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Concept: Klebsiella pneumoniae

163

Carbapenem-resistant Enterobacteriaceae (CRE) are among the most severe threats to the antibiotic era. Multiple different species can exhibit resistance due to many different mechanisms, and many different mobile elements are capable of transferring resistance between lineages. We prospectively sampled CRE from hospitalized patients from three Boston-area hospitals, together with a collection of CRE from a single California hospital, to define the frequency and characteristics of outbreaks and determine whether there is evidence for transfer of strains within and between hospitals and the frequency with which resistance is transferred between lineages or species. We found eight species exhibiting resistance, with the majority of our sample being the sequence type 258 (ST258) lineage of Klebsiella pneumoniae There was very little evidence of extensive hospital outbreaks, but a great deal of variation in resistance mechanisms and the genomic backgrounds carrying these mechanisms. Local transmission was evident in clear phylogeographic structure between the samples from the two coasts. The most common resistance mechanisms were KPC (K. pneumoniae carbapenemases) beta-lactamases encoded by blaKPC2, blaKPC3, and blaKPC4, which were transferred between strains and species by seven distinct subgroups of the Tn4401 element. We also found evidence for previously unrecognized resistance mechanisms that produced resistance when transformed into a susceptible genomic background. The extensive variation, together with evidence of transmission beyond limited clonal outbreaks, points to multiple unsampled transmission chains throughout the continuum of care, including asymptomatic carriage and transmission of CRE. This finding suggests that to control this threat, we need an aggressive approach to surveillance and isolation.

Concepts: Sample, Hospital, Antibiotic resistance, Enterobacteriaceae, Klebsiella pneumoniae, Klebsiella, Klebsiella oxytoca

39

Klebsiella pneumoniae is an important cause of multidrug-resistant infections worldwide. Recent studies highlight the emergence of multidrug-resistant K. pneumoniae strains which show resistance to colistin, a last-line antibiotic, arising from mutational inactivation of the mgrB regulatory gene. However, the precise molecular resistance mechanisms of mgrB-associated colistin resistance and its impact on virulence remain unclear. Here, we constructed an mgrB gene K. pneumoniae mutant and performed characterisation of its lipid A structure, polymyxin and antimicrobial peptide resistance, virulence and inflammatory responses upon infection. Our data reveal that mgrB mutation induces PhoPQ-governed lipid A remodelling which confers not only resistance to polymyxins, but also enhances K. pneumoniae virulence by decreasing antimicrobial peptide susceptibility and attenuating early host defence response activation. Overall, our findings have important implications for patient management and antimicrobial stewardship, while also stressing antibiotic resistance development is not inexorably linked with subdued bacterial fitness and virulence.

Concepts: Immune system, Inflammation, Gene, Bacteria, Evolution, Antibiotic resistance, Pseudomonas aeruginosa, Klebsiella pneumoniae

33

Klebsiella pneumoniae causes severe lung and bloodstream infections that are difficult to treat due to multidrug resistance. We hypothesized that antimicrobial resistance can be reversed by targeting chromosomal non-essential genes that are not responsible for acquired resistance but essential for resistant bacteria under therapeutic concentrations of antimicrobials. Conditional essentiality of individual genes to antimicrobial resistance was evaluated in an epidemic multidrug-resistant clone of K. pneumoniae (ST258). We constructed a high-density transposon mutant library of >430,000 unique Tn5 insertions and measured mutant depletion upon exposure to three clinically relevant antimicrobials (colistin, imipenem or ciprofloxacin) by Transposon Directed Insertion-site Sequencing (TraDIS). Using this high-throughput approach, we defined three sets of chromosomal non-essential genes essential for growth during exposure to colistin (n = 35), imipenem (n = 1) or ciprofloxacin (n = 1) in addition to known resistance determinants, collectively termed the “secondary resistome”. As proof of principle, we demonstrated that inactivation of a non-essential gene not previously found linked to colistin resistance (dedA) restored colistin susceptibility by reducing the minimum inhibitory concentration from 8 to 0.5 μg/ml, 4-fold below the susceptibility breakpoint (S ≤ 2 μg/ml). This finding suggests that the secondary resistome is a potential target for developing antimicrobial “helper” drugs that restore the efficacy of existing antimicrobials.

