Humans have been visiting Merri Creek for millennia. The waterway snakes from Wallan, north of Melbourne, down through the suburban sprawl and flows into the Yarra River. The Wurundjeri, the traditional owners, once camped on Merri’s banks, dug up yam daisy and collected shellfish from the creek bed. When the Melbourne founder, John Batman, stumbled upon the creek in 1835, he scribbled a note in his diary describing it as a “lovely stream of water”.
Almost 185 years later, Trevor Lithgow, a biochemist at Monash University, and a student in his charge, visited that same lovely stream, bent down at its bank with an empty flask attached to a broom pole, and retrieved a double shot of water. They bundled the sample into a bag and drove it back to examine at their laboratory.
There, they mixed the sample with a culture of Klebsiella pneumoniae, a rod-shaped bacteria, prevalent in nature, and one that colonises human stomachs and lines our intestines. It forms snot-like colonies, gobbling up and fermenting lactose to fuel itself. Usually, Klebsiella is harmless.
But in certain situations, Klebsiella can establish itself outside the gut – and then it becomes a threat. “You would not want to have an infection that’s driven by Klebsiella,” Lithgow says.
Klebsiella is defined by the World Health Organization as a “priority pathogen”. Some prefer to call it a “superbug”. It’s a bacteria that poses a major threat to global health because some strains have evolved to evade our most potent drugs, in a process known as antimicrobial resistance (AMR).
At Merri Creek, Lithgow was hoping to find something Klebsiella couldn’t evade.
The WHO notes AMR “puts many of the gains of modern medicine at risk” because it diminishes our ability to counter infectious disease, making routine surgery and chemotherapy much riskier.
But how did we get into this mess? Antimicrobials – drugs against bacteria (antibiotics), viruses (antivirals), parasites (antiparasitics) and fungi (antifungals) – have been crucial in our response to disease since the discovery of penicillin in the late 1920s. Agricultural antimicrobials first appeared in the 1930s, and by the 1940s penicillin had dramatically reduced suffering and death in humans, kickstarting the golden era of antibiotics.
By the 1960s, scientists and researchers realised our chemical weapons could misfire – disease-causing microbes evolved better defences, swapping and changing elements of their DNA to improve their own survival.
Imprudent use of antibiotics in agriculture, including to speed up growth in livestock, and our penchant for overprescribing them to humans, provided microbes more opportunities to evolve resistance and share it throughout the food chain.
In 2023, one-third of Australians had at least one antimicrobial prescribed. Overall, more than 22.1m prescriptions were dispensed.
“We’ve got one of the highest rates of antibiotic use per person in the world,” says Mark Blaskovich, a medicinal chemist at the University of Queensland.
It’s figures like these that worry researchers and clinicians because overuse is a key driver accelerating AMR.
It’s estimated that more than one million people die globally from an antimicrobial-resistant infection each year. By 2050, a study in the medical journal the Lancet suggests, the number of deaths associated with AMR could rise to beyond eight million.
To combat AMR and its extreme burden on global health, new weaponry is required.
When Lithgow and his team scooped a few hundred millilitres of water out of Merri Creek, they were prospecting for powerful artillery against the superbug threat. They suspected the creek would be home to an ally that has long been overlooked: bacteriophages, natural born bacteria-killers, uniquely attuned to hunt and kill microbes.
Bacteriophages – phages, for short – are everywhere. They are viruses that, like their prey, are found in practically every corner of Earth. Scientists have discovered them deep within the Mariana Trench, lurking in tropical rainforests, in the muck of sewage, bathing in hot springs and, yes, right there on your skin.
They’ve been described as the deadliest beings on the planet and in pure numbers it’s hard to argue with that. It’s estimated, in Earth’s oceans alone, bacteriophages infect and destroy between 20 and 40% of all microbes, every day.
Like all viruses, bacteriophages are a simple arrangement of proteins and genetic material, an unthinking sort-of-life with a single goal – to replicate. Bacteriophages come in many forms. Under powerful electron microscopes, some look like delicate dandelions. Others appear as alien moon landers with a boxy, 20-sided head and spindly legs.
A phage uses its spindly legs to attach to a bacterium wall, then injects the DNA enveloped in its head into the microbe. Once inside, the DNA turns the infected bacterium into a phage factory; instructing the host’s machinery to create and assemble thousands upon thousands of copies of the phage. The baby-phages secrete a molecule that splits apart the bacterium, killing it and allowing newly formed phages to find another host and begin the cycle anew.
In their Merri Creek sample, Lithgow’s team discovered a phage with spidery legs and a spiked collar. In lab-based experiments, they showed it was able to eliminate colonies of highly resistant Klebsiella. It was named by the traditional owners Merri-merri-uth nyilam marra-natj – “dangerous Merri lurker”.
