War on drugs resistance

Over the past year, the world has been gripped by a pandemic the likes of which hasn’t been seen since the H1N1 outbreak of 1918–19. At the time of writing, SARS-CoV-2 has infected more than 130 million people worldwide and caused close to three million deaths. Although tragic, Covid-19 mortality rates pale in comparison with that 1918 influenza virus, which killed 24–39 million people. However, it’s now thought that the majority of its victims in fact fell prey to secondary bacterial infections, most notably pneumonia. Fast forward 100 years, and advancements in medicine and technology have enabled us to prevent countless more deaths during this pandemic, thanks largely to speedily developed vaccines that can protect the most vulnerable patients from Covid-19’s deadliest effects.

But clinicians battling Covid-19 on the frontline have another tool in their arsenal – one that came ten years too late to help doctors treating flu patients in 1918–19, and one that might have saved millions of lives: antibiotics.

An immediate challenge for healthcare professionals when Covid-19 took hold was stopping sick patients from contracting and dying from nosocomial bacterial and fungal infections. To that end – recognising the risks of co-pathogenesis of respiratory tract viruses like Covid – a high proportion of patients presenting early symptoms without pneumonia or moderate disease with pneumonia during the pandemic received antibiotics.

A WHO review of studies published in May last year put that figure at around three-quarters (72%) of hospitalised Covid-19 patients. However, the same review estimated that just 8% of those actually had confirmed bacterial or fungal infections. In ICUs, where the risk of hospital-acquired infection increases with the use of equipment like ventilators, wider antibiotic use is more justified. Yet according to a large-scale study conducted in ICU wards in 88 countries in 2017, and published in JAMA last year, while just over half (54%) of admissions in the 24 hour research period had suspected or confirmed bacterial infection, 70% of all patients were given antibiotics.

Of course, the problem with the overuse and misuse of antibiotic agents is that the bacteria they are designed to combat adapt and become resistant to treatment. Antimicrobial resistance (AMR) not only limits our ability to treat the most common infections, but also perpetuates the spread of multidrug-resistant organisms (MDROs), or ‘superbugs’. So, as hospitals worldwide filled to bursting with Covid-19 patients receiving prophylactic antibiotics, could efforts to limit the pandemic’s devastation have been inadvertently driving something even more dangerous?

Gemma Buckland-Merrett is the science and research lead of the drug-resistant infections priority programme at the Wellcome Trust. She points out that there is as yet insufficient data to predict the extent of the long-term effects of Covid-related antibiotic use on antimicrobial resistance, but that evidence indicates there is likely to be some negative impact.

“We have seen reports and anecdotal evidence of increased antibiotic use during the pandemic,” she says, “and the strong suggestion that at least some of it has been inappropriate due to the fact that a lot of prescribing has been empirical.” In other words, patients have been given antimicrobial therapy anticipatorily, before a specific infecting pathogen is identified, or even shown to be present at all. Overuse of broad-spectrum antibiotics can certainly be a catalyst for drug resistance.

“We haven’t seen any data that has looked systematically at a number of different countries and contexts, so we can’t say for certain if there has been an increase in inappropriate antibiotic use, or whether that has definitely impacted antimicrobial resistance or drug-resistant infections,” continues Buckland-Merrett. “But what we do know is that inappropriate use of antibiotics is a huge driver of antibiotic resistance.”

Clean hands

One benefit to emerge from the Covid-19 pandemic is greater awareness of hand hygiene, even among healthcare workers. Before the pandemic, effective, frequent handwashing was one of a suite of infection prevention measures that hospitals had been emphasising to limit contamination and the spread of disease, as well as to tackle antimicrobial resistance.

Accordingly, a study conducted in four hospitals in Los Angeles in the early stages of Covid (published in autumn 2020 in the American Journal of Infection Control) reported that “infection-prevention initiatives fostered among healthcare workers have increased awareness of effective handwashing, cleaning equipment after use and appropriate personal protective equipment use, which has subsequently decreased healthcare-acquired infections with multidrug-resistant organisms.” A 25% increase in the use of hand soap and alcohol-based hand sanitiser between the first and second quarters of 2020 was a major factor in lowering infection rates, the authors said. Elsewhere, however, some front-line hospitals have had to relax or suspend infection prevention programmes because of the magnitude of Covid- 19’s burden on services and staff. For example, screening and diagnostics have fallen by the wayside, antimicrobial stewardship teams have been redeployed, and isolation rooms and areas have been pushed to capacity with Covid patients, making it more difficult to keep cases of MDRO infection separate from the rest of the hospital population.

“I suspect that antibiotic-resistant infection surveillance activities, and the quality of data they produce, may be impacted because some surveillance systems have just been stopped,” Buckland-Merrett adds. “With a singular focus on one pathogen, together with overcrowding in hospitals and overloading of healthcare systems, we could potentially see an increase in multidrug-resistant infections as well.”

Outside of hospital settings, a sharp rise in remote consultations is exacerbating empirical antimicrobial prescribing – another catalyst for AMR.

