The Slow Tsunami Is Coming

Imagine that you’re about to go on a holiday. You’re packed and prepared, wavering between excitement for your upcoming trip and the familiar, slightly panicked feeling that you’ve definitely forgotten something. You’re a little nervous about the flight, but as you take your seat, the pilot’s reassuring voice comes over the intercom. “Good afternoon,” he says. “This is a two-hour flight from London to Málaga. You have an 80 percent chance of safely reaching your destination.” A one-in-five chance of disaster? Surely those odds are far too high for a simple vacation trip. But if that’s the case, then why are such statistics acceptable in a healthcare setting? Dilip Nathwani, President of the British Society for Antimicrobial Chemotherapy, says, “We have a 50 to 70 percent chance of getting the right antibiotic for a patient’s infection – and we sit and congratulate ourselves on those odds.” To him, that’s unacceptable – and that’s only the surface of the problems with antimicrobial stewardship.

Antibiotic resistance is a critical issue in today’s medical care, so much so that even the United Nations General Assembly felt the need to tackle it head-on. It’s only the fourth time the UN has given such serious attention to a health issue, and they’ve taken a hard line, warning that antimicrobial resistance threatens worldwide development and requires a global response. All 193 member countries agreed – and all 193 of them have made a commitment to develop “superbug-fighting” action plans within the next two years.

What might these plans look like? There are three key aspects to a successful approach:

• Stewardship: a commitment to establishing and improving regulation and surveillance of antimicrobial use, sales and prescription;
• Research and development: not only of new types of antibiotics, but also of rapid diagnostics that can spot bacterial infections and identify effective treatments; and
• Education: both for healthcare professionals and for the general public.

With drug-resistant infections estimated to claim 700,000 lives per year globally – and that number expected to grow to 10 million by 2050 (1) – it’s not hard to understand why there’s a need for immediate intervention. But the $64,000 (or, in this case, $100 trillion) question is: what can we do?

The slow tsunami

Antimicrobial resistance has been referred to as a “slow tsunami.” There’s a steady increase in the number of drug-resistant pathogen strains – and not just to hard-hitting drugs like the carbapenems, but also to the common, low-cost drugs that are often prescribed for minor ailments. Nathwani says, “I think that we’re at a pivotal stage in the fight against antimicrobial resistance. One of the UN recommendations was for each country to have a plan in place within two years – but to me, the challenge is much more than that. Not only do we need action plans, but we need to actually implement them and achieve some measurable goals.” That, he says, is where the UN declaration falls short. “It doesn’t really come up with targets. I think those are critical, because you need that kind of leverage within political and healthcare systems to bring about the change we all desire,” (see “Steps to Success”).

A lever and a place to stand

The problem – according to Elizabeth Tayler, Senior Technical Officer of Antimicrobial Resistance for the WHO – is that we as humans tend to engage in short-term risk avoidance, rather than taking a long-term view. “If there’s a 5 percent chance that an infection might be bacterial, we’ll treat just in case,” she says. “If I take antibiotics, I might feel better slightly earlier, or be marginally less likely to get a secondary infection.” It’s a prevalent behavior, and one that can only be defeated through education. “The fundamental problem we have is making people more and more aware of the long-term risks.”

To that end, the WHO teamed up in 2015 with the UN’s Food and Agriculture Organization and the World Organization for Animal Health to develop a global action plan with five 
key objectives:

• Education “The first objective is to raise awareness among healthcare professionals, agricultural workers, and the public.”
• Surveillance “The second is about strengthening our knowledge base around resistance patterns and consumption.”
• Infection prevention “In low-income countries, a lot of that is about improving vaccination, water, and sanitation – community prevention. It’s also important to improve infection control in health facilities and in the animal sector.”
• Stewardship “We need to improve responsible use of antibiotics in both the human and animal sectors.”
• Resources “We need adequate resources to do all of this, and we need to improve the models for drug and diagnostic development to ensure sustainable investment.”

It’s a plan that was endorsed by the UN General Assembly – “and so now,” Tayler says, “what we have to do is action.” The first step is well on its way. “I’m sitting in Trinidad at the moment, working with the Caribbean countries to develop their national action plans. To date, 32 countries have plans in place and 59 more are working on them. That includes the big countries – India, China, Brazil, Mexico and so on – who arguably have the most significant impact on antimicrobial resistance. Our biggest challenge now is to translate those plans into action, but we’re seeing exciting signs that countries are beginning to take this seriously.”