And it’s not just in a lovely Melbourne stream where allies are found. A bacteriophage isolated from wastewater in Bangkok showed promising activity against Staphylococcus aureus. In the Sea of South Korea, scientists discovered pPa_SNUABM_DT01, with potential to kill Pseudomonas aeruginosa, a resistant bacteria that often infects the airways of patients with cystic fibrosis.
The hunt for the ‘fifth line of defence’
These expeditions to find new phages are emblematic of a worldwide scientific hunt, based on the belief the viruses can help tackle AMR.
“Phages are probably the leading solution,” says Ameneh Khatami, an infectious diseases paediatrician at the Children’s hospital at Westmead and member of Phage Australia, a network of researchers and clinicians professionalising the use of phage therapy to treat infections.
In part, that’s because development of new antibiotics has largely stalled over the last 50 years. Even with new classes of antimicrobials under investigation, it can take years to get through rigorous clinical trials and into patients. Mostly, it’s a problem of economics.
“The financial market for new antibiotics is just so totally screwed,” says Blaskovich. “People can’t make money.”
Blaskovich says the reality is that pharmaceutical companies are less likely to invest in antibiotics today because the return is small compared to producing other drugs, like those against cancer or cardiovascular disease. For instance, he notes that the newest cancer drugs may cost upward of $400,000 per treatment whereas the newest antibiotics are worth $15,000.
Even if those new drugs make it into the clinic and begin to be used routinely, they suffer the same problems as older antibiotics – eventually microbes will evolve new defences against them, and the expensive process starts all over again.
This is the crisis at the heart of infectious disease today. Antimicrobials remain powerful therapeutic options. Lithgow describes them as “the first, second, third and fourth line of defence”. But when patients are overwhelmed by a resistant microbe, there is no fifth line of defence.
Khatami says highly resistant infections are still uncommon, particularly in her field of paediatrics. However, she occasionally runs into cases that give her cold sweats, where even the most hardy antibiotics do not clear an infection.
“When they happen, they’re terrifying,” she says. “Any clinician you speak to has had cases where we’ve had absolutely no options.”
Steffanie Strathdee, an infectious diseases epidemiologist at the University of California San Diego, understands the fear of AMR all too well. Her husband, Tom Patterson, became ill while holidaying in Egypt in 2015. His condition deteriorated so quickly that he was medevacked first to Germany, then to the US. It was discovered he had acquired a multidrug-resistant strain of Acinetobacter baumannii, one of the world’s “most wanted” superbugs. “The doctors were all terrified,” she recalls.
The medical team threw every antibiotic at the infection – all conventional lines of defence had failed. The doctors told Strathdee and her daughters that Patterson wouldn’t make it.
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For Patterson, all conventional lines of defence failed. Strathdee and the medical team attending to Patterson decided to try something different: phage therapy.
Patterson was the first patient in the US to be treated with an injection of bacteriophage, targeted against his infection. He lived. It was heralded as a watershed moment for phage therapy in the US, highlighting the potential for treatment to clear resistant infections. But the idea had been around long before AMR threatened to upend global health.
Phages in the precision medicine age
Arguably the most famous bacteriophage clinic in the world stands close to the banks of the Kura River in Tbilisi, Georgia. It’s known as the George Eliava Institute of Bacteriophages, Microbiology and Virology and it opened in 1923.
Although the western world tilted toward antibiotics after the discovery of penicillin in 1928, and the second world war solidified antibiotics as the drug of choice against infectious disease, in places such as Georgia, Poland, Ukraine and other former Soviet states, phages were a promising alternative. They were cheap to produce and appeared effective, though lack of robust clinical trials and a poor understanding of efficacy prevented more widespread adoption.
It’s only in the last decade that phage therapy has exploded in interest across the globe, mostly as a response to the challenge of AMR.
There are advantages to using phages compared to traditional antibiotics, according to those advocating for their increased use. First, they act very specifically on bacteria and do not attack human cells. That also means they aren’t as disruptive to our microbiome – the collection of microbes that live within and upon us – as antibiotics. They’re also able to penetrate some of the more hardy bacterial protections, such as the snot-like biofilms produced by Klebsiella. Antibiotics have trouble there.
And though evolving resistance to phages occurs naturally in the fight for survival between species, this can be addressed more easily than antibiotic resistance.
“The benefits of phage include their ability to adapt and overcome these mechanisms of bacterial resistance,” says Lucy Furfaro, a microbiologist at the University of Western Australia exploring bacteriophage therapy. She also notes there is emerging evidence phages may re-sensitise microbes to antibiotics. “In order to become resistant to the phage it has mutated and become sensitive to antibiotics again,” Furfaro explains.
