Pandemic preparedness: Fighting antimicrobial resistance in the community

It was a dreary winter’s day in February 1941. Police constable Albert Alexander was rushed into the Radcliff Infirmary in Oxford County in the UK, when his facial wounds – sustained from an exploding bomb – had developed into a painful, deadly bacterial infection. His head was covered with abscesses that were oozing pus from his eyes, scalp and in his lungs. With all treatment options exhausted, his physician Charles Fletcher decided to administer Alexander with a new, experimental therapy – penicillin*.

On 12 February 1941, Alexander became the first patient to receive penicillin and within days, his condition dramatically improved and fever subsided. However, the exhilaration from this ground-breaking N=1 trial was short-lived. The penicillin ran out, and despite the team’s efforts to prolong the treatment by extracting penicillin from the patient’s urine and re-administering it back to him, he became acutely weaker and succumbed to his relapse.

Chris Butler pauses from his story and looks thoughtfully out of his office window. A general practitioner by training, Chris is also the lead coordinator of ECRAID-Prime and a professor of primary care at the University of Oxford, where he leads the PRINCIPLE and PANORAMIC trials of community treatments for COVID-19. In fact, his Oxford office is just around the corner from the old Radcliff Infirmary, where a blue plaque commemorates the first use of penicillin.

Antimicrobial resistance – a silent pandemic

The South African native completed his medical training in Cape Town and was a medical registrar at a hospital in a large township in the Eastern Cape Province of South Africa, where infectious diseases accounted for a vast majority of the acute medical intake. It was here that he first witnessed the power of antibiotics: “Patients often close to death would literally get up and walk after treatment,” he says.

After moving to the UK in the 1990s, he was struck by the contrast in the usage of antimicrobials between both countries.

He became fascinated with the huge and growing discrepancy in antimicrobial resistance among people in different countries - notably between developed and less developed nations, something that stayed with him throughout his career. 

Left unchecked, antimicrobial resistance could kill as many as 10 million people across the world every year by 2050 if it is not tackled, warned the Review on Antimicrobial Resistance, published in December 2014. In 2019 alone, antimicrobial resistance has killed nearly five million people worldwide**. 

“In some communities, I’ve seen patients with multi-drug resistant tuberculosis succumb to their illnesses because there were no useful antimicrobials available. However, I’ve also seen patients often close to death who would literally get up and walk after being treated with antibiotics. And when I first came to the UK in the 1990s, I saw doctors prescribing Amoxicillin to large numbers of people with a viral cold. So much so that over time, in the developed world, we have lost respect for these ‘miracle drugs’ and many have become complacent,” he says.

A reservoir of antimicrobial sensitivity

Not long after penicillin was discovered as a powerful treatment for pneumonia, it became an increasingly common treatment for coughs, and then for colds, despite a lack of clinical studies or evidence of benefit in the community setting. That is, until studies like the multi-country trial from the EU-funded GRACE consortium (led by Herman Goossens) proved conclusively that antibiotics do not provide clinically meaningful benefits to help treat cough and discoloured sputum.

Chris explains, “Most antibiotics are prescribed in primary care. After 50 to 60 years of using these antibiotics, we find out that they have all too often been prescribed to people who couldn’t ever benefit from using them. Over time, as bacteria develop a growing resistance to these drugs, people are going to be sicker more often and for much longer, treatments will have to be escalated because of resistance, and we find ourselves in a silent pandemic.”

In reality, antimicrobial resistance impacts not only the sickest and frailest patients in hospital intensive care units, but also people with common infections such as urinary tract infections (UTI) in the community: outpatients with a UTIs caused by a resistant bacteria will consume far more antibiotics and be unwell for about twice as long.

Alongside bacterial resistance, viruses develop resistance to antiviral treatments, shares Chris. “Viral mutations are the reason we have lost the use of several treatments for SARS-Cov-2 infection and as yet, we don’t know if the use of oral antiviral drugs at scale in the community will drive mutations that are resistant to these new drugs.”

Primary care – a central piece of the healthcare system

When it comes to fighting antimicrobial resistance and pandemics, a strong primary care research infrastructure is central to a society’s pandemic and epidemic preparedness, says Chris. One that is battle-ready for when the next pandemic hits.

Today, the vast majority of people with infections such as influenza and COVID-19 are cared for entirely in the community. There are several new drugs for infections like these in the pipeline, and it is in the primary care setting where early treatment with antiviral drugs could have the biggest reach and impact in a respiratory infection pandemic. It is therefore crucial to test these drugs in the very setting in which they will be most often used; and to this end, ensure that there is the right infrastructure, resources, skilled research professionals, and clinicians to contribute to this ambitious project.

Currently there is a missing piece in the jigsaw of pan-European infectious disease trials capability, says Chris says. "Together, we will achieve a complete research capability panorama across all aspects of healthcare including primary care, hospital, and intensive care treatment; and that the pieces are seamlessly integrated and available to efficiently research new treatments.”

ECRAID-Prime - key to building sustainable clinical research infrastructure

This is where ECRAID-Prime comes in. The EU-funded project is tasked with setting up a new concept: an ongoing platform trial that is permanently ready. This means that when the next outbreak happens, clinical research and randomised evaluation for new drugs can be started quickly and performed with much shorter lead times to deliver results that are applicable and useful during (or at the earlier stages of) outbreaks.

And there is reason why. Only 20% of all interventional trials for COVID-19 have been done with outpatients. Chris says, “There have been far too few trials in primary care patients with infectious diseases. Traditional approaches have meant that trials tend to not recruit enough participants during outbreaks resulting in a lack of findings. It is extremely costly and inefficient to set up a whole new study every time a new drug or treatment requires evaluation.

ECRAID-Prime will build on the streamlined recruitment approach pioneered by ALIC4E, PRINCIPLE, PANORAMIC, PRUDENCE and Ecraid’s experienced primary care research network, as well as REMAP-CAP’s adaptive platform trial to develop a well-established and sustainable clinical research infrastructure. One that is constantly “ready, willing and able" to rapidly open randomised comparisons and generate rigorous trial findings.

Christopher Butler is a Professor of Primary Care in the Nuffield Department of Primary Care Health Sciences at the University of Oxford, United Kingdom, and a practising general practitioner in south Wales. Born in Cape Town, South Africa, Chris completed his medical training in Cape Town and was a medical registrar at Cecilia Makiwane Hospital in Mdantsane, a large township in the Eastern Cape Province of South Africa, where infectious diseases accounted for the vast majority of the acute medical intake. He moved to the United Kingdom in the 1990s to train in general practice in St-Ives, Cambridgeshire.

Chris is the lead coordinator of ECRAID-Prime, one of the six EU-funded projects to study vaccines and therapeutic clinical trials to boost COVID-19 prevention and treatment. ECRAID-Prime will build on the successful experience of past European platform trials in primary care networks across Europe, including the ongoing COVID-19 PRINCIPLE trial in the UK – co-led by Chris, and focus on efficacy trials for therapeutics that can be administered in the primary care setting.

Sources:

* Wood, Jonathan (2020). "Penicillin: the Oxford story." https://www.ox.ac.uk/news/science-blog/penicillin-oxford-story.

** Murray, Christopher JL, et al (2022). "Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis." The Lancet 399 (10325): 629-655.