in  mortality in older children with large confidence intervals. But what I am more concerned by is the potential increase in mortality of up to 40% in Malawi and 60% in Tanzania.

How precise was the estimate of treatment effect?

The trial was designed to detect a 10% reduction in all-cause mortality. The assumption was that mortality would be between 14 and 20 deaths per 1000 person years in the placebo group.

Were all clinically important outcomes considered?

Death is the most important outcome. The trialists performed verbal autopsies of 250 deaths at each of the three sites. Approximately 41% were due to malaria, 18% to diarrhoea or dysentry and 12% to pneumonia. Cause of death did vary by country with more deaths occurring due to malaria in Niger and more due to pneumonia in Tanzania.

Are the benefits worth the harms and costs?

Given that 279,353 doses of azithromycin were given it is worth considering the potential adverse effects. 20 hospitalizations occurred due to azithromycin but it was impossible to collect data on more minor side effects. These include allergy, diarrhoea, abdominal pain and rash. The FDA reports an approximately 4.3% incidence of diarrheoa and 1% incidence of each of the other adverse effects. This would equate to 12012 more cases of diarrheoa in this study population.

The FDA does not approve azithromycin use in children under 6 months of age of age and recommends a dose of 10mg/kg on D1 and 5mg/kg on D2-5. Infantile hypertrophic pyloric stenosis has also been linked with macrolide usage, especially in children under two weeks of age, though the risk may persist up to 6 weeks.

The has been some controversy regarding the association between azithromycin usage and cardiovascular death due to QT prolongation in the developed world.

In our poached ivory towers we have seen the harms of indiscriminate antibiotic usage with a rise in resistant organisms. In a continent that still relies on streptokinase as it’s primary method of treating acute ST elevation myocardial infarcts what harm will come from potential antimicrobial resistance? The author are clear that indiscriminate distribution of azithromycin would select for macrolide resistance in S.pneumoniae and  E.coli.

 

The authors conclusions

Amongst post-natal, preschool children in sub-Saharan Africa, childhood mortality was lower in communities randomly assigned to mass distribution of azithromycin, with the largest effect seen in Niger.

 

Why might Niger be different?

Niger is ranked 187th out of 188 in the United Nations Human Development Index and has one of the lowest literacy rates in the world. 71.3% of the population cannot read. It has had a turbulent political history with three separate military regimes in power since independence in 1958. Around 45% of the countries budget is derived from foreign aid.

As the population continues to expand with a growth rate of 3.3% there is an average of 7.1 children per mother!  Unfortunately, according to Save the Children, it also has one of the world’s highest infant mortality rates (81.80 per 1000 live births). Contrast this with Malawi (43.4 per 1000 live births) and Tanzania (39.9 per 1000 live births).

Research in Africa

Thinking that Malawi, Tanzania and Niger are the same smatters of neo-Colonialism. Since liberation from their European overlords (Niger from France in 1958, Tanzania from Great Britain in 1961, Malawi from Great Britain in 1964) each country has established its own unique identity.

The authors should be applauded for their efforts in carrying out such a massive trial. Studies like this, the FEAST trial and some of the large HIV vaccine trials show that quality research can, and should be done, in Africa.

 

My bottom line

On balance, I would be more circumspect in my conclusions. Certainly, it does appear that mass distribution of azithromycin in Niger reduces mortality in post-natal, pre-school age children. I think it is a little harder to generalize the findings to the whole of sub-Saharan Africa.

Selected References

Chidambaram JD, Alemayehu W, Melese M, et al. Effect of a single mass antibiotic distribution on the prevalence of infectious trachoma. JAMA 2006;295: 1142-6.

Eberly MD, Eide MB, Thompson JL, Nylund CM. Azithromycin in early infan- cy and pyloric stenosis. Pediatrics 2015; 135:483-8.

Gaynor BD, Amza A, Kadri B, et al. Impact of mass azithromycin distribution on malaria parasitemia during the low- transmission season in Niger: a cluster- randomized trial. Am J Trop Med Hyg 2014;90:846-51.

