The combination drug ceftazidime-avibactam (CZA) is a last line of defense against the common Pseudomonas aeruginosa hospital bug: It’s the drug that gets called in when nothing else works, but there’s now evidence that it may not keep working for long.
Based on an analysis of two critically ill patients with P. aeruginosa infections, the bacteria are developing genetic mutations that change the enzymes they produce – and can ward off an attack from CZA.
Researchers led by a team from Tongji University in China have now published a new paper in Microbiology Spectrum detailing the mutations and what it might mean for fighting P. aeruginosa in the future.
However, there’s also an intriguing twist in the tale: The adaptations that are helping P. aeruginosa repel CZA might also leave it vulnerable to older medications.
“Pseudomonas aeruginosa is a well-recognized opportunistic pathogen and a leading cause of healthcare-associated infections,” write the researchers in their paper.
“The shrinking effectiveness of available antimicrobial therapies has intensified the global threat posed by carbapenem-resistant P. aeruginosa (CRPA).”
Carbapenems are the class of heavy-duty antibiotics that this bacterium has evolved to block, and that’s the reason CZA has become necessary. It’s a public health concern that has spread worldwide.
Now it seems CZA might become less effective than we’d hoped too – though it’s worth bearing in mind that these mutations have only been found in two cases so far.
The researchers identified altered versions of enzymes called KPC-71 and KPC-78 in the P. aeruginosa samples. When tested against CZA, they showed improved resistance to it, essentially by taking down the drug’s built-in shields (the ‘avibactam’ part of ceftazidime-avibactam).
These mutant enzymes team up with other defenses already integrated in the bacteria, the researchers think, making the bug much harder to kill.
“While the specific KPC mutations are the primary determinants of CZA resistance, our data indicate that intrinsic resistance mechanisms in P. aeruginosa play a synergistic role,” write the researchers.
However, resistance in these mutated strains was weakened when it came to the older carbapenem drugs – an unexpected trade-off that offers some hope for being able to treat this bug in the future.
frameborder=”0″ allow=”accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share” referrerpolicy=”strict-origin-when-cross-origin” allowfullscreen>Further investigation is needed, but it might be that carbapenem medications (including the imipenem and meropenem types mentioned in the paper) will once again become effective at treating P. aeruginosa.
That said, there’s also the risk that the bacteria develop carbapenem resistance all over again, and come back even stronger.
“This ‘see-saw’ effect highlights the plasticity of the KPC enzyme but also warns clinicians that phenotypic susceptibility to carbapenems in these strains may be deceptive, as reversion mutations could theoretically restore carbapenem resistance under imipenem or meropenem pressure,” write the researchers.
Pseudomonas aeruginosa is found pretty much everywhere in the environment, and can lurk in soil and in water. However, it’s only really dangerous to people already weakened by ill health – which is why it’s such a problem in hospitals.
It’s a particular issue when it comes to medical equipment (including ventilators and catheters), where the bug can hide out and cause infection. Following good hygiene and cleaning practices can help reduce the risk of P. aeruginosa infections, but these infections are hard to prevent completely.
A specific family of the P. aeruginosa bacteria known as ST463 has recently caused concern for health officials in China, and the samples studied here are from that family: they’re highly infectious, cause severe illness, and are especially drug-resistant, even without the new mutations.
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With that in mind, the researchers are calling for increased vigilance so we can stay ahead of future mutations.
“Given the widespread dissemination of the ST463 lineage in China, the emergence of these variants highlights the urgent need for clinicians to monitor for CZA resistance development during therapy,” write the researchers.
The research has been published in Microbiology Spectrum.
This article was fact-checked by Carly Cassella and edited by Michelle Starr. While we pride ourselves on our process, we are only human. If you spot a mistake, please let us know.
