Successful Treatment of Bloodstream Infection due to a KPC-Producing Klebsiella Pneumoniae Resistant to Imipenem/Relebactam in a Hematological Patient

Abstract

Novel carbapenem-β-lactamase inhibitor combination, imipenem/relebactam (IMI-REL), has been recently approved for treatment of infections with limited or no alternative treatment options. In this study, we described the emergence of the IMI-REL-resistance in a KPC-producing Klebsiella pneumoniae (KPC-Kp) strain collected from a hematological patient with no evidence of prior colonization. Interestingly, IMI-REL-resistance was associated with meropenem/vaborbactam (MER-VAB) cross-resistance but was not associated with cross-resistance to ceftazidime/avibactam (CAZ-AVI). Although treatment with CAZ-AVI and gentamicin completely eradicated the infection due KPC-Kp cross-resistance to IMI-REL and MER-VAB, the patient became colonized subsequently by KPC-Kp strains susceptible to IMI-REL and MER-VAB. Whole-genome sequencing performed by hybrid approach using Illumina and Oxford Nanopore platforms demonstrated that all KPC-Kp strains isolated from hematological patient belonged to the ST512 and were clonally related. Analysis of antimicrobial and porins genes demonstrated that cross-resistance to IMI-REL and MER-VAB was associated with increased blaKPC-3 copy number and truncated OmpK35 and OmpK36 with GD134-135 insertion. Phylogenetic analysis demonstrated that KPC-Kp cross-resistance to IMI-REL and MER-VAB was clonally related to a KPC-Kp resistant to IMI-REL as previously described, demonstrating the spread of this multidrug resistant clone in the hematological unit. In conclusion, the results presented in this study reported the emergence of cross-resistance to MER-VAB and IMI-REL in a KPC-Kp strain isolated from a hematological patient and highlight the potential development and diffusion of new multidrug resistance traits.

Klebsiella pneumoniae Susceptibility to Carbapenem/Relebactam Combinations: Influence of Inoculum Density and Carbapenem-to-Inhibitor Concentration Ratio

“…Moreover, the same mechanisms of K. pneumoniae resistance to combinations of imipenem with relebactam were also described in vivo. It was reported that the K. pneumoniae clinical isolate initially susceptible to imipenem/relebactam acquired resistance to this combination during antimicrobial therapy of a hematology patient with a bloodstream infection [ 32 ]. The resistance mechanism of this K. pneumoniae isolate was associated with an increased bla KPC-3 copy number and disruptions of porins ( OmpK 35 and OmpK 36).…”

Comparison of Broth Microdilution, Disk Diffusion and Strip Test Methods for Cefiderocol Antimicrobial Susceptibility Testing on KPC-Producing Klebsiella pneumoniae

“…Genomic DNA was extracted from purified cultures of K. pneumoniae using DNeasy Blood&Tissue Kit (Qiagen, Basel, Switzerland) by following the manufacturer’s instructions and further cleaned up with AMPure XP magnetic beads (Beckman Coulter). Whole genome analysis was performed as previously described [ 20 ]. Briefly, bacterial genomes libraries were prepared using Illumina DNA Prep paired-end kit and sequenced by the Illumina iSeq 100 platform (iSeq Reagent Kit v2, Illumina, San Diego, CA, USA) using iSeq Reagent kit v2 with 2 × 150 paired-end reads.…”

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

“…Genomic DNA was extracted from purified cultures of Klebsiella pneumoniae using DNeasy Blood&Tissue Kit (Qiagen, Basel, Switzerland), following the manufacturer’s instructions, and was further cleaned with AMPure XP magnetic beads (Beckman Coulter, Krefeld, Germany). Whole-genome analysis was performed as previously described [ 28 ]. Briefly, bacterial genomes were sequenced using the Illumina iSeq 100 platform (iSeq Reagent Kit v2, Illumina, San Diego, CA, USA) with an iSeq Reagent kit v2 and 2 × 150 paired-end reads after using Illumina DNA Prep paired-end library preparation.…”

“…Porin genes were manually investigated using BLAST analysis against a reference protein (OmpK35 [O87753], OmpK36 [D6QLX8] and OmpK37 [S5UDN6]), and prophage regions within the KPC-Kp genome were assessed using PHASTER ( , accessed on 9 October 2022). 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 ].…”

“…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 ].…”