Increased bla _KPC Copy Number and OmpK35 and OmpK36 Porins Disruption Mediated Resistance to Imipenem/Relebactam and Meropenem/Vaborbactam in a KPC-Producing Klebsiella pneumoniae Clinical Isolate

Abstract

Herein, we report the in vivo evolution of imipenem/relebactam-resistance in KPC-producing K. pneumoniae (KPC-Kp) isolated from a critically-ill patient treated with multiple combination therapies based on ceftazidime-avibactam or meropenem-vaborbactam. Imipenem/relebactam-resistance was associated to meropenem-vaborbactam cross-resistance and was due to truncated OmpK35 and OmpK36 porins and increased copy of bla KPC copy number.

Impact ofompk36genotype and KPC subtype on thein vitroactivity of ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam against KPC-producingK. pneumoniaeclinical isolates

“…Thus, isolates harbouring a GD duplication may not demonstrate outright resistance to imipenem/relebactam unless other mechanisms, such as an increased bla KPC copy number are present. 26 , 27 …”

“… 29 To date, only two cases of meropenem/vaborbactam treatment-emergent non-susceptibility have been described, and ompK36 mutations were implicated in both. 19 , 26 Like meropenem, vaborbactam accesses the periplasmic space through OmpK36, 30 and thus both agents are reliant upon intact porin channels for cell entry.…”

Epidemiology and In Vitro Activity of Ceftazidime/Avibactam, Meropenem/Vaborbactam and Imipenem/Relebactam against KPC-Producing K. pneumoniae Collected from Bacteremic Patients, 2018 to 2020

“…Sequencing the resistant KPC-Kp strains revealed that mutations in the bla KPC-3 gene are involved in resistance to CAZ-AVI [ 20 ], while resistance to MER-VAB in KPC-3-producing K. pneumoniae strains is mostly associated with loss-of-function in the OmpK36 porin protein [ 21 ]. Finally, IMI-REL resistance is linked to the concomitant increase in MIC values for MER-VAB and CAZ-AVI, suggesting that cross-resistance could represent a mechanism for the onset of resistance between novel βL-βLICs [ 22 ].…”

“…The phylogenetic tree was generated using core genome SNP analysis as previously described [ 28 ]. SNPs and insertion-deletions (Indels) between CAZ-AVI and/or MER-VAB and/or IMI-REL resistant genomes were investigated as previously described [ 22 , 28 ].…”

MALDI-TOF MS-Based Approaches for Direct Identification of Gram-Negative Bacteria and BlaKPC-Carrying Plasmid Detection from Blood Cultures: A Three-Year Single-Centre Study and Proposal of a Diagnostic Algorithm

“…Interestingly, the method was able to identify 14 out of the 17 KPC-producing K. pneumoniae isolates that tested negative to NG-Test ® CARBA 5 immunoassay but positive to Eazyplex ® SuperBug CRE molecular testing. Nine of these isolates were previously investigated by DNA sequencing revealing mutations in bla KPC associated with ceftazidime/avibactam resistance (substitution D179Y, n = 8; duplication EL167–168, n = 1) [ 23 , 24 , 25 ]. KPC variants conferring ceftazidime/avibactam resistance are an increasing concern as characterized to be undetectable by the main phenotypic carbapenemase detection methods including immunochromatographic assays [ 23 , 24 , 26 ].…”