Genomic analysis of the emergence and evolution of multidrug resistance during a Klebsiella pneumoniae outbreak including carbapenem and colistin resistance

Abstract

Carbapenem resistance required production of the DHA-1 β-lactamase and decreased permeability, but fosfomycin resistance depended only on permeability. Resistance to colistin might be related to an alteration in the regulation of the phoPQ system. Hypermutation is not related to the selection of porin mutants. Plasmid instability might be due to the high number of mobile elements and suggests a major role for antibiotic selection pressure in the emergence and evolution of this outbreak.

In Vivo Evolution to Colistin Resistance by PmrB Sensor Kinase Mutation in KPC-Producing Klebsiella pneumoniae Is Associated with Low-Dosage Colistin Treatment

“…Recently, we demonstrated that inactivation of the mgrB gene, which encodes a negative-feedback regulator of the PhoQ/PhoP signaling system (10), is a genetic mechanism responsible for acquired colistin resistance in KPC-KP strains of ST258 following exposure to colistin treatment (11), and a similar resistance mechanism was subsequently reported for a colistin-resistant clinical isolate of K. pneumoniae of ST37 that produces an AmpC-type ␤-lactamase (12). This mechanism leads to upregulation of the PhoQ/PhoP system, which eventually activates the PmrHFIJKLM system responsible for modification of the lipid A colistin target by decoration with 4-amino-4-deoxy-L-arabinose (l-Ara4N), which neutralizes the negative charge and decreases colistin binding (11,13,14).…”

Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes

“…Other alterations, such as insertions or deletions of small nucleotide sequences in the mgrB gene, or even some complete deletions of the mgrB locus, have been reported (120,130,131). Insertional inactivation caused by diverse insertion sequences (IS), belonging to several families and inserted at different locations within the mgrB gene, is often responsible for acquired resistance to colistin in K. pneumoniae (105,117,120,(130)(131)(132) and Klebsiella oxytoca (133,134). Recently, the transposition of genes encoding extended-spectrum ␤-lactamases (ESBLs) or carbapenemases, leading to disruption of the chromosomal mgrB gene, was reported as a source of resistance to colistin (135,136).…”

In Vitro Susceptibility to Ceftazidime-Avibactam of Carbapenem-Nonsusceptible Enterobacteriaceae Isolates Collected during the INFORM Global Surveillance Study (2012 to 2014)

“…The majority (94%) of the carbapenem-nonsusceptible Enterobacteriaceae that did not contain a carbapenemase harbored ESBLs and/or Ambler class C ␤-lactamases that were encoded by chromosomally located or plasmidcarried genes. The presence of these ␤-lactamases, coupled with reduced expression or loss of function of one or more outer membrane pore-forming proteins, is most likely the reason for the reduced susceptibility to carbapenems observed among these isolates (6)(7)(8). Whereas susceptibility to carbapenems was lost in these isolates, this resistance mechanism did not impact the activity of ceftazidime-avibactam, with 94.7% of the isolates remaining susceptible to this combination.…”

“…Two clinically important mechanisms of resistance to carbapenems among Enterobacteriaceae have been identified. One is the production of carbapenemases, such as serine carbapenemases (KPC and OXA) and metallo-␤-lactamases (VIM, IMP, and NDM) (5), and the other is the production of ESBLs or Ambler class C ␤-lactamases coupled with reduced expression or loss of function of one or more outer membrane pore-forming proteins (6)(7)(8).…”