Leach AJ, Shelby-James TM, Mayo M, et al. A prospective study of the impact of community-based azithromycin treatment

of trachoma on carriage and resistance of Streptococcus pneumoniae. Clin Infect Dis 1997;24:356-62.

O’Brien KS, Cotter SY, Amza A, Kadri B, Nassirou B, Stoller NE, Zhou Z, West SK, Bailey RL, Keenan JD, Porco TC. Childhood Mortality After Mass Distribution of Azithromycin: A Secondary Analysis of The PRET Cluster-Randomized Trial in Niger. The Pediatric infectious disease journal. 2018 Apr 19.

Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012; 366:1881-90.

Solomon AW, Holland MJ, Alexander ND, Massae PA, Aguirre A, Natividad-Sancho A, Molina S, Safari S, Shao JF, Courtright P, Peeling RW. Mass treatment with single-dose azithromycin for trachoma. New England Journal of Medicine. 2004 Nov 4;351(19):1962-71.

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A grim fairy tale

The theme for this year’s Don’t Forget The Bubbles conference is Science and Story. We recognise that stories, both those of patients and practitioners, are a wonderful way of passing knowledge. Last year we showcased stories as a means of promoting mental illness in healthcare practitioners and the challenges of neonatal retrieval at DFTB17, amongst others. The patient experience will, once again, be a key component of the conference. But here is a grim patient that you won’t see.

Consider the story of Persinette or Petrosinella. You might know her as Rapunzel. Whatever version you are aware of – that by Giambattista Basile, the Brothers Grimm or the Mandy Moore-voiced version that seems to be on constant repeat in my house, the story is the same…

A young woman, in the first trimester of pregnancy, gets a craving for rampion. Her husband, eager to please, finds some in the local market and brings it back for her to nibble on (perhaps with some cottage cheese and bread). The market stores soon run low but luckily he spies some growing in the grounds of the rundown cottage next door. In the middle of the night, shoes bound with hessian strips to dampen the noise, he sneaks into the garden and begins to forage. Unfortunately for the young man the owner of the cottage, Dame Gothel, is a light sleeper and confronts him.  Desperate to please his wife he promises to give her the child when she is born in exchange for a regular supply of rampion (or rapunzel as it is also known). The pregnancy continues without issue and when the baby girl is born the heartbroken couple reluctantly hand over their child.

Dame Gothel names the child Rapunzel, after the plant.

When she reaches the age of twelve, the witch (because that is what Mother Gothel clearly is) locks her up in a tower, away from the world.  She bricks up the door so the child cannot escape and uses an alternative means of access and egress – the window.

“Rapunzel, Rapunzel, let down your hair – so I might climb without a care.”

There are some problems with having such long hair though.

Rapunzel syndrome

Vaughan JE, Sawyers JL, Scott JH. The Rapunzel syndrome. An unusual complication of intestinal bezoar. Surgery. 1968 Feb;63(2):339-43.

Trichophagia and trichotillomania are uncommon. Unlike the old wives tale of what happens when you swallow chewing gum it does have a tendency to get stuck and form a hairball, or bezoar, in the stomach. This paper by Vaughan et al is the first documented case of what is known as Rapunzel syndrome. As human hair is relatively smooth it tends to resist normal peristaltic expulsion through the pylorus so it bundles up in the stomach. Like a wayward fisherman’s net it accumulates mucus and partially digested food until an impacted bezoar forms. Rapunzel syndrome occurs when the tail of the bezoar extends through the pylorus into the small intestine. Of all of the reported cases to date only one has taken place in a male patient, but perhaps, with the rise of man-buns, we might see more.

from http://www.humpath.com/spip.php?article12809

Trichobezoars have been linked with cases of intussusception, bowel obstruction and even death due to mucosal perforation. Patients may also present more innocuously with iron deficiency anaemia and weight loss on a background of psychiatric illness. These glistening balls of keratin are not visible on plain x-ray though may be picked up by ultrasound.

 

Day after day Dame Gothel calls out to fair Rapunzel to let down her golden braids for her to climb, little knowing the harm she was doing to her poor little head.

