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-to- treat 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 SARS- CoV-2. Th e 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. Perhaps the most well-known infection becoming notoriously difficult to treat is gonorrhoea, caused by the Neisseria gonorrhoeae bacterium. WHO reports that 78 million people are infected with gonorrhoea each year – cases in the US have increased by 75.2 per cent since 2009. Ninety-seven per cent of countries affected by gonorrhoea report the presence of drug-resistant strains.
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.
Paralleling the rise of resistance is the upsurge in antibiotic consumption. Between 2000 and 2015, antibiotic use per day increased by 65 per cent. Our profligacy with antibiotics selects for strains of bacteria that are resistant. Problematically, when bacteria become resistant to one antibiotic, a different type is needed to treat the infection. This phenomenon has forced the clinical field into an arms race, where new antibiotics must be developed at a faster rate than infections can develop resistance.
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 such a strategy: on 17 June 2020, the UK government announced that the NHS will be offering 2 contracts to pay pharmaceutical companies using a ‘subscription-style’ payment model. ‘This new way of buying antibiotics for patients in the NHS breaks down restrictive barriers to offer companies a vital springboard to foster innovation and develop potentially life-saving new products,’ said the UK’s health secretary Matt Hancock, in the accompanying press release. Outterson explains that this model will be vital to mitigate the disincentives of doctors withholding antibiotic subscriptions: ‘the doctors ultimately get to make the decision on whether or not to prescribe new antibiotics, but the companies producing the antibiotic doesn’t go bankrupt.’
Lobbying is being carried out at the policy level to amend the restrictive healthcare structure in the US. ‘Right now, there is a strict cap on how much hospitals are reimbursed by Medicare for inpatient services, which deters use of new targeted antibiotics that might be the best course of therapy for patients with superbug infections,’ wrote clinician Julie Gerberding, in an open letter on 23 March. ‘In the US, the DISARM Act bill has been put forward – a bipartisan bill that would reform Medicare reimbursement to make it easier for hospitals to use the antibiotic that is most appropriate for a patient.’
‘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.’