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

Paolo Gaibani,Milo Gatti,Matteo Rinaldi,Cristina Crovara Pesce,Tiziana Lazzarotto,Maddalena Giannella,Donatella Lombardo,Stefano Amadesi,Pierluigi Viale,Federico Pea,Simone Ambretti

doi:10.1016/j.ijid.2021.10.028

Abstract

ObjectivesCeftazidime-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. MethodsWhole-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. ResultsThe 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 blaKPC-3 and T243M mutation in KPC-Kp isolated from bronchoalveolar lavage and D179Y mutation in those isolated from blood. ConclusionThese 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.

Highlights

Paolo Gaibani, Milo Gatti, Matteo Rinaldi, Cristina Crovara, Tiziana Lazzarotto, Maddalena Giannella, Donatella Lombardo, Stefano Amadesi, Pierluigi Viale, Federico Pea, Simone Ambretti
We describe the dynamic evolution of a KPC-producing Klebsiella pneumoniae (KPC-Kp) infection in a critically ill patient treated with CAZ-AVI-tigecycline combination therapy
The low antibiotic pressure may have selected hybrid subpopulations harboring blaKPC-3 and T243M mutation in KPC-Kp isolated from broncho-alveolar lavage (BAL) and D179Y mutation in those isolated from blood. These results suggest the high adaptability of KPC to CAZ-AVI due to rapid resistance evolution and highlight the importance that optimal PK/PD target may have in preventing such an event from occurring in critically ill patient with pneumonia due to KPC-Kp

Summary

Discussion

We described the emergence of CAZ-AVI -resistant KPC-Kp strains in a critically ill patient probably due to suboptimal drug exposure. Genome comparison of longitudinal clinical strains demonstrated that few mutations differentiated KPC-Kp isolates and that emerging rapid mutation within blaKPC gene were found to be linked to the CAZ-AVI resistance in strains These data are in agreement with previous studies demonstrating that CAZ-AVI-based antibiotic treatment is the main cause of the development of resistance (Shields et al 2018; Gaibani et al 2018). Deep sequence analysis demonstrated that KPC-Kp resistant both to CAZ-AVI and meropenem was composed by complex subpopulations carrying different blaKPC alleles responsible of hybrid phenotype These data are in agreement with previous WGS studies demonstrating that specific mutation in blaKPC gene is responsible for CAZ-AVI-resistance phenotype associated with reverted carbapenem-susceptibility and those mixed subpopulations are associated with hybrid phenotype in longitudinal intrapatient samples (Shields et al 2018; Gaibani et al 2018)

Conclusion

Findings

Genetic Determinant Resistances