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https://hdl.handle.net/2183/45468 Simultaneous and divergent evolution of resistance to cephalosporin/β-lactamase inhibitor combinations and imipenem/relebactam following ceftazidime/avibactam treatment of MDR Pseudomonas aeruginosa infections
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Alonso-García, Isaac
Vázquez-Ucha, Juan Carlos
Lasarte-Monterrubio, Cristina
González-Mayo, Elena
Lada-Salvador, Paula
Vela-Fernández, Ramón
Aja-Macaya, Pablo
Guijarro-Sánchez, Paula
Rumbo-Feal, Soraya
Muíño-Andrade, María José
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Alonso-García I, Vázquez-Ucha JC, Lasarte-Monterrubio C, González-Mayo E, Lada-Salvador P, Vela-Fernández R, Aja-Macaya P, Guijarro-Sánchez P, Rumbo-Feal S, Muíño-Andrade M, Fernández-González A, Martínez-Guitián M, Beceiro A, Rodríguez-Iglesias M, Oliver A, Arca-Suárez J, Galán-Sánchez F, Bou G. Simultaneous and divergent evolution of resistance to cephalosporin/β-lactamase inhibitor combinations and imipenem/relebactam following ceftazidime/avibactam treatment of MDR Pseudomonas aeruginosa infections. J Antimicrob Chemother. 2023 May 3;78(5):1195-1200.
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Abstract
[Abstract]
Objectives: To describe and characterize the emergence of resistance to ceftolozane/tazobactam, ceftazidime/avibactam and imipenem/relebactam in a patient receiving ceftazidime/avibactam treatment for an MDR Pseudomonas aeruginosa CNS infection.
Methods: One baseline (PA1) and two post-exposure (PA2 and PA3) isolates obtained before and during treatment of a nosocomial P. aeruginosa meningoventriculitis were evaluated. MICs were determined by broth microdilution. Mutational changes were investigated through WGS. The impact on β-lactam resistance of mutations in blaPDC and mexR was determined through cloning experiments and complementation assays.
Results: Isolate PA1 showed baseline resistance mutations in DacB (I354A) and OprD (N142fs) conferring resistance to conventional antipseudomonals but susceptibility to ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. Post-exposure isolates showed two divergent ceftazidime/avibactam-resistant phenotypes associated with distinctive mutations affecting the intrinsic P PDC β-lactamase (S254Ins) (PA2: ceftolozane/tazobactam and ceftazidime/avibactam-resistant) or MexAB-OprM negative regulator MexR in combination with modification of PBP3 (PA3: ceftazidime/avibactam and imipenem/relebactam-relebactam-resistant). Cloning experiments demonstrated the role of PDC modification in resistance to ceftolozane/tazobactam and ceftazidime/avibactam. Complementation with a functional copy of the mexR gene in isolate PA3 restored imipenem/relebactam susceptibility.
Conclusions: We demonstrated how P. aeruginosa may simultaneously develop resistance and compromise the activity of new β-lactam/β-lactamase inhibitor combinations when exposed to ceftazidime/avibactam through selection of mutations leading to PDC modification and up-regulation of MexAB-OprM-mediated efflux.