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)."The researchers analyzed how KPC variants including KPC-78 interacted with CZA. (Yang et al., Microbiol. Spectr., 2026)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.