Aminoglycoside Resistance: The Emergence of Acquired 16S Ribosomal RNA Methyltransferases.

Knowledge regarding the genomic structure of Enterobacter spp., the second most prevalent carbapenemase-producing Enterobacteriaceae, remains limited. Here we sequenced 97 clinical Enterobacter species isolates that were both carbapenem susceptible and resistant from various geographic regions to decipher the molecular origins of carbapenem resistance and to understand the changing phylogeny of these emerging and drug-resistant pathogens. Of the carbapenem-resistant isolates, 30 possessed blaKPC-2, 40 had blaKPC-3, 2 had blaKPC-4, and 2 had blaNDM-1. Twenty-three isolates were carbapenem susceptible. Six genomes were sequenced to completion, and their sizes ranged from 4.6 to 5.1 Mbp. Phylogenomic analysis placed 96 of these genomes, 351 additional Enterobacter genomes downloaded from NCBI GenBank, and six newly sequenced type strains into 19 phylogenomic groups—18 groups (A to R) in the Enterobacter cloacae complex and Enterobacter aerogenes. Diverse mechanisms underlying the molecular evolutionary trajectory of these drug-resistant Enterobacter spp. were revealed, including the acquisition of an antibiotic resistance plasmid, followed by clonal spread, horizontal transfer of blaKPC-harboring plasmids between different phylogenomic groups, and repeated transposition of the blaKPC gene among different plasmid backbones. Group A, which comprises multilocus sequence type 171 (ST171), was the most commonly identified (23% of isolates). Genomic analysis showed that ST171 isolates evolved from a common ancestor and formed two different major clusters; each acquiring unique blaKPC-harboring plasmids, followed by clonal expansion. The data presented here represent the first comprehensive study of phylogenomic interrogation and the relationship between antibiotic resistance and plasmid discrimination among carbapenem-resistant Enterobacter spp., demonstrating the genetic diversity and complexity of the molecular mechanisms driving antibiotic resistance in this genus. IMPORTANCEEnterobacter spp., especially carbapenemase-producing Enterobacter spp., have emerged as a clinically significant cause of nosocomial infections. However, only limited information is available on the distribution of carbapenem resistance across this genus. Augmenting this problem is an erroneous identification of Enterobacter strains because of ambiguous typing methods and imprecise taxonomy. In this study, we used a whole-genome-based comparative phylogenetic approach to (i) revisit and redefine the genus Enterobacter and (ii) unravel the emergence and evolution of the Klebsiella pneumoniae carbapenemase-harboring Enterobacter spp. Using genomic analysis of 447 sequenced strains, we developed an improved understanding of the species designations within this complex genus and identified the diverse mechanisms driving the molecular evolution of carbapenem resistance. The findings in this study provide a solid genomic framework that will serve as an important resource in the future development of molecular diagnostics and in supporting drug discovery programs.

Comprehensive Genome Analysis of Carbapenemase-Producing Enterobacter spp.: New Insights into Phylogeny, Population Structure, and Resistance Mechanisms

Background/purpose Multidrug-resistant strains of Citrobacter have emerged, which carry Amp-C β-lactamase (Amp-C), broad-spectrum β-lactamase, extended-spectrum β-lactamase (ESBL), and other resistance mechanisms. These strains are associated with a higher rate of in-hospital mortality. The object of this study is to determine the mortality risk factors, susceptibility pattern to antibiotics, and prevalence of resistance genes in patients with Citrobacter freundii bacteremia. Methods From January 2009 to December 2014, blood isolates of C . freundii were collected in MacKay Memorial Hospital, Taipei, Taiwan. PCR technique and sequencing were performed for resistance genes. Pulsed-field gel electrophoresis (PFGE) was done using Xba I restriction enzyme. The clinical characteristics and risk factors for mortality are demonstrated. Results The 36 blood isolates of C . freundii belonged to 32 different PFGE pulsotypes, and 15 isolates (41.7%) were polymicrobial. The most common source of infection was intra-abdominal origin (61.1%), followed by unknown sources (22.2%), the urinary tract (8.3%), intravascular catheter (5.6%), and soft tissue (2.8%). High degree of antibiotic resistance was noted for cefazolin (100%), cefoxitin (97.2%), and cefuroxime (66.7%). The bla TEM-1 resistance gene was present in 16.7% isolates. 72.2% isolates carried bla AmpC and 5.6% isolates carried ESBL genes ( bla SHV-12 or bla CTX-M-15 ). Multivariate analysis indicated that the independent risk factor for 28-day mortality was carrying the bla TEM-1 resistance gene. Conclusion For patients with C . freundii bacteremia, carrying the bla TEM-1 resistance gene was an independent risk factor for 28-day mortality. Carbapenems, fourth-generation cephalosporins, amikacin, and quinolones are still reliable agents for drug-resistant strains.

