Characterization of KPC-82, a KPC-2 Variant Conferring Resistance to Ceftazidime-Avibactam in a Carbapenem-Nonsusceptible Clinical Isolate of Citrobacter koseri

Abstract

KPC-82 is a KPC-2 variant, identified in a carbapenem non-susceptible Citrobacter koseri that confers high-level resistance to ceftazidime-avibactam. Genomic analysis revealed that bla KPC-82 is carried by a chromosomally integrated Tn 4401 transposon (disrupting porin gene phoE ) and evolved by a 6-nucleotide tandem-repeat duplication causing a two-amino-acid insertion (Ser-Asp) within the Ala 267 -Ser 275 loop. Similar to related KPC variants, KPC-82 showed decreased carbapenemase activity when expressed in a heterologous background and remained susceptible to carbapenem/β-lactamase inhibitor combinations.

Emergence of a KPC-90 Variant that Confers Resistance to Ceftazidime-Avibactam in an ST463 Carbapenem-Resistant Pseudomonas aeruginosa Strain

“…Most KPC mutations conferring CZA resistance can result in carbapenem susceptibility in strains. These mutations include KPC-33 ( 13 ), KPC-41 ( 14 ), KPC-50 ( 15 ), and KPC-82 ( 16 ). KPC-90 was also able to produce a phenotype of CZA- resistant, and meropenem- and imipenem-susceptible phenotype.…”

“…CZA resistance in Enterobacteriaceae strains is usually associated with mutations in the bla KPC gene ( 13 – 16 ), especially in the omega-loop of the protein (amino acid positions 164 to 179). In contrast to Enterobacteriaceae , the resistance of P. aeruginosa to CZA caused by KPC mutations has not been reported.…”

Multiple Novel Ceftazidime-Avibactam-Resistant Variants of bla KPC-2 -Positive Klebsiella pneumoniae in Two Patients

“…To date, a total of 88 bla KPC gene subtypes have been published, the detection of which has presented an uptrend since 2015 and has shown blowout growth since 2020, and 52.3% of them (46/88) were released after 2020. Based on previous reports and data from GenBank database ( https://www.ncbi.nlm.nih.gov/pathogens/refgene/#gene_family :(blaKPC), by August 16, 2021), bla KPC gene subtypes mediating inhibitor resistance have successively emerged by 2016 and are now mainly reported in Europe, China, and the United States ( 18 – 20 ). Especially in the recent 3 years, 53.8%(28/52) novel bla KPC gene subtypes are resistant to inhibitors.…”

Comparison of Four Carbapenemase Detection Methods for bla KPC-2 Variants

“…However, with the clinical application of these drugs, KPC-producing strains have mutated to adapt to the pressure of new antibiotics, generating new bla KPC subtypes, such as bla KPC-14 , bla KPC-28 , and bla KPC-33 , based on mutations in bla KPC-2 or bla KPC-3 ( 11 , 12 ). So far (as of July 2021), 88 KPC alleles have been uploaded to the NCBI database ( 13 ). The most critical phenotypic features of KPC variants are their resistance to ceftazidime-avibactam and their restoration of susceptibility to meropenem or imipenem, which is mainly due to amino acid substitutions and conformational changes in the carbapenemase active site ( 11 – 14 ).…”