Emerging resistance mechanisms to newer β-lactams in Pseudomonas aeruginosa.

Abstract

Background: Although the introduction of novel β-lactams and/or combinations with β-lactamase inhibitors over the last decade is helping to mitigate the threat of extensively drug-resistant/difficult-to-treat-resistant (XDR/DTR) Pseudomonas aeruginosa infections, the problem is far from being solved, due to the capacity of this pathogen for developing resistance.

Objectives: This study aims to provide a comprehensive analysis of the emerging/evolving resistance mechanisms to the antipseudomonal β-lactams introduced over the last decade.

Sources: Sources include literature review of published studies before December 31 2024 analysing P. aeruginosa resistance mechanisms for ceftolozane/tazobactam, ceftazidime/avibactam, cefiderocol, imipenem/relebactam, meropenem/vaborbactam, and/ aztreonam/avibactam.

Content: Among the emerging resistance mechanisms are noteworthy the mutations in the catalytic centres (mostly the Ω-loop) of AmpC, the horizontally acquired OXA-2/OXA-10 enzymes or of the class A carbapenemases (GES/KPC). These mutations typically confer ceftolozane/tazobactam and ceftazidime/avibacm resistance. They also frequently increase cefiderocol Minimal Inhibitory Concentrations (MICs), and some of them, such as the L320P AmpC mutation, affect cefiderocol specifically. However, most of these mutations confer collateral susceptibility to carbapenems. Efflux pumps are also relevant, given their capacity to extrude both, the β-lactam and their partner β-lactamase inhibitor. Moreover, beyond the classical mutational overexpression of efflux pumps, emerging resistance is driven by the selection of structural mutations leading to modified (enhanced) substrate recognition. Other emerging mechanisms include β-lactam target mutations (particularly Penicillin-binding protein 3 (PBP3)), large genomic deletions, the activation of two-component regulators (such as ParRS or CpxRS) or the mutations in iron transport systems (such as Piu or Pir) involved in cefiderocol resistance.

Implications: A deep understanding of emerging resistance mechanisms, including their conferred cross-resistances and collateral susceptibilities, should be useful for the optimization of treatments of severe XDR/DTR P. aeruginosa infections.