Post-antibiotic reality

As the global pipeline of antibiotics dries up, scientists face the challenge of finding new ways of treating MDROs. Close to Buckland-Merrett’s heart, CARB-X (Combating antibiotic-resistant bacteria) – led by Boston University and part-funded by the Wellcome Trust – is the world’s largest non-profit venture aimed at accelerating research into drugresistant bacteria and development of new antibiotics and vaccines. Still, finding new antibiotics is just one part of the solution. Others involve repurposing existing drugs and exploring new approaches to treating MDROs. One such project is examining how a natural enemy of bacteria can be harnessed to fight dangerous, antibiotic-resistant pathogens.

Bacteriophages – or phages, for short – are viruses that target and kill bacteria without harming human cells. Discovered in the early 20th century, phages were largely sidelined when antibiotics came to market, but re-emerged in 2015 after they were used experimentally to treat a US man dying from an infection with a bacterium called Acinetobacter baumannii. Post-doctoral researcher Jeremy Barr was part of the team that came up with the therapy, ultimately saving the patient’s life.

“We found that phages were effective for three to four weeks, then – in the same way bacteria become resistant to antibiotics – they also become resistant to phages,” Barr explains. “But an interesting observation was that once the bacterium became phage-resistant, it somehow became resensitised to antibiotics.”

Six years on, and now senior lecturer at the school of biological sciences at Melbourne’s Monash University, Barr leads a 14-strong laboratory team exploring phages in different contexts, including their therapeutic potential. His recent work has centred on examining the mechanism by which bacteria re-expose themselves to the threat of antibiotics when they start to resist phages. Barr chose to focus again on Acinetobacter baumannii, which tops the WHO’s list of ‘critical-priority pathogens’ that pose the greatest danger to human health, and for which new treatments need to be found. The superbug, which can cause infections in the blood, urinary tract and lungs, is most commonly found in hospital ICUs, primarily among long-stay patients and those on ventilators. Some studies have found that infection rates have increased among cohorts of patients infected with Covid-19.

The team demonstrated that to target the specific pathogen, a phage recognises and binds to a bacterium’s thick outer layer,. It’s then able to take over the bacterium from within and turn it into a “phage factory”, killing the pathogen and releasing hundreds of new phages. However, the bacterium soon outsmarts the phage and genetically mutates so that it no longer produces a capsule – and without its capsule, the once-fatal phage can no longer identify and attack the pathogen.

Crucially, however, a bacterium’s capsule is what protects it from the body’s immune system and attack from antibiotics. No capsule? No defence against the drugs it previously staunchly resisted. “We isolated two new phages against Acinetobacter baumannii, and showed that when they lost their capsule, as well as becoming vulnerable to antibiotics they were also less virulent and caused less severe infection and disease,” Barr explains. Of nine antibiotics tested on the phage-resistant version of the superbug, three were successful. With preclinical animal-model trials currently under way, and successful results shown in a small number of critically ill human patients, the potential for wider application of phage therapy in treating MDROs like Acinetobacter baumannii is vast and exciting.

Unlike antibiotics, phages are in infinite supply in the environment. But their therapeutic development is limited by widespread underinvestment in AMR, and the fact that treatment is highly individualised. Bacteriophages infect a specific species of bacteria, but that species could have tens of thousands of strains, only a handful of which are susceptible to a particular phage. Treating one patient would involve isolating their specific strain, then screening a bunch of phages to match them to that pathogen. As such, tackling AMR in the future requires a multipronged attack. “We have antibodies and vaccines, antimicrobial peptides, ionic metals, and immune drugs and therapies,” Barr comments. “Many of them are in the research and development phase at the moment, so it’ll take years before they are available in clinical settings.”

New global priority

For now, then, improving antimicrobial stewardship must be a global priority, and it requires multisystem change. “We need to look at the policy landscape of how antibiotics are used, at medicines’ management and prescription processes, at the use of technology for optimising antibiotics prescription, and – most importantly – at the context, culture and behaviour around use,” stresses Buckland-Merrett.

These approaches to tackling antimicrobial resistance need to be underpinned by robust data, which she says is a missing piece of the puzzle. The Wellcome Trust has funded a body of work – the Global Burden of AMR (GRAM) project – that is currently modelling data collected over several years. Another large-scale study across 11 countries is aimed at discovering whether (and how) the Covid-19 virus has impacted drug resistance.

“This data,” Buckland-Merrett concludes, “would clearly demonstrate that drug-resistant infections are impacting millions of lives and have the potential to be what we call a slow-moving pandemic.” The last thing the world needs is another one of those.

The threat of multidrug-resistant organisms and AMR

By 2050, AMR could be responsible for ten million deaths each year across the world – some 1.8 million more than currently die from cancer annually.

In the context of viral pandemics like Covid-19, infection with drug-resistant bacteria remains a significant factor in mortality. Bacteria had caused the deaths of almost half of people with Covid in a Wuhan hospital by the end of January 2020. During the 2009 H1N1 ‘swine flu’ pandemic, up to 55% of the 300,000 deaths globally were the result of secondary bacterial pneumonia.