Emergence of ceftazidime-avibactam resistance in bla(KPC-33)-harbouring ST11 Klebsiella pneumoniae in a paediatric patient.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses immense threats to the health of infected patients worldwide, especially children. This study reports the infection caused by CRKP in a paediatric intensive care unit (PICU) child and its drug-resistant mutation during the treatment. Twelve Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains were isolated from the child. Broth microdilution method, plasmid transformation assay, and whole genome sequencing (WGS) were performed to investigate the antimicrobial susceptibility, resistance mechanisms, and genetic structural features of CRKPs. The results showed that 12 strains were highly resistant to most available antimicrobial agents. Among them, K. pneumoniae FD11 and K. pneumoniae FD12 were resistant to ceftazidime-avibactam (CZA, MIC >64 mg/L) and restored the carbapenem susceptibility (Imipenem, MIC =0.25 mg/L; Meropenem, MIC =2 mg/L). The patient improved after treatment with CZA in combination with aztreonam. Plasmid transformation assay demonstrated that the blaKPC-33-positive transformant increased MICs of CZA by at least 33-fold and 8-fold compared with the recipient Escherichia coli DH5α and blaKPC-2-positive transformants. WGS analysis revealed that all strains belonged to the ST11-KL64 type and showed highly homologous (3-26 single nucleotide polymorphisms [SNPs]). A single base mutation (G532T) of blaKPC-2 resulted in a tyrosine to aspartic acid substitution at Ambler amino acid position 179 (D179Y), which conferred CZA resistance in K. pneumoniae. This is the first report of a drug-resistant mutation evolving into blaKPC-33 during the treatment of blaKPC-2-positive CRKP in paediatric-infected patients. It advises clinicians that routine sequential antimicrobial susceptibility testing and KPC genotyping are critical during CZA therapy in children infected with CRKP.

Zhou J ，Yan G ，Tang C ，Liu J ，Fu P ，Ding L ，Yang W ，Guo Y ，Wang C ，Lu G ，Hu F ... -  《-》

Molecular Mechanisms Driving the In Vivo Development of KPC-71-Mediated Resistance to Ceftazidime-Avibactam during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections.

Li X ，Ke H ，Wu W ，Tu Y ，Zhou H ，Yu Y ... -  《mSphere》

Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne bla(KPC-3) Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections.

Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor with activity against carbapenem-resistant (CRE) that produce carbapenemase (KPC). We report the first cases of ceftazidime-avibactam resistance to develop during treatment of CRE infections and identify resistance mechanisms. Ceftazidime-avibactam-resistant emerged in three patients after ceftazidime-avibactam treatment for 10 to 19 days. Whole-genome sequencing (WGS) of longitudinal ceftazidime-avibactam-susceptible and -resistant isolates was used to identify potential resistance mechanisms. WGS identified mutations in plasmid-borne , which were not present in baseline isolates. mutations emerged independently in isolates of a novel sequence type 258 sublineage and resulted in variant KPC-3 enzymes. The mutations were validated as resistance determinants by measuring MICs of ceftazidime-avibactam and other agents following targeted gene disruption in , plasmid transfer, and cloning into competent In rank order, the impact of KPC-3 variants on ceftazidime-avibactam MICs was as follows: D179Y/T243M double substitution > D179Y > V240G. Remarkably, mutations reduced meropenem MICs ≥4-fold from baseline, restoring susceptibility in from two patients. Cefepime and ceftriaxone MICs were also reduced ≥4-fold against D179Y/T243M and D179Y variant isolates, but susceptibility was not restored. Reverse transcription-PCR revealed that expression of encoding D179Y/T243M and D179Y variants was diminished compared to expression in baseline isolates. In conclusion, the development of resistance-conferring mutations in within 10 to 19 days of ceftazidime-avibactam exposure is troubling, but clinical impact may be ameliorated if carbapenem susceptibility is restored in certain isolates.

Shields RK ，Chen L ，Cheng S ，Chavda KD ，Press EG ，Snyder A ，Pandey R ，Doi Y ，Kreiswirth BN ，Nguyen MH ，Clancy CJ ... -  《-》

A large-scale surveillance revealed that KPC variants mediated ceftazidime-avibactam resistance in clinically isolated Klebsiella pneumoniae.

Qiao S ，Xin S ，Zhu Y ，Zhao F ，Wu H ，Zhang J ，Yao B ，Yu Y ，Fu Y ，Jiang Y ，Xie X ，Zhang J ... -  《Microbiology Spectrum》

KPC-2 allelic variants in Klebsiella pneumoniae isolates resistant to ceftazidime-avibactam from Argentina: bla(KPC-80), bla(KPC-81), bla(KPC-96) and bla(KPC-97).

Sanz MB ，Pasteran F ，de Mendieta JM ，Brunetti F ，Albornoz E ，Rapoport M ，Lucero C ，Errecalde L ，Nuñez MR ，Monge R ，Pennini M ，Power P ，Corso A ，Gomez SA ... -  《Microbiology Spectrum》