In Vivo Resistance To Ceftolozane/Tazobactam In Pseudomonas Aeruginosa Arising By Ampc- And Non-Ampc-Mediated Pathways

Two pairs of ceftolozane/tazobactam susceptible/resistant P. aeruginosa were isolated from 2 patients after exposure to -lactams. The genetic basis of ceftolozane/tazobactam resistance was evaluated, and -lactam-resistant mechanisms were assessed by phenotypic assays. Whole genome sequencing identified mutations in AmpC including the mutation (V213A) and a deletion of 7 amino acids (P210-G216) in the -loop. Phenotypic assays showed that ceftolozane/tazobactam resistance in the strain with AmpC(V213A) variant was associated with increased -lactamase hydrolysis activity. On the other hand, the deletion of 7 amino acids in the -loop of AmpC did not display enhanced -lactamase activity. Resistance to ceftolozane/tazobactam in P. aeruginosa is associated with changes in AmpC; however, the apparent loss of -lactamase activity in AmpC7 suggests that non-AmpC mechanisms could play an important role in resistance to -lactam/-lactamase inhibitor combinations.