Covid-19 has reignited concerns about antibiotic resistance. Is the market for new drugs in need of reform?
An inconvenient truth: as the Covid-19 pandemic ploughs on, a slower-acting pandemic may follow closely behind. Prior to the emergence of the novel coronavirus, the development of antibiotic resistance – in which infectious diseases become resistant to our arsenal of antibiotics – was referred to as the ‘silent pandemic’. Many clinicians are now concerned that the number of patients with Covid-19 being treated with antibiotics could exacerbate resistance, leading to more difficult-totreat infections in the future.
Studies show that one in seven patients hospitalised with Covid-19 have acquired a dangerous secondary bacterial infection on top of their infection with SARSCoV-2. The need to treat these secondary infections is paramount: half of those who have died with Covid-19 have carried them. However, emerging data show that antibiotics might be being prescribed too readily, leading to misuse that could drive antibiotic resistance. An early study of Covid-19 patients treated in Wuhan – the centre of the initial outbreak – found that 95 per cent were treated with antibiotics. A more recent clinical review shows that while 72 per cent of Covid-19 patients have received antibiotics, only eight per cent demonstrated bacterial or fungal infections. ‘In the early stages of the pandemic, doctors were appropriately cautious because they didn’t want people to survive the virus, but die from secondary bacterial infections,’ explains Kevin Outterson, antibiotics expert and executive director of CARB-X, an antibiotics innovation fund. ‘You would need to have been a physician at their hospital, in the context of a pandemic, to be in a position to judge their thinking. But, without a doubt, there have been a lot of patients who have taken antibiotics, who in retrospect did not need them – and that is guaranteed to drive antibiotic resistance.’
As the world’s attention is gripped by the Covid-19 pandemic, top-tier clinicians are urging us not to lose sight of the silent pandemic. ‘The challenge of antibiotic resistance could become an enormous force of additional sickness and death across our health system as the toll of coronavirus-related pneumonia stretches critical-care units beyond their capacity,’ wrote
Julie Gerberding, a physician who was director of the US Centers for Disease Control and Prevention during the George W Bush administration, in an open plea published on 23 March.
Her warning became a call to reform the antibiotic development process: ‘To fight these superbugs, we desperately need new antibiotics. An important question policymakers should be asking themselves is: why don’t we have powerful antibiotics on hand when we need them the most?’
Today, antibiotic-resistant infections cause 700,000 deaths per year – a figure that the World Health Organization estimates will rise to 10 million per year by 2050 at current trajectories. The number of resistant infections is growing worldwide. An unprecedented epidemic of antibiotic-resistant typhoid caused by Salmonella enterica has occurred in parts of Asia and Africa; 5,274 people were infected with antibiotic-resistant typhoid during an outbreak in Sindh Province in Pakistan between 2016 and 2018.
In a 2017 report, DRIVE-AB – an antibiotics research investment initiative – predicted that deaths from respiratory pathogens (including those known to cause secondary infections in Covid-19 patients), such as Klebsiella pneumoniae, may double by 2050.
The problem is that clinicians are faced with a barren pharmaceutical pipeline – no new antibiotic classes have been discovered since the 1970s. New antibiotics that have entered the market have been derivatives of established drugs. A fragile commercial environment with extremely high development costs and very low returns on investment is largely to blame. ‘The science of antibiotics is not the problem here. It’s the economics that are broken,’ says Outterson. Achaogen, the company that manufactured Plazomicin, declared bankruptcy in 2019 after the first year of sales of the new antibiotic totalled less than US$1 million. It wasn’t alone. In fact, four of the last 14 antibiotics approved by the FDA went into bankruptcy in 2019. There were 18 global pharmaceutical companies developing antibiotics in 1990 – today there are five.
Pharmaceutical companies are disincentivised to develop antibiotics because they are taken for short periods of time, unlike medication for chronic conditions such as diabetes or arthritis. Companies aren’t willing to take on the financial risks of clinical development, which can take a minimum of nine years and US$1 billion upfront.