Concepts: Gene, Bacteria, Evolution, Antibiotic resistance, Enterobacteriaceae, Klebsiella pneumoniae, Klebsiella, Klebsiella oxytoca

30

To characterize the genomic context of New Delhi metallo-β-lactamase-1 (NDM-1) and Klebsiella pneumoniae carbapenemase (KPC), we sequenced 78 Enterobacteriaceae isolates from Pakistan and the United States encoding KPC, NDM-1, or no carbapenemase. High similarities of the results indicate rapid spread of carbapenem resistance between strains, including globally disseminated pathogens.

Concepts: Gene, Genome, United States, Enterobacteriaceae, New York City, Humid subtropical climate, Klebsiella pneumoniae, Klebsiella

30

Klebsiella pneumoniae is now recognized as an urgent threat to human health because of the emergence of multidrug-resistant strains associated with hospital outbreaks and hypervirulent strains associated with severe community-acquired infections. K. pneumoniae is ubiquitous in the environment and can colonize and infect both plants and animals. However, little is known about the population structure of K. pneumoniae, so it is difficult to recognize or understand the emergence of clinically important clones within this highly genetically diverse species. Here we present a detailed genomic framework for K. pneumoniae based on whole-genome sequencing of more than 300 human and animal isolates spanning four continents. Our data provide genome-wide support for the splitting of K. pneumoniae into three distinct species, KpI (K. pneumoniae), KpII (K. quasipneumoniae), and KpIII (K. variicola). Further, for K. pneumoniae (KpI), the entity most frequently associated with human infection, we show the existence of >150 deeply branching lineages including numerous multidrug-resistant or hypervirulent clones. We show K. pneumoniae has a large accessory genome approaching 30,000 protein-coding genes, including a number of virulence functions that are significantly associated with invasive community-acquired disease in humans. In our dataset, antimicrobial resistance genes were common among human carriage isolates and hospital-acquired infections, which generally lacked the genes associated with invasive disease. The convergence of virulence and resistance genes potentially could lead to the emergence of untreatable invasive K. pneumoniae infections; our data provide the whole-genome framework against which to track the emergence of such threats.

Concepts: Gene, Genetics, Infectious disease, Nosocomial infection, Staphylococcus aureus, Infection, Antibiotic resistance, Klebsiella pneumoniae

28

A retrospective study was conducted at a Taiwanese medical center to characterize bloodstream infections caused by IMP-8 metallo-β-lactamase (MBL)-producing Enterobacteriaceae isolates and to assess the need for laboratory detection of IMP producers. We analyzed 37 patients infected with IMP-8 producers (two Escherichia coli, nine Klebsiella pneumoniae, 25 Enterobacter cloacae, and one Citrobacter freundii) and 107 patients infected with non-IMP-8 producers (eight E. coli, 26 K. pneumoniae, 70 E. cloacae, and three C. freundii) that were interpreted as carbapenem-nonsusceptible based on the updated Clinical and Laboratory Standards Institute (CLSI) 2010 guidelines. Only 18 (48.6 %) of the IMP-8 producers were regarded as potential carbapenemase producers based on the CLSI 2012 guidelines. The production of extended-spectrum β-lactamases (ESBLs) was more common in the MBL group (73.0 %) than in the non-MBL group (41.1 %). There were no significant differences in carbapenem susceptibilities, clinical characteristics, carbapenem use for empirical and definitive treatment, and mortality rates between the two groups. Eighteen IMP-8 producers could be deemed as resistant to all carbapenems [minimum inhibitory concentration (MIC) of any carbapenem ≥2 μg/mL]; patients with these isolates had a lower, but non-significant, 28-day mortality rate (27.8 %) than patients infected with non-MBL producers having similar carbapenem MICs (39.0 %) (p = 0.41). A multivariate analysis revealed severity of acute illness as the single independent variable associated with both 7-day and 28-day mortality rates (p < 0.01) for infections caused by Enterobacteriaceae with decreased carbapenem susceptibilities. Our findings suggest that the clinical detection of IMP-producing Enterobacteriaceae is not required even when the "old" CLSI criteria are used.

