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

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.

[1]  A. Oliver,et al.  Activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam against ceftolozane/tazobactam- and ceftazidime/avibactam-resistant Pseudomonas aeruginosa. , 2022, The Journal of antimicrobial chemotherapy.

[2]  D. Van Tyne,et al.  Evolution of imipenem-relebactam resistance following treatment of multidrug-resistant Pseudomonas aeruginosa pneumonia. , 2022, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[3]  A. Oliver,et al.  Selection of AmpC β-Lactamase Variants and Metallo-β-Lactamases Leading to Ceftolozane/Tazobactam and Ceftazidime/Avibactam Resistance during Treatment of MDR/XDR Pseudomonas aeruginosa Infections , 2021, Antimicrobial agents and chemotherapy.

[4]  V. Cooper,et al.  In Vitro Susceptibility of Multidrug-Resistant Pseudomonas aeruginosa following Treatment-Emergent Resistance to Ceftolozane-Tazobactam , 2021, Antimicrobial Agents and Chemotherapy.

[5]  A. Oliver,et al.  Molecular mechanisms driving the in vivo development of OXA-10-mediated resistance to ceftolozane/tazobactam and ceftazidime/avibactam during treatment of XDR Pseudomonas aeruginosa infections. , 2020, The Journal of antimicrobial chemotherapy.

[6]  R. Bonomo,et al.  Resistance to Novel β-Lactam-β-Lactamase Inhibitor Combinations: The "Price of Progress". , 2020, Infectious disease clinics of North America.

[7]  Ivan Titov,et al.  A Randomized, Double-blind, Multicenter Trial Comparing Efficacy and Safety of Imipenem/Cilastatin/Relebactam Versus Piperacillin/Tazobactam in Adults With Hospital-acquired or Ventilator-associated Bacterial Pneumonia (RESTORE-IMI 2 Study) , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[8]  A. Oliver,et al.  Molecular and biochemical insights into the in vivo evolution of AmpC-mediated resistance to ceftolozane/tazobactam during treatment of an MDR Pseudomonas aeruginosa infection. , 2020, The Journal of antimicrobial chemotherapy.

[9]  A. Oliver,et al.  In vitro dynamics and mechanisms of resistance development to imipenem and imipenem/relebactam in Pseudomonas aeruginosa. , 2020, The Journal of antimicrobial chemotherapy.

[10]  A. Oliver,et al.  Activity of Imipenem-Relebactam against a Large Collection of Pseudomonas aeruginosa Clinical Isolates and Isogenic β-Lactam-Resistant Mutants , 2019, Antimicrobial Agents and Chemotherapy.

[11]  Y. Doi.  Treatment Options for Carbapenem-resistant Gram-negative Bacterial Infections , 2019, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[12]  T. File,et al.  RESTORE-IMI 1: A Multicenter, Randomized, Double-blind Trial Comparing Efficacy and Safety of Imipenem/Relebactam vs Colistin Plus Imipenem in Patients With Imipenem-nonsusceptible Bacterial Infections , 2019, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[13]  A. Oliver,et al.  Challenging Antimicrobial Susceptibility and Evolution of Resistance (OXA-681) during Treatment of a Long-Term Nosocomial Infection Caused by a Pseudomonas aeruginosa ST175 Clone , 2019, Antimicrobial Agents and Chemotherapy.

[14]  A. Oliver,et al.  Deciphering &bgr;-lactamase-independent &bgr;-lactam resistance evolution trajectories in Pseudomonas aeruginosa , 2018, The Journal of antimicrobial chemotherapy.

[15]  A. Oliver,et al.  Evolution of the Pseudomonas aeruginosa mutational resistome in an international Cystic Fibrosis clone , 2017, Scientific Reports.

[16]  R. Bonomo,et al.  Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-Lactam/β-Lactamase Inhibitor Combinations. , 2016, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[17]  P. Nordmann,et al.  Emerging broad-spectrum resistance in Pseudomonas aeruginosa and Acinetobacter baumannii: Mechanisms and epidemiology. , 2015, International journal of antimicrobial agents.