J Korean Med Sci.  2024 Jul;39(25):e208. 10.3346/jkms.2024.39.e208.

Evolution of bla_KPC Under the Pressure of Carbapenems and Ceftazidime/ Avibactam in a Patient With Persistent Bacteremia Caused by Klebsiella pneumoniae

• Won EJ
• Park K
• Jeong YS
• Kim J
• Choi Y
• Kim SH
• Kim MN
• Sung H

• KMID: 2557773
• DOI: http://doi.org/10.3346/jkms.2024.39.e208

Abstract

A 30-year-old Korean man with myelodysplastic syndrome admitted hospital due to undifferentiated fever and recurrent skin lesions. He received combination therapy with high doses of meropenem, tigecycline and amikacin, yielding carbapenem resistant Klebsiella pneumoniae (CRKP) harboring K. pneumoniae carbapenemase (KPC)-2 from blood cultures on hospital day (HD) 23. Ceftazidime/avibactam was started at HD 37 and CRKP was eradicated from blood cultures after 5 days. However, ceftazidime/avibactam-resistant CRKP carrying KPC-44 emerged after 26 days of ceftazidime/avibactam treatment and then ceftazidime/ avibactam-resistant, carbapenem-susceptible K. pneumoniae carrying KPC-135 was isolated on HD 65. The 3-D homology of KPC protein showed that hot spot changes in the omega loop could be attributed to ceftazidime/avibactam resistance and loss of carbapenem resistance. Whole genome sequencing of serial isolates supported that phenotypic variation was due to clonal evolution than clonal replacement. The treatment regimen was changed from CAZ/AVI to meropenem-based therapy (meropenem 1 g iv q 8 hours and amikacin 600 mg iv per day) starting with HD 72. CAZ/AVI-susceptible CRKP was presented again from blood cultures on HD 84, and the patient expired on HD 85. This is the first Korean report on the acquisition of ceftazidime/avibactam resistance through the emergence of bla_KPC variants.

Keyword

Klebsiella pneumonia; Carbapenem Resistant Klebsiella pneumoniae; Carbapenemase; bla_KPC; Ceftazidime/Avibactam; 3-D Homology; Whole-Genome Sequencing

Figure

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  Fig. 1 Chronological changes in the susceptibility of Klebsiella pneumoniae (KPN) isolated during the course of this case (being treated with ceftazidime/avibactam and meropenem) to ceftazidime/avibactam and carbapenem. KPN isolates were serially recovered from blood cultures (square), respiratory cultures (circle), and stool cultures (diamond).KPC = K. pneumoniae carbapenemase.

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  Fig. 2 Representative view of the overall KPC-2 or its variants of Klebsiella pneumoniae strains in this study. (A) KPC-2 structure of A5593, (B) KPC-44 structure of A7408, and (C) KPC-135 structure of A8177. The blue dotted circle indicates the omega loop region and the yellow dotted circle indicates the terminal loop.KPN = K. pneumoniae carbapenemase.

• 

  Fig. 3 Whole-genome sequencing analysis of blood isolates of Klebsiella pneumoniae in this study. Minimum spanning tree based on the phylogeny of 14 isolates using core genome multi-locus sequence typing with eight ST307 domestic and global isolates. The red dotted circle indicates the strains isolated before HD 41 and the blue dotted circle indicates the strains isolated after HD 63, respectively.HD = hospital day.

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