A global balancing act

Both Tayler and Nathwani are clear about one thing – that if we are going to succeed in defeating antimicrobial resistance, we need to take a broader view. This means considering not just the long term, but also the long distance. “If I take a global view,” says Nathwani, “although we need to preserve the effectiveness of current antimicrobials, we also need to ensure that, in the parts of the world with little access to antibiotics, these treatments become available. There’s a rather staggering statistic – that more people die from lack of access to antibiotics than die of drug-resistant infections. We need to reach a balance between stewarding our antibiotics and ensuring that everyone has sustainable access to them.” It’s a balance he hopes can be achieved by emphasizing infection prevention through methods like vaccination, hygiene, sanitation, and clean water – and by ensuring that, when antibiotics are made available, they’re prescribed by professionals who understand their use.

Tayler points out that the rise in resistance to affordable antibiotics disproportionately affects resource-poor countries. “Those drugs have been the backbone of medicine in developing countries,” she says, “but those countries are going to be very vulnerable if the drugs no longer work – so we’re in a difficult position at the moment.” And working within weak health systems to improve standards isn’t easy. “Part of the problem is simple inertia. Even when people and organizations are enthusiastic for change, actually making it happen is another matter. “I think the impact is greatest in the poorest countries,” says Tayler. “Those are the ones buffeted by Zika, by yellow fever, by political instability. It’s interesting talking to people there, because there’s a lot of enthusiasm – but when people change, or political systems change, inertia takes over.”

Perhaps even more significant is the challenge of enforcement. “When you have poor or non-existent clinical governance, improving stewardship or enforcing regulations becomes much more difficult,” says Tayler. “Although there can be quite good legislation, for instance as regards over-the-counter sales or restrictions on agricultural use, actually having the capacity to enforce that is very difficult – and there are plenty of people with a vested interest in maintaining the status quo. It’s a challenging environment in which to try to make progress.” Nathwani chimes in with an example: “In India, where they have significant problems with unregulated antibiotic use, they’ve introduced a ‘red line’ concept. Antibiotic packages feature a dark red line, which signals that they should not be taken unless prescribed by a qualified professional. But that’s very difficult to enforce, and its impact is as yet unmeasurable. So there’s a lot of ambition, but actually enforcing the regulations is a huge challenge.”

A question of resources

It’s clear that developing countries will need special attention as we work to steward our antibiotics and stem the rise of resistance. But what about healthcare professionals in countries with more resources? The availability of funding and infrastructure doesn’t guarantee that those things will be appropriately allocated – and there are already concerns that the approximately US$790 million pledged by the UN won’t be enough (3).

“I think the resource question is critical. It’s important that antimicrobial resistance is not seen as a specific project. It should be built in when we strengthen agricultural, health or laboratory systems – not treated as an add-on. Why? Because if we do it that way, it’s much more likely to be sustained.” Although we still have to make the case for additional resources, Tayler has some powerful arguments to suggest. “The O’Neill report (1) talked about a potential 2–3.5 percent fall in GDP by 2050. That’s like something the size of the UK economy dropping out of the world market. The World Bank has done similar studies and says that the financial impact of antimicrobial resistance will be similar to the 2008 financial crisis, but much more protracted (4). These are the kinds of data that have a serious impact on policymakers.”

That isn’t to say that we haven’t already made strides. “In the United Kingdom, we’ve seen fantastic results in primary care,” says Nathwani. “We are beginning to reduce both overall antibiotic use and the misuse of broad-spectrum antibiotics.” Nonetheless, he says, this impact – especially in hospital practice – needs to be greater still. In Scotland, where Nathwani practises, he says they’ve significantly reduced the use of cephalosporins and quinolones, but not total prescribing. “We must not be complacent,” he warns. “We need to focus our efforts on the hospital and long-term care facility setting – but without underestimating the importance of community prescribing, because 80 percent of all human prescribing occurs outside specialized 
care facilities.”

Maintaining momentum

So what’s the biggest factor in all of this? Is it the amount of funding available? The pace of research into new drugs? According to Tayler and Nathwani, it’s communication.

“It’s quite interesting how you communicate things,” observes Tayler. “Sometimes, people are much more captivated by the scary numbers; sometimes, it’s the personal stories, or the fact that procedures like Caesarean sections, joint replacements or cancer treatment will become much riskier without the protective cover of antibiotics.” She emphasizes, though, that the role of diagnostic professionals is critical. “You have the credibility, and also the local data. We are very short of good data in many contexts. At the WHO, we can talk about the global picture – but people are inherently worried about what’s going on locally. Showing them that this problem exists in their own backyards focuses attention very well.

“People still trust doctors, and we need to leverage that to change the way we think about infection and antibiotics. We have a window of opportunity at the moment, while politicians are engaged and interested, but we know they’ll move on. So it’s vital that we put in a concerted effort to sustain that interest – or at least to revive it periodically.”