One day a handsome prince (because they are always handsome) espies the lovely Rapunzel at the windows. As he peeps out of the bushes he spots the elderly Dame approaching, calling up to fair Rapunzel, and then ascending. He waits, of so patiently, for her to climb back down again and once she has gone on her way he calls up to her.

“Rapunzel, Rapunzel, let down your hair – so I might climb without a care.”

Little did he know that it would not support his weight.

Traction alopecia

Zimmerman B, Ivars M, Cordoro KM. Bibbidi bobbidi bald: Two “hairowing” tales of Princess Package hairstyles. Pediatric dermatology. 2018 Apr 15.

The weight of a wrinkly witch is enough to detach growing follicles from the scalp. The article cited above describes cases where young girls, in their attempt to look like a Disney princess, have had their hair scraped and chignoned then finished off with some extensions. Unfortunately the tension on the scalp probably leads to localised ischaemia then erythema, followed by a grey necrotic crust and a patch of alopecia a fortnight or so later. Longer term follow-up showed a lack of hair growth in the area of the necrotic patch.

 

There is great power in storytelling and sharing. Come along to www.dftb18.com in August and join the adventure.

Selected references

Dalshaug GB, Wainer S, Hollaar GL. The Rapunzel syndrome (trichobezoar) causing atypical intussusception in a child: a case report. Journal of pediatric surgery. 1999 Mar 1;34(3):479-80.

Frey AS, McKee M, King RA, Martin A. Hair apparent: Rapunzel syndrome. American Journal of Psychiatry. 2005 Feb 1;162(2):242-8.

Naik S, Gupta V, Naik S, Rangole A, Chaudhary AK, Jain P, Sharma AK. Rapunzel syndrome reviewed and redefined. Digestive surgery. 2007;24(3):157-61.
Pul N, Pul M. The Rapunzel syndrome (trichobezoar) causing gastric perforation in a child: a case report. European journal of pediatrics. 1996 Jan 1;155(1):18-9.
Slepyan AH. Traction alopecia. AMA archives of dermatology. 1958 Sep 1;78(3):395-8.
Ventura DE, Herbella FA, Schettini ST, Delmonte C. Rapunzel syndrome with a fatal outcome in a neglected child. Journal of pediatric surgery. 2005 Oct 1;40(10):1665-7.

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DFTB go to South Africa

When Annet Alenyo Ngabirano spoke about Ubuntu at DasSMACC one of things everyone wanted to know was how could they help. There was talking about donating to Supadel or supporting African academics and writers via. Another suggestion was for those of us who ware lucky enough to get a study budget to go to Africa and share our knowledge and experience. When Kat Evans came to Brisbane last year to speak at DFTB17 she was very excited about her upcoming secret project. BADEMFest18 was conceived as a very different type of conference. There was to be no staying in corporate hotels and heading back to our rooms at the end of a busy day of learning – this was a chance to sleep under canvas, drink glorious South African wine, and listen to talented local musician, all whilst listening to some great talks.

 

The Place

The last time I visited South Africa was 10 years ago, for my honeymoon (Editors note: Remind me it’s my tin anniversary this year) so it took a little convincing to be allowed to go on my own. For those of you that are geographically challenged Capetown is 10,308km and three flights from Melbourne.

When Kat told us that her dream was for a conference with a festival vibe I had flashbacks to Glastonbury, dome tents and the great unwashed.  I could not have been more wrong. The town of Greyton was an hour and a half outside of Capetown proper and the effects of the most devastating drought in recent history was apparent. Once lush fields had become dust bowls and everywhere there were signs reminding us to conserve water.

The campsite was something to behold. A village of eight-seven canvas tents house all of the delegates. But these were not ordinary tents. There was no sleeping on the floor (the scorpions might get you after all) and there was everything the budding glamper could need.

The conference area proper was a short walk from the campsite and based in a large bedouin tent with surprisingly good acoustics. The intimacy of all of us sitting under the canvas together helped foster a bond. We all sat and chatted with our neighbours, no matter what nationality or speciality. And whilst spotty wifi has been the downfall of some conferences it was not an issue here. Instead of getting frustrated with the lack of access we just put our phones down and actually talked to each other.

