Simultaneous and divergent evolution of resistance to cephalosporin/β-lactamase inhibitor combinations and imipenem/relebactam following ceftazidime/avibactam treatment of MDR Pseudomonas aeruginosa infections

Autor: Isaac Alonso-García, Juan Carlos Vázquez-Ucha, Cristina Lasarte-Monterrubio, Elena González-Mayo, Paula Lada-Salvador, Ramón Vela-Fernández, Pablo Aja-Macaya, Paula Guijarro-Sánchez, Soraya Rumbo-Feal, María Muíño-Andrade, Ana Fernández-González, Marta Martínez-Guitián, Alejandro Beceiro, Manuel Rodríguez-Iglesias, Antonio Oliver, Jorge Arca-Suárez, Fátima Galán-Sánchez, Germán Bou
Rok vydání: 2023
Předmět:
Zdroj: Journal of Antimicrobial Chemotherapy. 78:1195-1200
ISSN: 1460-2091
0305-7453
DOI: 10.1093/jac/dkad062
Popis: 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.
Databáze: OpenAIRE
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