The Drugs Don’t Work

Words: Viel Richardson
Portrait: Orlando Gili

In 1928, when Alexander Fleming discovered a benzylpenicillin culture thriving in history’s most famous petri dish, he began the process that gave the world antibiotics—a tool for controlling infections that has in the intervening decades completely transformed medicine and saved countless lives. Nearly a century later, however, these vitally important drugs are now losing the battle against bacteria. And if this trend continues, it could prove catastrophic for us all.

Dr Marc Sprenger, director of the Antimicrobial Resistance Secretariat at the World Health Organization (WHO), lays out the problem with a clarity that defies misunderstanding: “Some of the world’s most common, and potentially most dangerous, infections are now proving drug-resistant,” he says. “Antimicrobial resistance (AMR) is a serious threat to global public health. Simply put, if we don’t address this problem now, we will no longer be able to treat common infections in the future.”

Antimicrobials—agents that kill microorganisms or stop their growth—include antibiotics, which target bacteria, and antifungals, which are used against fungal infections. Penicillin is the most famous antimicrobial, but it is by no means the only one. The whole edifice of global infection control is based on a wide variety of antimicrobials, including aminoglycosides, carbapenems, cephalosporins, tigecycline, glycopeptides and many besides.

Most antibiotics are highly specialised, effective only against specific bacteria. If a strain of bacteria develops resistance to a particular antibiotic, then another drug needs to be developed to tackle it, or else the infection becomes essentially untreatable. The problems is that, according to the UK five-year action plan for antimicrobial resistance, published this year, no new classes of antibiotic have been discovered since the 1980s.

Misplaced faith
“The pipeline is drying up,” says Professor Alison Holmes, professor of infectious diseases at Imperial College London and a fellow of the Academy of Medical Sciences, who served for nine years as an expert member of the Governmental Advisory Committee on AMR and Healthcare Associated Infection. “Out of about 40 drugs being developed at present, there is only one new antibiotic. There has been this idea that when an antibiotic loses efficacy we will simply develop another one—we believed that there would be a never-ending supply of new antibiotics. That faith is proving to have been hugely misplaced.”

Several WHO investigations confirm that the foundations of our infection control edifice are beginning to crumble. The organisation’s Global Antimicrobial Surveillance System (GLASS) published its latest report last year, analysing the incidence of AMR in 68 countries around the world, the findings of which made truly disturbing reading. Resistance to specific antibiotics varies from country to country—in a global version of a postcode lottery, whether some of the most effective weapons against infection we have ever known will cure your illness depends on where the bacteria that infected you originated—but any complacency on the part of those countries where AMR is currently lower can be addressed by Dr Sprenger’s observation that “pathogens don’t respect national borders”. Taken has a whole, reports from the field the world over are telling the same terrifying story: antimicrobial resistance is on the rise.

The root cause of the problem is clear: the overuse of antimicrobials both in humans and in the animals we eat. “Society needs a whole new relationship with antimicrobials,” Prof Holmes insists. “We have been handing them out like Smarties, and we really need to start treating them as the extremely precious commodity they are. But we have to ensure that this in no way compromises access to these drugs for those who need them, especially the poorer sections of society.”

She takes pride in the fact that the UK has taken a global leadership role in this sphere: “It has been very impressive. We were one of the first countries to establish a National Action Plan on AMR as early as 2000.” The latest UK plan, which presents a 20-year vision for tackling AMR, focuses on three key aims: reducing the need for and unintentional exposure to antimicrobials; optimising use of present antimicrobials; and investing in new ways to supply antimicrobials and improve access to those who need them. The plan sets several short-term targets, including reducing the number of specific drug-resistant infections by 10% by 2025, reducing UK antimicrobial use in humans by 15% by 2024, and reducing UK antibiotic use in food-producing animals by 25% by 2020.

The stakes are high
These are ambitious targets, but they need to be, as the stakes are so high. The WHO estimates that AMR infections cause 700,000 deaths each year globally. That figure is predicted to rise to 10 million by 2050 if no action is taken. This comes with a cumulative financial cost of $100 trillion and threatens many of the United Nation’s Sustainable Development Goals. The World Bank estimates that an extra 28 million people could be forced into extreme poverty by 2050 unless AMR is contained.

The scale of the problem may seem daunting, but from the healthcare perspective it is almost entirely based on a simple and commonplace interaction: a doctor prescribing medication for a patient. As mundane as it may seem, this process is at the heart of the problem. Over time, prescribers have developed something of a dependence on broad spectrum antibiotic medications, designed to tackle several bacteria at once. These are still seen by some as a panacea for a wide range of infections, leading to their over-prescription. But this means that millions of us are coming into contact with antimicrobials that we do not need, increasing the chances of resistance developing.

“What you want to do is target the specific bacteria causing your illness. We have now become more accurate at identifying specific bacteria and targeting them with the right medication,” Prof Holmes explains. “There is still a place for these broad spectrum medications. When the patient in front of you is very sick, you want to get to the infection as soon as possible and they are very useful for that. But then it is incredibly important that you do not leave them on that medication. You should test to identify the bacteria present and deliver a highly targeted prescription as soon as possible.”

Prescribing is a complex social process influenced by lots of factors. Decisions are subject to hierarchies, sometimes controlled by legal procedures and other times by cultural ones. There is precedent and peer pressure. Some doctors don’t like to change a prescription someone else has written, so patients can stay on the same script for years, despite having several doctors. As part of the UK AMR strategy, NHS hospitals try to ensure that patients get their initial prescriptions reviewed within 72 hours—that is a hugely positive change, but we now need to replicate it in the wider world of primary and community healthcare.