 

The People

Given that this event was a first of its kind in South Africa it was important that it was as inclusive. With the support of the Supadel program delegates came from all over Africa to share their experience of Brave African medicine. For me, this was one of the highlights. It is one thing to read accounts of life in the Emergency Centre but to talk to these amazing clinicians, nurses and paramedics about their day-to-day life humbled me. When you are sitting in a talk on the ultrasound findings for HIV associated tuberculosis then you know you dealing with something a little out of the ordinary.

 

The Talks

As you might imagine from a conference born from the SMACC phenomenon there was a healthy mix of clinical and non-clinical topics – all relevant to the setting. Luckily for you all Simon Carley was sitting in front of me with his laptop open taking copious notes. You can read the St Emlyn’s account of all things BAD here.

Day 1

 

The Workshops

Whilst the single stream of talks kept everyone together it was the workshops that we were all talking about over the campfire. Every decision was a tough one with so many amazing options available. I decided to broaden my horizons and find out about things I knew very little about.

I started at the HIV and TB workshop and soon realised that, despite having done an ID elective at the height of the AIDS epidemic in Chicago, that I knew nothing. Local experts soon taught me the basics of the FASH exam and how the answer to every potential ID question in South Africa is “It’s probably TB”. Whilst it is unlikely that the knowledge I gained will be of much use in middle class suburbia I feel I have a much greater idea of the burden of disease in a place where residents routinely perform 5 or 6 lumbar punctures a night.

Then I signed up for this workshop. Working where I do I am used to dealing with Ice affected adults on a daily basis and I thought I might learn the nuances of chemical sedation. How wrong I was. I learnt something far more important. I learnt three key points:-

  • Avoid
  • Escape
  • Gain a tactical advantage

At six foot three and mumble-mumble kilos I think I am invincible. I am not. And neither are you. Almero Oosthuizen has encouraged me to do something and learn, for myself, a little more about self defence.

The final amazing workshop was the Simulation workshop, hosted by Ian Summers and Jo Park-Ross. The lucky delegates rotated around the big five stations talking with and learning from an international who’s who of simulation and education including Sandra Viggers, Morten Lindquist, Rowan Duys, Ross Hofmeyr, Natalie May, Penny Wilson Ross Fisher – and myself. It was a great opportunity for us to learn from the delegates and, once again, to realise that what might work in our bright and shiny institutions might not be applicable in lower middle income countries.

 

The Feels

Perhaps it was because I was 10,308km away from home and had my first undisturbed nights sleep since my eldest child was born but I felt refreshed. I loved the talks but #BadEMFest18 was much more than the talks, or the speakers, or the venue. It was a conference where I could sit by the campfire and chat with strangers or sit and gaze up at the stars on my own. It was a conference where people were not afraid to hug each other or shed tears, either on stage or in the audience. It was a conference where, on the last day, so many of us wondered if we could just keep the feeling going a little bit longer.

Coming back to reality has been hard. Don’t get me wrong, I am thankful for the ability to have a three minute shower and a working toilet but I miss the early morning chats in front of the coffee cart. I miss sitting on the grass and sipping Six Dogs gin whilst listening to some amazing live music. I miss the deep philosophical discussions about kindness, to oneself and to others.

As I was decompressing in my hotel, en route back to Melbourne, all I could do was write to as many of those people that I had had the good fortune to meet, and say thank you.

 

But don’t just take my word for how different it was – read the thoughts of some of the other delegates.

Penny Wilson – So BAD, it’s good

Dan Roberts – Lessons for Worthing from the Western Cape

Kaleb Lachenicht – Inside the bubble of #BadEMFest18

and of course, Simon Carley

 

Extra special thanks to the organizers for allowing me to speak about something that is not medical (but still so important) for a change. I loved the challenge. And thanks especially to Michelle Alisio who made sure I got to Greyton and back in one piece.

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