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Results from antibiotic resistance trial “astounding”

Results from antibiotic resistance trial “astounding” - Featured Image

An Australian-led trial, published in JAMA , has made a promising breakthrough in the fight against antibiotic resistance, finding that meropenem is successful at reducing the number of deaths from a deadly superbug.

Co-author of the study and Director at the University of Queensland Centre for Clinical Research (UQCCR), Professor David Paterson, said that researchers had never been sure whether piperacillin-tazobactam and meropenem (a carbapenem) were equally effective at treating antibiotic resistant strains of Escherichia coli and Klebsiella pneumoniae. This randomised MERINO Trial set out to get an answer by comparing the two drugs.

“The finding that meropenem was associated with a lower mortality was really a quite astounding result and one we didn’t expect.”

“We went into the study with equipoise – we thought they should be as good as each other – so to really find a difference was quite eye-opening and it’s something that’s got a huge potential to change practice,” Professor Paterson said.

The MERINO Trial involved patients infected with multi-drug resistant bacteria

Historically, Escherichia coli and Klebsiella pneumoniae have been effectively treated with beta-lactam antibiotics. However there has been a sharp global increase in the prevalence of bacterial strains which are resistant to these “first-line” antibiotics, such as ceftriaxone.

Typically, this occurs because the bacteria acquire genes that encode for mechanisms which can destroy these antibiotics, via enzymes called “extended-spectrum beta-lactamases” or ESBLs.

The MERINO Trial involved 379 patients with bloodstream infections caused by ESBL-producing Escherichia coli or Klebsiella pneumoniae. They were recruited from 26 hospitals across 9 countries, including Singapore, Australia and Turkey.

The researchers found that 12.3% of patients randomised to piperacillin-tazobactam met the primary outcome of mortality at 30 days, compared to 3.7% randomized to meropenem. The absolute risk difference was 8.6%, falling beyond the 5% non-inferiority threshold. As a result, the researchers could not reject the null-hypothesis, and the results did not support the use of piperacillin-tazobactam for these patients.

Huge potential to change clinical practice

Lead author of the study, UQCCR Postdoctoral Research Fellow Dr Patrick Harris, said that the results of this unique trial will have significant implications for clinical practice. The findings can provide clinicians with greater certainty in selecting appropriate treatment for patients with severe infections caused by these multi-drug resistant strains.

“A carbapenem drug, such as meropenem, should therefore be the recommended treatment of choice for these patients”, Dr Harris said.

Professor Paterson said it was important to remember that this study looked at a definitive therapy – that is, when an organism was known to be an ESBL producer.

“What is really tricky though are the implications – does this mean doctors should use meropenem empirically before we know the resistance profile? That has its downside in that we don’t want to be breeding resistance to meropenem and the carbapenem class, because that really is our go-to drug with seriously ill patients.”

“That really then speaks to the importance of infection control, good antibiotic stewardship and the development of new antibiotics that would be able to treat carbapenem resistant organisms”, he said.

New antibiotics are being developed

The Paterson group at UQCCR are planning a number of trials to help define the best treatment for highly-resistant organisms, including carbapenem-resistant Enterobacteriaceae, Pseudomonas or Acinetobacter.

“Our group is working with the developer of a new antibiotic, and we would be the first in the world to study that for bloodstream infections. That’s a real potential opportunity for Australian patients if they do have a significant carbapenem resistant organism”, Professor Paterson said.

Dr Harris said that as new drugs become available for these difficult-to-treat organisms, pragmatic clinical trials will play a vital role in assessing how these new medications can be used to treat the patients most in need.

“Understanding how these drugs perform in ‘real-world’ circumstances will be critical to guiding clinical practice.”