In Georgia, cocktails of phages against resistant strains of bacteria such as Staphylococcus aureus and E coli can be bought without prescription. Places such as the George Eliava also administer phage therapy intravenously, both as cocktails featuring a mix of different phages and personalised preparations of single phages, targeting hard-to-treat infections. Russia, too, has off-the-shelf phage therapeutics.
As routine as phage therapeutics are in those places, none have been approved for use in the US, across the EU, UK or Australia. They’re still considered experimental therapies, only provided to patients within national frameworks for compassionate use. For instance, in Australia, access to phage therapy can be granted as a last resort treatment via the Therapeutic Goods Administration’s special access scheme. Similar regulatory frameworks exist in France, the UK and the US.
There’s evidence, predominantly from Georgia and Russia, that phages are safe and can be effective at clearing resistant infections, but charting a course to widely available therapeutics has been difficult due to regulatory hurdles and a lack of standardisation in testing, making it hard to draw conclusions about efficacy.
“Unfortunately, a lot of phage therapy, historically, has been a bit of sort of bucket chemistry,” Khatami says. “We’re trying to bring phages from the early 1900s into the current century, where our patients expect precision medicine and quality medicine.”
Today, with the threat of AMR bearing down on public health, there are more than 90 clinical trials under way across the world to establish the safety and efficacy of phage therapy. They’re assessing patients with chronic UTIs, cystic fibrosis, diabetic foot infections and bacteremia caused by all manner of multiresistant pathogens.
In Australia, Khatami leads a unique trial known as the Stamp study, which aims to standardise the way phage therapy is administered.
Stamp is not testing if phage X can destroy bacteria Y. It’s built to monitor how phages, individualised to each patient, interact with the body after they’re administered, how quickly the body clears them, immune responses, changes in the microbiome and optimal dosing strategies to understand how to best use phage therapy. The trial’s first patient was treated in April 2022.
“We’re coming up to the 30th patient, where we will do our interim analyses,” Khatami says. She hopes to recruit about 50 patients, but says the team should be able to answer most of the questions around standardisation and monitoring before then. Even so, Stamp will continue to take on new cases, because it provides a route of access for patients with hard-to-treat infections.
A global fight
Phage therapy is not quite ready for primetime but its bona fides have often been hyped by headlines suggesting it’s a singularly powerful way to counter the scourge of AMR. The Merri-merri-uth nyilam marra-natj in Merri Creek, for instance, was sold as a “slick superbug killer that could save millions”.
Researchers and clinicians working in the field are more nuanced with their predictions. They’re aligned in their views that bacteriophages are likely not the sole saviour, but rather a substantial tool to bolster our efforts to combat disease.
“I find it difficult to see how they can be developed to become the frontline therapy,” says Blaskovich, from the University of Queensland.
Lithgow, the biochemist from Monash who discovered the Merri Creek bacteriophage, suggests the best strategy to tackle AMR is the most difficult one: prevent people from getting infections in the first place. “It’s probably the only way in which we’ll see the rate of people dying from resistant infections come down,” he says.
Researchers point to the incredible success of vaccination strategies across the world as a public health measure that slows the rising tide of resistance. Vaccines have been shown to directly and indirectly reduce the spread of antimicrobial infections because they both decrease antimicrobial use and limit the ability for resistance to spread. For instance, multiple studies have demonstrated vaccination against influenza reduced the prescription of antibiotics.
Developing new vaccines against emerging resistant microbes could also prevent AMR. A WHO study, published in July 2023, suggested vaccines for AMR-related infections such as Klebsiella and against tuberculosis, caused by Mycobacterium, could help avert more than half a million deaths. It showed that two-thirds of these deaths would be averted in Africa and south-east Asia, where the burden of AMR is greatest.
Places such as sub-Saharan Africa and south Asia are at high risk of emergence and spread of antimicrobial resistant disease as they contain many low- and middle-income countries, as well as inadequate housing and sanitation that might accelerate the ability for resistant organisms to emerge. Many nations in the region also lack developed stewardship programs, and inappropriate antibiotic use is high, particularly in central Asia.
“We need to tackle the problem on a global scale,” Khatami says. “As Covid has shown us, microorganisms don’t understand borders.”
It may seem like an insurmountable problem, especially as climate change and extreme weather events provide increasing opportunities for antimicrobial resistance to emerge and spread.
But there is room for optimism. Khatami takes a hopeful tone when considering the future. “Human beings are pretty resilient and pretty inventive,” she says.