“I think the clinical community needs to understand what the laboratory can offer,” Nathwani adds, meaning not just the capabilities of medical science, but also its limitations. “Sometimes, I think the community expects too much of the laboratory. But if we understand each other and work together, then the outcome of each consultation will be more effective. I think pharmacists, nurses and infection specialists need to come together with primary care physicians to monitor antibiotic prescribing. Pharmacists can identify prescriptions that don’t comply with policy; nurses can identify where intravenous drugs aren’t required or question why a broad-spectrum antibiotic is in use where a narrower one would suffice. I think you need a culture of effective teamwork across the disciplines, working very closely with the laboratory, to ensure that the quality of prescribing is good.”

Nathwani’s own hospital sets the standard. “We’re quite protective of broad-spectrum antibiotics like the carbapenems. If one is prescribed on a surgical ward, the prescription will be reviewed by a pharmacist the next day – and if there isn’t a good reason for it, that person will have a conversation with the attending team. If there’s still no reasonable response, then the pharmacist will email the stewardship and infectious disease teams, and we’ll review the patient that same day and make an analysis based on the clinical situation. And if we feel that the antibiotic is not appropriately prescribed, we’ll have a conversation of our own with the attending team at a clinician-to-clinician level and recommend changing or stopping the drug. We also train and empower our nurses to get involved, asking questions like, ‘Why can’t we administer this treatment orally?’ or ‘Have you taken the blood level for this drug?’ All of us – nurses, pharmacists, junior doctors, specialists – work together to optimize each prescription.”

Damaging diagnostic discrepancies

“One major challenge to prescription reduction is diagnostic uncertainty. If you’re a clinician and you’re not sure of your diagnosis, then you’re likely to prescribe or continue antibiotic treatment. I think that if we’re really going to personalize medicine, we need a diagnostic test to determine whether infections are viral or bacterial – and, if bacterial, what antibiotics might be effective. We need these results in a timeframe rapid enough to inform clinical decision-making. And that’s something we don’t currently have.” Nathwani believes that such tests hold the key to the future of antimicrobial stewardship – and he’s not thinking only of those that are under development. Many biomarkers and point-of-care tests, like procalcitonin or C-reactive protein, already exist, but simply aren’t available in many areas. “Although we rely on new solutions,” he says, “we already have effective tests that will reduce diagnostic uncertainty; they just need to be brought to the bedside more quickly. I think the laboratory community needs to embrace them and lobby for them to be made available – because these kinds of tests are cost-effective and will ultimately bring about a reduction in 
antibiotic consumption.”

He does caution that new tests need to be combined with good stewardship, though. “Clinicians love sexy new diagnostics because they’re ‘better.’ But their benefits are often overblown – and what they really do is make people over-investigate and overtreat. If you can’t combine rapid diagnostics with specialists who are able to interpret them and provide advice, then the tests alone are useless.”

Tayler’s expectations for the future are similar. “I think that research on diagnostics is really important, because if we can get cheap, rapid tests that help people to prescribe more appropriately and manage the risk of missing something, that’s a way to change behavior.” She also believes that emerging evidence of the microbiome’s positive effects will change people’s perceptions of antibiotic risk. “If it’s possible that I could be harming myself by taking antibiotics – not to mention the long-term harm to society – then I think that changes the inherent risk calculation, and I think that’s important.” She hopes that a desire to preserve the helpful microbiome may make patients think twice about demanding antibiotics when there’s no real need.

Think big

Eric Reynolds, Melbourne Laureate Professor at the Melbourne Dental School, points out a major concern healthcare professionals may not always consider – the widespread use of not just antibiotics, but antimicrobials. “We have recently shown that long-term use of chlorhexidine (used as a disinfectant) is associated with the presence of multi-drug-resistant bacteria,” he says. “The bacteria exchange genes for ‘efflux pumps’ to pump out small antimicrobial molecules like chlorhexidine and triclosan – but these efflux pumps can also be used to pump out conventional antibiotics. Therefore, these bacteria develop resistance not only to the antimicrobials, but also to antibiotics. They can then survive on skin or in mouths without causing any problems until we become otherwise immunocompromised.” It’s not just antibiotics that must be carefully stewarded, he warns – disinfectants and other antimicrobial agents need to be considered with the same level of caution.

But how can we encourage such significant changes? Nathwani thinks that targets are the key. Measuring and feeding back data on consumption and quality is fundamental, because if that information is available to the clinicians and managers of healthcare systems, it can be used to inform metrics and future targets – and those can be powerful in influencing them to prescribe more effectively. “The other bit,” he adds, “is to ensure that antibiotic prescription becomes a patient safety issue. I think that if you’re prescribing poorly, then people coming into your healthcare facility should be told that they are not in a safe environment – and I think that kind of language will help people recognize that it’s important to get this right.”

Tayler has one more reminder for pathologists and laboratory medicine professionals involved in antimicrobial resistance. “I think this is one of the most exciting and important challenges that we face, so the work you’re doing is massively important, and it’s underpinning a global movement. Don’t forget that – and instead of just focusing on the challenges that face your area, think about what you can do that will have the greatest global impact.”