L2 β-lactamase contributes to ceftolozane-tazobactam resistance in Pseudomonas aeruginosa

Investigators examined a novel genotype associated with high-level ceftolozane-tazobactam resistance in Pseudomonas aeruginosa from one patient. Whole-genome sequencing compared the resistant isolate with a susceptible isolate collected from the same patient two months earlier. The isolates belonged to different high-risk clones: the earlier isolate was sequence type ST111, whereas the resistant isolate was ST235.

The ST235 isolate had a ceftolozane-tazobactam minimum inhibitory concentration (MIC) exceeding 256/4 µg/mL and carried five copies of a genetic element containing blaL2 and a truncated ampRL2 regulator gene. These genes commonly occur together in Stenotrophomonas maltophilia. Comparative genomic analysis found no alternative explanation for the observed resistance. Introducing blaL2 into genetically distinct P. aeruginosa strains increased ceftolozane-tazobactam MICs.

Screening archived isolates identified two additional clinical isolates carrying one and two copies of the element, respectively. In the single-copy isolate, disrupting blaL2 reduced the MIC, whereas disrupting the truncated regulator did not. These findings support an L2-mediated contribution to resistance independent of its canonical regulator. The evidence is limited to a single-patient investigation and laboratory experiments; the sequential isolates represent different clones, not demonstrated resistance evolution within one strain. The abstract provides no prevalence estimate or treatment-outcome data.