Concepts: Escherichia coli, Phage therapy, Enterobacteriaceae, Escherichia, Gram negative bacteria, Enterobacteria, Klebsiella pneumoniae, Klebsiella

28

Klebsiella bacteria have emerged as an increasingly important cause of community-acquired nosocomial infections. Extensive use of broad-spectrum antibiotics in hospitalised patients has led to both increased carriage of Klebsiella and the development of multidrug-resistant strains that frequently produce extended-spectrum β-lactamases and/or other defences against antibiotics. Many of these strains are highly virulent and exhibit a strong propensity to spread. In this study, six lytic Klebsiella bacteriophages were isolated from sewage-contaminated river water in Georgia and characterised as phage therapy candidates. Two of the phages were investigated in greater detail. Biological properties, including phage morphology, nucleic acid composition, host range, growth phenotype, and thermal and pH stability were studied for all six phages. Limited sample sequencing was performed to define the phylogeny of the K. pneumoniae- and K. oxytoca-specific bacteriophages vB_Klp_5 and vB_Klox_2, respectively. Both of the latter phages had large burst sizes, efficient rates of adsorption and were stable under different adverse conditions. Phages reported in this study are double-stranded DNA bacterial viruses belonging to the families Podoviridae and Siphoviridae. One or more of the six phages was capable of efficiently lysing ~63 % of Klebsiella strains comprising a collection of 123 clinical isolates from Georgia and the United Kingdom. These phages exhibit a number of properties indicative of potential utility in phage therapy cocktails.

Concepts: DNA, Bacteria, Microbiology, Virus, Bacteriophage, Phage therapy, Klebsiella pneumoniae, Klebsiella

27

Necrotizing soft tissue infections (NSTI) are rare but carry high mortality rates. NSTI with Klebsiella species have been previously described as associated with Klebsiella liver abscesses and endophthalmitis. Here, we describe 6 cases of NSTI in liver transplant recipients associated with Klebsiella pneumoniae, 4 of which were K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae (CRKP). Increased awareness of this emerging pathogen and its association with necrotizing skin and soft tissue infection is critical, as early recognition and debridement may improve survival. Antimicrobial treatment of CRKP infections remains an ongoing challenge and implementation of enhanced infection control measures is essential.

Concepts: Immune system, Inflammation, Infectious disease, Pneumonia, Klebsiella pneumoniae, Klebsiella

27

Severe infections caused by carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) are becoming a significant problem worldwide and are associated with high morbidity and mortality rates (1-3).…

Concepts: Inflammation, Mortality rate, Pneumonia, Streptococcus pneumoniae, Enterobacteriaceae, Klebsiella pneumoniae, Klebsiella

27

The spread of carbapenemases in Enterobacteriaceae is among the most important issues in the antimicrobial resistance. The rapid and recent diffusion of class A and B carbapenemases determined the need of specific diagnostic tests able to detect with high sensitivity this type of resistance and to discriminate between the different enzymes. The aim of this study was to test two carbapenemase detection assays, the Rosco Synergic and the Hyplex polymerase chain reaction-enzyme-linked immunosorbent assays for screening carbapenemase-producing Enterobacteriaceae. The phenotypic and genotypic tests were evaluated among 108 clinical isolates, including Klebsiella pneumoniae carbapenemase (KPC) (n=50) and metallo-β-lactamase- (MBL) (n=20), and AmpC- (n=10) producing Enterobacteriaceae. The commercial phenotypic assay showed a high sensitivity performance detecting all KPC and MBL producers, including New Delhi MBL 1 (NDM-1) strains. In addition, the Rosco Synergic assay was able to distinguish specifically between the different mechanisms that confer resistance to carbapenems in Enterobacteriaceae. We also demonstrated that the genotypic test was able to detect all the class A and B carbapenemases showing high sensitivity (100%) and specificity (98%) in a fast and reliable time. Based on these results, both the commercial phenotypic and the genotypic assays could be helpful as confirmatory and discriminatory tests for the detection of class A and class B carbapenemases.

Concepts: DNA, Gene, Evolution, Type I and type II errors, ELISA, Enterobacteriaceae, Klebsiella pneumoniae, Klebsiella