Real change
“In order to achieve real change, we have to accept that prescribing is as much a social process as a clinical one, and unless we understand the pressures driving certain prescribing behaviours, we will never be able to change them,” Prof Holmes says, with some passion. “It is very important that we look at supporting clinical decision makers. We need to support them in the decision to use narrower spectrum antibiotics—they need this, as there will be some resistance from other clinicians and public alike. I believe that ingrained cultural pressures are driving over-prescription and we must tackle them if we are to change prescription behaviours. People think that just having a policy is enough. It is not.”

Around 35% of all patients in hospital at any one time are on antibiotics. When you aggregate the millions of people who pass through NHS hospitals every year, this adds up to a huge amount of medication. As the NHS is a nationwide, interconnected medical institution, once a procedure is identified and implemented throughout the system it is possible to make a serious impact on the general population. It also gives you a wonderful data set to examine, allowing meaningful conclusions to be drawn about how a specific practice is working.

“The NHS makes it much easier to share data, share best practice, look at the information together from different fields to see how things are working,” Prof Holmes says excitedly. “Also, to share initiatives and get the feedback from those. But there are challenges in such a large organisation and being a little more joined up would always help. Things have gone well and we are just moving in the right direction, but there is no room for complacency.”

This summer, Prof Holmes and her colleagues at Imperial College London are hosting a summit that seeks to answer some important questions about antimicrobial optimisation. Can we use the power of artificial intelligence (AI) to help achieve accurate prescribing very quickly? How can we analyse huge amounts of data in a way that makes decisions easier for the clinician and more accessible to the patient? When prescribing the same antimicrobial, what is the correct dose for an old woman, a young man or a child? How about if the patient is on steroids or other medications? The aim of the summit is to rethink how our healthcare systems make use of all the advances in technology, biochemistry, drug manufacture, information technology and other advances from within and outside the world of healthcare.

Innovative thinking
Such a change is going to call for innovative thinking as well as resources, and Prof Holmes is one of those leading the way in this area. “I am very lucky to have been awarded National Institute of Health (NIH) research funding for a project linked to the NHS, as well as Public Health England. I am looking at the issues of antimicrobial resistance and healthcare associated infection. My role has been to bring together research from different teams to look at the issues. What has been really fantastic is this has enabled me to take a real multidisciplinary approach. It means you can get social scientists and microbiologists working with the people in bio-engineering.”

Prof Holmes believes that this is such a complex problem, you cannot simply look at it through one lens. For her, it is important that we bring together different fields of expertise and tackle the problem from several angles at once. “It is my belief that we have to develop researchers who are comfortable working with people from other fields. Whether you are mathematical or interested in ethnography, you can all look at the problem together. I absolutely love that. I have talked about using game designers to design really clever, very effective interfaces to help with access and education in medical and clinical matters. These people build user interfaces that get lots of complex information over to players in a quick, understandable and engaging manner, so why not use them to help patients and doctors engage with medical information? The skills and expertise these programmers possess are extraordinary and we should be using that.”

All this leads to an obvious question: are there any alternatives to the antimicrobials upon which we have become so dependent? It turns out that there might be. It seems that immunotherapies can have a role to play. Researchers have been looking at alternative ways to use immunomodulators to help the immune system itself fight off bacterial infections. There is work being done with bacteriophages, commonly known as phages. These are tiny little viruses that can infect and replicate within bacteria, thereby killing them. Some researchers are extremely excited about the possibilities they contain. There is also hope that we may be able to alter the microbiome in people’s bodies to promote our ability to fight infection.

For now, though, despite these promising avenues of exploration, our infection control system remains grounded in the effectiveness of antimicrobials, so our first priority must be to preserve the efficacy of the ones we have. “Antimicrobial optimisation and infection prevention have to be our priorities,” Prof Holmes says. “That means effective use of vaccines and comprehensive infection prevention in all surgery and clinical practice that reduces the possibility of infection—anything that will minimise the need for antibiotics in the first place. We have made good progress in the UK, but there is still a long way to go here, and some other countries are far behind us. A paper led by Alessandro Cassini published in The Lancet in January 2019 stated that the impact of antimicrobial resistance in the EU and the European Economic Area was similar to the impact of HIV and tuberculosis combined, and the cause of 75% of those infections was healthcare related. That is shocking and needs to be addressed.”

Preserving efficacy
Everyone agrees that a flood of new antibiotics is currently not a realistic prospect, so we need to preserve the efficacy of those we have, and the few that do arrive, for as long as possible. The idea is to stop making the mistakes we have been making for nearly a century. “It is an absolute imperative that we get our act together. We need political leadership, on the same level as we need in the fight against climate change,” Prof Holmes says, with real feeling. “This political leadership needs to be global as well as national. There is so much as stake. We are making incredible innovations in medicine and surgery. We are developing extraordinary abilities to save and improve lives that would have been science fiction 25 years ago. But it could all fall away if we can’t control infections after operation. You simply cannot do many of the operations we take for granted without effective antibiotics.”

It is a sobering thought. Without widespread and concerted action, the picture for the near future looks troubling. The vast majority of our medical care is underpinned by the antimicrobials given to us after Alexander Fleming’s discovery of benzylpenicillin. If we squander his legacy, we are in danger of returning to the days when the phrase “the operation was a success, but the patient died because of an infection” was all-too commonly heard. Sadly, in some areas of the world this may already be the case.