Suboptimal drug exposure leads to selection of different subpopulations of ceftazidime-avibactam-resistant Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae in a critically ill patient. (December 2021)

• Record Type: Journal Article
• Authors: Gaibani, Paolo; Gatti, Milo; Rinaldi, Matteo; Crovara Pesce, Cristina; Lazzarotto, Tiziana; Giannella, Maddalena; Lombardo, Donatella; Amadesi, Stefano; Viale, Pierluigi; Pea, Federico; Ambretti, Simone
• Is Part Of: International journal of infectious diseases. Volume 113(2021)
• Page Start: 213
• Page End: 217
• Publication Date: 2021-12
• Subjects: ceftazidime-avibactam-resistance -- PK/PD -- critically ill patient -- whole-genome sequencing; Communicable diseases -- Periodicals; Communicable Diseases -- Periodicals; Communicable diseases; Periodicals; Electronic journals; 616.9
• DOI: 10.1016/j.ijid.2021.10.028
• Languages: English
• ISSNs: 1201-9712

Abstract

Highlights: Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) Suboptimal ceftazidime-avibactam exposure is associated to resistance in KPC-Kp Mutations within bla KPC-3 are associated to resistance to ceftazidime-avibactam Mixed subpopulations harboring different bla KPC genes associated to hybrid phenotype Abstract: Objectives: Ceftazidime-avibactam (CAZ-AVI) is a promising novel agent with activity against carbapenem-resistant Enterobacteriaceae . Here, we describe the dynamic evolution of a Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) infection in a critically ill patient treated with CAZ-AVI-tigecycline combination therapy. Methods: Whole-genome sequencing was performed on longitudinal intrapatient KPC-Kp strains isolated from different sites during CAZ-AVI treatment. The pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed on the basis of therapeutic drug monitoring of ceftazidime. Results: The development of resistance due to mutations in the blaKPC gene was observed in KPC-Kp strains isolated from bronchoalveolar lavage and blood during CAZ-AVI treatment. PK/PD analysis demonstrated that during the first days of treatment CAZ- AVI blood exposure was suboptimal (steady-state concentration/minimum inhibitory concentration ratio 2.85). Of note, the low antibiotic pressure may have selected hybrid subpopulations harboring bla KPC-3 and T243M mutation in KPC-Kp isolated from bronchoalveolar lavage and D179Y mutation in those isolated from blood. Conclusion: These results suggest the high adaptability of KPC to CAZ-AVI due to the rapid evolution of resistance and highlight the importance of identifying the optimal PK/PD target to prevent such an event from occurring again in a critically ill patient with pneumonia due to KPC-Kp.