Infection control 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 drug- resistant 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.
Practical Patient Care /
www.practical-patient-care.com
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.
37 72% Hospitalised
Covid-19 patients that received antibiotics, even though perhaps just 8% of those actually had confirmed bacterial or fungal infections. WHO
25–39
In millions, the estimated number of people killed by the 1918 influenza pandemic, compared with 2.8 million who have died from Covid-19 so far. Our World in Data
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59