If we’re to stop ourselves from being cast back into the pre-antibiotic era of healthcare, Outterson thinks we must fix these broken economics. ‘There’s no other sectors of the economy where the most innovative product is actively discouraged from being developed. If this was the case with mobile phones, we’d still be talking on bricks. We need a different way to reimburse antibiotics development to encourage innovation.’ Incentive initiatives are emerging. CARB-X is a partnership between governments and philanthropic organisations that pulls funds together to help pharmaceutical companies push new antibiotics through early clinical development. So far, CARB-X has invested more than US$240 million across 64 projects, yielding 16 potential new classes of antibiotics. Similarly, the AMR Action Fund is a nearly US$1 billion fund put forward by 23 major players in the pharmaceutical industry. By helping to fund the expensive latter stages of clinical development, they aim to bring two to four new antibiotics to market by 2030.
At the post-approval stage of clinical development, a new payment model could transform reimbursement. ‘A subscription payment model could mean that antibiotics get reimbursed based on their value to society, rather than the volume prescribed and sold,’ says Outterson. The UK is already implementing this strategy: on 17 June, the UK government announced that the NHS will be offering two contracts to pay pharmaceutical companies using a ‘subscription-style’ payment model. ‘Covid-19 has taught us a lot about how damaging it is to be underprepared,’ says Outterson. ‘The costs are astronomical. We need to fix the broken economics of antibiotics by taking appropriate action and making small investments, so that my grandchildren don’t continually live through what we’re living through right now with Covid-19.’
From March, lockdowns across the globe saw streets become ghost-like relics of familiar, bustling centres of commerce. Travel restrictions grounded airplanes, train travel screeched to a halt and the sound of car engines was largely silenced. The peculiarities of this time are manifold and run deep. Seismologists have discovered that lockdowns across the world resulted in the longest and most pronounced quiet period of ‘seismic noise’ in recorded history.
To detect earthquakes, geoscientists use seismometers to eavesdrop on the seismic noise emitted from tectonic shifts that ripple through the Earth. However, human activity on the surface also causes vibrations that propagate into the ground as high-frequency seismic waves. ‘Whether we drive our car, catch the train, or touchdown on an airport runway, each of us contributes to anthropogenic seismic noise,’ explains Stephen Hicks, a seismologist at Imperial College London.
The Royal Observatory of Belgium, along with five academic institutions, including Imperial, have gathered seismic noise data from a global network of 268 seismic stations in 117 countries. During lockdowns, they recorded a global median reduction in seismic noise of up to 50 per cent – leading some researchers to coin the term ‘anthropause’. Predictably, the strongest reductions in seismic noise occurred in populated environments: a 50 per cent reduction was recorded as tourism was grounded in Barbados and the Sri Lankan city of Kandy; while a 33 per cent reduction was seen in Brussels, where lockdowns were enforced from 18 March.
The pronounced period of quiet has its uses. The muting of anthropogenic noise allows scientists to focus on natural tectonic sounds. ‘Anthropogenic noise has always been an unwanted artefact on seismographs. Smaller signals from natural tectonic sources can get lost in noise resulting from the anthropogenic activity occurring at the surface,’ says Hicks.
Large-magnitude earthquakes are generally accompanied by smaller signatures of tectonic sounds that are often obscured by the hubbub of anthropogenic activity. Lockdowns present the best opportunity to date for seismologists to pinpoint these small signatures. ‘If we can detect the signatures of
The unprecedented pause in human activity that took place during global lockdowns has provided seismologists with a unique opportunity
smaller earthquakes that occurred during lockdown, we might be able to go back through the archives of seismograph data and find similar signatures that might, for example, accompany larger earthquakes,’ says Hicks.
Discoveries are already being made. During lockdown, a magnitude-five earthquake occurred southwest of Petatlán, Mexico. Due to the reduction in anthropogenic noise, seismologists were able to hear its tectonic sound signatures more clearly. The newly identified signals could be used as templates to monitor tectonic unrest in the future, potentially hastening earthquake-prediction methods.
Hicks explains that lockdowns have provided a rare opportunity for his field. ‘With growing urban populations in tectonically active areas, such as Tokyo, San Francisco, or Santiago, anthropogenic noise is going to increase,’ he says. ‘With urbanisation, it’s becoming more important that we understand the small tectonic sound signatures, so that we can better forecast large-magnitude earthquakes. We’ve never really been able to quieten anthropogenic noise because we’ve never had a coherent shutdown – now, new avenues of research are opening up.’
The unnaturally empty streets of London