Superbugs: finding the path of least resistance

Each time a patient arrives at hospital with a life-threatening bacterial infection, doctors face a dilemma. While they wait for test results detailing the bacteria’s antibiotic resistance status, which antibiotic do they administer? And, since over-use of the best broad-spectrum antibiotics increases the chances of creating rampant ‘superbug’ bacteria, how can they prevent this?

In emergency rooms, it’s damned if you do and damned if you don’t. “We might have a sick person going for 48 hours on a best-guess antibiotic,” explains Professor David Paterson, an infectious diseases physician who directs The University of Queensland’s Centre for Clinical Research (UQCCR). “If we guess incorrectly, that patient’s risk of dying might increase, because they haven’t had the most effective antibiotics.”

But, taking the possibly safer bet of using ‘big gun’ broad spectrum antibiotics every time will dramatically hasten the development of resistance to some of our last-line therapies against other multi-drug resistant bacteria. Drug-resistant infections already cause at least 700,000 deaths globally each year. The United Nations is warning that by 2050, up to 10 million people could die annually from superbugs. “The more we use any class of antibiotic, the quicker we are going to lose it,” Paterson explains. So, which drug to reach for?

Reducing the guesswork in antibiotic selection is one of Paterson’s main goals, along with his team and their international group of collaborators. Supported by a National Health and Medical Research Council Investigator Award, in 2018, the group completed the MERINO clinical trial with almost 400 people, the world’s largest randomized controlled clinical trial comparing the ability of different drugs to treat infections caused by antibiotic-resistant gram-negative bacteria – in this case Escherichia coli and Klebsiella pneumoniae.

Historically, patients with serious bacterial infections in their bloodstream were given antibiotics called cephalosporins. “We wanted to know what would be the best choice if you knew your bacteria were resistant to cephalosporins?” Paterson explains. “Should you go for the biggest gun, a broad-spectrum antibiotic called carbapenem? Or should you go for a workhorse antibiotic that we already commonly use in hospitals?” The team hoped the workhorse option, a piperacillin/tazobactam combination therapy, would be just as effective as carbapenem, enabling the big gun to be kept in reserve, and delaying the spread of resistance against it.

In fact, the trial showed patients given a drug called meropenem (a carbapenem antibiotic) had an improved survival rate, compared with standard piperacillin/tazobactam combination. “That disappointed us, but also provided incredibly important information. When we balance up the risks, we now know in this instance, we have to respect antibiotic resistance and pull out the big guns when faced with it,” Paterson says.

A MERINO II trial is now underway to compare the effectiveness of meropenem and piperacillin/tazobactam on blood infections cause by Enterobacter, which most often shows up in hospitals in immunocompromised hosts and in those on mechanical ventilation.

Both these trials, says Paterson, are designed to answer questions clinicians thought could change their clinical practice. “We sent a survey to all infectious diseases doctors in Australia, New Zealand and Singapore, and they got a chance to vote on the questions we would ask in our research.”

Another new UQCCR research project is looking to tackle drug resistance, but from a different angle. The 48-hour wait to find out what strain is responsible for a serious infection is the crux of an emergency room doctor’s dilemma when it comes to choosing antibiotics. “Most of the techniques we use to diagnose serious bacterial infections are the same ones used 100 years ago,” Paterson explains. A sample of the patient’s bacteria are grown and tested for their susceptibility profile in a lab, all of which takes a couple of days to complete.

Several tests in development promise to dramatically speed up this process. “A number of exciting technologies being evaluated would tell us, on the same day a person gets sick, what the bacteria are and the best antibiotics to choose,” Paterson says. The approaches include rapid, whole-bacterial-genome sequencing; using targeted DNA amplification to look for certain resistance genes; or using nuclear magnetic resonance to identify resistance biomarkers in the sample. UQCCR is currently looking at the best ways to speed up diagnosis for children.

The University of Queensland School of Public Health is also an active participant in health networks monitoring outbreaks of antibiotic resistant bacteria strains across Australia. Researchers there are working on technologies for more effective global surveillance, and studying predictors of inappropriate antibiotic prescribing in Australian general practice.

This ‘One Health’ approach to solving the puzzle of antibiotic resistance doesn’t end there. Currently, the very last line of defence against the toughest multi-drug resistant bacteria is the antibiotic colistin. In many parts of the world, farmers routinely feed colistin to livestock as a growth promoter. This practice also promotes colistin resistance, which can be transferred to human pathogens via people consuming tainted products or water.

“We wrote a piece in The Lancet saying we can’t have this end-of-the-line antibiotic being used in agriculture in this way,” Paterson explains. The Chinese government subsequently restricted colistin use in agriculture, and in July 2019, India followed suit. “The wheels are slowly turning; we are getting people talking about the solutions.”

Paterson says new federal government funding in 2019 means his team will continue to conduct large, meaningful clinical trials on best practice antibiotic treatment. He adds that input from doctors on the front line has allowed him to do these studies on a comparatively modest budget. “It is really wonderful that when doctors are faced with challenges, they will still bend over backwards to take part in a clinical trial,” he says. “All to try to find answers for their patients.”