Wouldn’t it be wonderful if there were a silver lining to this pandemic? If history is anything to go by there may actually turn out to be a number of them, though we can’t quite see them yet, but here’s one that is just beginning to gleam. In the words of Prof Kevin Outterson: “Today, people understand the social disruption from an untreatable infection.”
Outterson teaches health law at Boston University, but you could also think of him as an activist on the cause of antimicrobial resistance (AMR), the rising tide of microbial evolution that threatens to sweep away a central pillar of modern medicine – antibiotics, or more generally, anti-infectives. This tide has been rising for decades, though for a long time only medics and those who directly experienced the horrifying consequences of AMR realised what a threat it posed. Covid-19 could change that.
But let’s not get ahead of ourselves. It’s human nature to realise the value of something just as we’re about to lose it, and that could also be the case here. Covid-19 has almost certainly exacerbated AMR, and it seems to have done so in a variety of ways. We know that resistant bugs can transfer the genes that confer that resistance vertically, from one generation to the next, but that transfer can also happen horizontally – between unrelated bugs and even between unrelated species.
For that reason, hospitals operate strict protocols that require personnel to, for example, change personal protective equipment (PPE) between patients, but because of the pressure many healthcare workers have been under this year – exacerbated by shortages of PPE earlier in the pandemic – they haven’t always been able to observe those protocols.
Covid-19 is caused by a virus, meaning that antibiotics are ineffective against it, but severe cases are often complicated by bacterial infections that cause pneumonia, so those cases do warrant treatment with antibiotics. Studies have shown that in some countries, however, antibiotics are being prescribed for about 70% of Covid-19 patients, even though their use is only justified in about one in 10 of them. Inappropriate prescription of antibiotics has also increased in primary care due to the shift from in-person to online consultations. Because GPs can’t examine their patients through a screen, and are often less sure of their diagnosis as a result, they’re more likely to prescribe antibiotics as a precautionary measure.
So the tide has risen a little faster this year, and that’s a worry because anti-infectives are as essential a component of our critical health infrastructure as clean water and good sanitation. Without them, it’s back to 18th-century medicine, and sawing off gangrenous legs to prevent infection from spreading. There are pockets of untreatable infection in the world already. Neonatal sepsis or blood infection in south Asia is increasingly untreatable – meaning even so-called “last resort” antibiotics don’t work against it – and it is threatening to reverse hard-won gains against infant mortality in the affected countries.
In fact AMR could, potentially, cause the next pandemic. Sally Davies, the UK’s special envoy on AMR, captures the difference between that hypothetical pandemic, and the one that’s buffeting us now, in a vivid metaphor: “Covid’s a lobster dropped into boiling water, making a lot of noise as it expires, whereas AMR is a lobster put into cold water, heating up slowly, not making any noise.” Those who study AMR warn the water is pretty hot.
What would a pandemic of AMR look like? Well it would consist not of one infection but of many – and these would be chronic and untreatable. Perhaps an individual would find that an infection that started on her skin had travelled to her bone, out of which pus would pour for the rest of her life – if the infection didn’t go to her blood and kill her first. Something similar might happen to others in her immediate environment – whether that be an ICU or a camp for displaced persons or a prison where drug-resistant tuberculosis was rife.
The hotspots of resistance would join up. The wave would sweep across the world – more slowly than Covid, because bacteria tend to have larger genomes than viruses and to evolve more slowly – but it would be possible to imagine the wave accelerating as it went, in Davies’ view, due to that capacity of bacteria for horizontal gene transfer. “You’d get chronic infections, high death rates, and you’d lose modern medicine,” she says.
That’s the apocalyptic vision, and it may be closer than we think. There wouldn’t be an obvious starting point to this pandemic. It might happen over a decade or two, and the fear is that we’re already several years into it. Something could happen to speed it up, too: bacteria tend to profit from crises – war, extreme weather events, viral pandemics – to gain a foothold.
Reining in the inappropriate use of antibiotics, in humans and in farmed animals, is key to staying ahead of AMR, but we also need novel anti-infectives coming down the pipeline – new last resorts. The thing holding up that pipeline to date has been the same thing that meant we had no coronavirus vaccines at the start of this pandemic: the economic incentives are few. Because antibiotics tend to be needed in relatively small quantities at a time, there are no economies of scale to be had either.
That’s the bad news; now for the good. Efforts are afoot to stimulate the development of novel anti-infectives. Outterson is the founder and executive director of CARB-X, which is funded by the British and German governments, the Wellcome Trust, the Bill & Melinda Gates Foundation and several arms of the US government, and which promotes the early stages of R&D – technically, the preclinical and phase 1 clinical phases. Meanwhile, last July the International Federation of Pharmaceutical Manufacturers and Associations launched a $1bn initiative, the AMR Action Fund, to finance the much more expensive phase 2 and 3 clinical trials that bring a drug – the few that get that far – to the threshold of regulatory approval. And the UK is experimenting with a new subscription-style payment model that pays drug companies upfront for access to novel antibiotics, so decoupling profit from volume sold.
In the view of American physician and AMR activist John Rex, we need new anti-infectives at a rate of between two and four a decade, and this is now looking achievable. He’s excited that he no longer has to explain the problem to finance ministers – at least not to all of them – and that proof now exists, in the form of a clutch of Covid-19 vaccines, that the world can react swiftly when it grasps the scale of the threat. But this is a race that will never be over, and to stay ahead we have to up our game.