Citrobacter freundii bacteremia: Risk factors of mortality and prevalence of resistance genes

Carbapenemases have become a significant mechanism for broad-spectrum β-lactam resistance in Enterobacteriaceae and other Gram-negative bacteria such as Pseudomonas and Acinetobacter spp. Intestinal carriage of carbapenemase-producing organisms (CPOs) is an important source of transmission. Isolation of carriers is one strategy that can be used to limit the spread of these bacteria. In this review, we critically examine the clinical performance, advantages, and disadvantages of methods available for the detection of intestinal carriage of CPOs. Culture-based methods (Centers for Disease Control and Prevention [CDC] protocols, chromogenic media, specialized agars, and double-disk synergy tests) for detecting carriage of CPOs are convenient due to their ready availability and low cost, but their limited sensitivity and long turnaround time may not always be optimal for infection control practices. Contemporary nucleic acid amplification techniques (NAATs) such as real-time PCR, hybridization assays, loop-mediated isothermal amplification (LAMP), or a combined culture and NAAT approach may provide fast results and/or added sensitivity and specificity compared with culture-based methods. Infection control practitioners and clinical microbiologists should be aware of the strengths and limitations of available methods to determine the most suitable approach for their medical facility to fit their infection control needs.

Intestinal Carriage of Carbapenemase-Producing Organisms: Current Status of Surveillance Methods

NS is currently funded through
a Public Health England/University of Oxford Clinical Lectureship; the sequencing work was also partly funded
through a previous Wellcome Trust Doctoral Research Fellowship (#099423/Z/12/Z). Additional funding support
was provided by a research grant from Calgary Laboratory Services (#10006465), and by the Health Innovation
Challenge Fund (a parallel funding partnership between the Wellcome Trust [WT098615/Z/12/Z] and the
Department of Health [grant HICF-T5-358]). This research was supported by the National Institute for Health
Research (NIHR) Oxford Biomedical Research Center (BRC) Program, and the Health Protection Research Unit
(NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at the University of Oxford,
in partnership with Public Health England (PHE).

/pdf/genomic-epidemiology-of-global-klebsiella-pneumoniae-4jf2k416vh.pdf

Genomic epidemiology of global Klebsiella pneumoniae carbapenemase (KPC)-producing Escherichia coli.

Twelve nonduplicated KPC-2-producing enterobacterial isolates, including three Escherichia coli, two Citrobacter freundii, two Enterobacter cloacae, four Enterobacter aerogenes, and one Klebsiella oxytoca, were collected from various clinical samples within 18 months (March 2011 to September 2012). Two of the 12 patients died from infections caused by KPC-2-producing pathogens, while the rest of the patients with KPC-2-producing pathogens improved or were cured. The majority of the clinical isolates exhibited a high-level of resistance to oxyimino-cephalosporins and carbapenems, and possessed self-transferable blaKPC-2-carrying plasmids with sizes ranging from 20 to 120 kb. Most isolates carried blaCTX-M and plasmid-mediated quinolone resistance genes, while some isolates produced 16S rRNA methylases (ArmA or RmtB). The genetic environment of blaKPC-2 of most clinical strains was consistent with the genetic structure surrounding blaKPC-2 on the plasmid pKP048, which contains an integration structure of a ...

Characterization of KPC-2-Producing Escherichia coli, Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, and Klebsiella oxytoca Isolates from a Chinese Hospital

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Characterization of KPC-2-Producing Escherichia coli, Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, and Klebsiella oxytoca Isolates from a Chinese Hospital