Transporter Genes and fosA Associated With Fosfomycin Resistance in Carbapenem-Resistant Klebsiella pneumoniae

Abstract

Infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) are of significant clinical concern worldwide. Fosfomycin is one of the limited treatment options for CRKP. However, resistance to fosfomycin in CRKP has been observed. In this study, we aimed to investigate the fosfomycin resistance mechanism of CRKP. Fosfomycin-resistant Klebsiella pneumoniae isolates were collected from four medical centers in Taiwan from 2010 to 2018. The genes that contributed to fosfomycin resistance were amplified and sequenced. Carbohydrate utilization assays and mutagenesis studies were performed to determine the mechanisms underlying fosfomycin resistance. Forty fosfomycin-resistant CRKP strains were collected and used for further analysis. Fourteen strains exhibited low-level resistance (MIC = 256–512 mg/dl), while 26 strains showed high-level resistance (MIC ≥ 1,024 mg/dl). Chromosomal fosAKP I91V was detected in 39/40 fosfomycin-resistant CRKP strains. We observed that amino acid substitution of chromosomal fosAKP I91V increased the MIC of fosfomycin by approximately eight folds, and this was the only mechanism elucidated for low-level fosfomycin resistance. Among the 26 high-level resistance strains, fosAKP I91V combined with transporter deficiencies (18/26, 69.2%) was the most common resistant mechanism, and one strain showed transporter deficiency only. Plasmid-borne fosA3 accounted for 27.0% (7/26) of high-level resistance. Various G3P and G6P transporter gene mutations, including three novel single amino acid mutations (glpT E299D, glpT D274V, and uhpC A393V) were detected in 19 strains. No murA mutation was found in this study. Our study highlights the need for new therapeutic agents for CRKP infections in Taiwan.

Characterizing Antimicrobial Resistance in Clinically Relevant Bacteria Isolated at the Human/Animal/Environment Interface Using Whole-Genome Sequencing in Austria

“…However, IS10 was not found in any of these isolates in the surroundings of the fosA6 gene nor was a plasmid detected, pointing to a chromosomal location. On the contrary, the two fosA5 isolates were fosfomycin-susceptible, in agreement with other authors, and although IncR and/or one IncFIB_K plasmids were detected in these isolates, they did not harbor the fos A5, therefore indicating a possible chromosomal location [ 46 ].…”

Resistance and virulence features of hypermucoviscous Klebsiella pneumoniae from bloodstream infections: Results of a nationwide Italian surveillance study

“…Even if the strain described in this work was carbapenem-susceptible and none of most common carbapenemase classes was detected, the content of acquired resistance mechanisms was notable, including a bla CTX–M–65 a bla DHA–1 beta-lactamases and the fosA3 fosfomycin resistance gene. Interestingly, these two latter resistance mechanisms are strongly epidemiologically linked to the Asiatic continent ( Taniguchi et al, 2017 ; Hennequin et al, 2018 ; Hao et al, 2021 ; Wang et al, 2022 ). To our best knowledge, this is the first description of a FosA3 producing Kp reported from Italy.…”

An outbreak of extensively drug-resistant and hypervirulent Klebsiella pneumoniae in an intensive care unit of a teaching hospital in Southwest China

“…None of the bla KPC -bearing plasmids from all strains in this study was successfully transferred into E. coli J53, which may be related to the host range and growth conditions of the strains, but did not exclude that the plasmids in this study could be transferred under other circumstances ( Carattoli, 2009 ). In addition, mutations on fosA (Ile91Val) combined with the presence of fosA3 in all strains could explain the resistance to Fosfomycin ( Ito et al., 2017 ; Wang et al., 2022 ). The strains in this study were resistant to quinolones, caused by mutations in gyrA (Asp87Gly, Ser83Ile) and parC (Ser80Ile) of QRDR.…”