Emergence of carbapenem, beta-lactamase inhibitor and cefoxitin resistant lineages from a background of ESBL-producing<i>Klebsiella pneumoniae</i>and<i>K. quasipneumoniae</i>highlights different evolutionary mechanisms

Heinz, Eva; Ejaz, Hasan; Jb, Scott; Wang, N; Guanjaran, S; Pickard, Derek; Wilksch, Jonathan J.; Haq, Ikram Ul; Dougan, Gordon; Ra, Strugnell

doi:10.1101/283291

Cited by 5 publications

(5 citation statements)

References 94 publications

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“…The only non-Norwegian ST15 isolates harbouring iuc were 30 isolates from Pakistan and the closely related Romanian isolate, all of which carried iuc and rmpA2 loci in addition to bla CTX-M-15 and multiple other AMR genes. The convergence of AMR and virulence was noted in the original study reporting these genomes from Pakistan; 22 however, it is not possible to determine from the draft genomes whether iuc is co-localized on the same plasmid as AMR genes. Mapping of all ST15 read sets to pKp104014_1 showed that iuc + isolates from Pakistan and iuc − isolates from Nepal (alongside a small number of iuc − isolates from other countries) share many genes with the mosaic plasmid pKp104014_1 (55.7%–68.5% coverage for Pakistan isolates and 52.2%–0.2% coverage for Nepal isolates) (Figure 2 and Figure S1).…”

Section: Resultsmentioning

confidence: 98%

Convergence of virulence and MDR in a single plasmid vector in MDR Klebsiella pneumoniae ST15

Lam

Wyres

Wick

et al. 2019

Journal of Antimicrobial Chemotherapy

108

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Background MDR and hypervirulence (hv) are typically observed in separate Klebsiella pneumoniae populations. However, convergent strains with both properties have been documented and potentially pose a high risk to public health in the form of invasive infections with limited treatment options. Objectives Our aim was to characterize the genetic determinants of virulence and antimicrobial resistance (AMR) in two ESBL-producing K. pneumoniae isolates belonging to the international MDR clone ST15. Methods The complete genome sequences of both isolates, including their plasmids, were resolved using Illumina and Oxford Nanopore sequencing. Results Both isolates carried large mosaic plasmids in which AMR and virulence loci have converged within the same vector. These closely related mosaic hv-MDR plasmids include sequences typical of the K. pneumoniae virulence plasmid 1 (KpVP-1; including aerobactin synthesis locus iuc ) fused with sequences typical of IncFII K conjugative AMR plasmids. One hv-MDR plasmid carried three MDR elements encoding the ESBL gene bla CTX-M-15 and seven other AMR genes ( bla TEM , aac3'-IIa , dfrA1 , satA2 , bla SHV , sul1 and aadA1 ) . The other carried remnants of these elements encoding bla TEM and aac3'-IIa , and bla CTX-M-15 was located in a second plasmid in this isolate. The two isolates originated from patients hospitalized in Norway but have epidemiological and genomic links to Romania. Conclusions The presence of both virulence and AMR determinants on a single vector enables simultaneous transfer in a single event and potentially rapid emergence of hv-MDR K. pneumoniae clones. This highlights the importance of monitoring for such convergence events with stringent genomic surveillance.

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Section: Resultsmentioning

confidence: 98%

Convergence of virulence and MDR in a single plasmid vector in MDR Klebsiella pneumoniae ST15

Lam

Wyres

Wick

et al. 2019

Journal of Antimicrobial Chemotherapy

108

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“…Similar mechanism of action among these newer drugs has led to potential evolution of crossresistance in bacteria. While synthetic modifications to some pre-existing antibiotics have temporarily extended their clinical usefulness (Fair and Tor, 2014), this approach has also selected for broader resistance mechanisms, such as extended spectrum beta lactamases (Heinz et al, 2018), adaptive changes that are perhaps more easily evolved compared to de novo resistance mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria

Kortright

Chan

Koff

et al. 2019

Cell Host & Microbe

848

585

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Phage therapy, long overshadowed by chemical antibiotics, is garnering renewed interest in Western medicine. This stems from the rise in frequency of multi-drug-resistant bacterial infections in humans. There also have been recent case reports of phage therapy demonstrating clinical utility in resolving these otherwise intractable infections. Nevertheless, bacteria can readily evolve phage resistance too, making it crucial for modern phage therapy to develop strategies to capitalize on this inevitability. Here, we review the history of phage therapy research. We compare and contrast phage therapy and chemical antibiotics, highlighting their potential synergies when used in combination. We also examine the use of animal models, case studies, and results from clinical trials. Throughout, we explore how the modern scientific community works to improve the reliability and success of phage therapy in the clinic and discuss how to properly evaluate the potential for phage therapy to combat antibiotic-resistant bacteria.

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“…The reasons for the apparent separation of MDR and hypervirulence are unclear but there are growing reports of convergence from both directions, i.e. hypervirulent strains gaining MDR plasmids [25–30] and MDR strains gaining a virulence plasmid plus/minus an ICE Kp [27,31,32]. Most such reports are sporadic, but in 2017 Gu and colleagues described a fatal outbreak of MDR, carbapenem-resistant K .…”

Section: Introductionmentioning

confidence: 99%

Distinct evolutionary dynamics of horizontal gene transfer in drug resistant and virulent clones of Klebsiella pneumoniae

et al. 2019

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Klebsiella pneumoniae has emerged as an important cause of two distinct public health threats: multi-drug resistant (MDR) healthcare-associated infections and drug susceptible community-acquired invasive infections. These pathotypes are generally associated with two distinct subsets of K . pneumoniae lineages or ‘clones’ that are distinguished by the presence of acquired resistance genes and several key virulence loci. Genomic evolutionary analyses of the most notorious MDR and invasive community-associated (‘hypervirulent’) clones indicate differences in terms of chromosomal recombination dynamics and capsule polysaccharide diversity, but it remains unclear if these differences represent generalised trends. Here we leverage a collection of >2200 K . pneumoniae genomes to identify 28 common clones (n ≥ 10 genomes each), and perform the first genomic evolutionary comparison. Eight MDR and 6 hypervirulent clones were identified on the basis of acquired resistance and virulence gene prevalence. Chromosomal recombination, surface polysaccharide locus diversity, pan-genome, plasmid and phage dynamics were characterised and compared. The data showed that MDR clones were highly diverse, with frequent chromosomal recombination generating extensive surface polysaccharide locus diversity. Additional pan-genome diversity was driven by frequent acquisition/loss of both plasmids and phage. In contrast, chromosomal recombination was rare in the hypervirulent clones, which also showed a significant reduction in pan-genome diversity, largely driven by a reduction in plasmid diversity. Hence the data indicate that hypervirulent clones may be subject to some sort of constraint for horizontal gene transfer that does not apply to the MDR clones. Our findings are relevant for understanding the risk of emergence of individual K . pneumoniae strains carrying both virulence and acquired resistance genes, which have been increasingly reported and cause highly virulent infections that are extremely difficult to treat. Specifically, our data indicate that MDR clones pose the greatest risk, because they are more likely to acquire virulence genes than hypervirulent clones are to acquire resistance genes.

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Emergence of carbapenem, beta-lactamase inhibitor and cefoxitin resistant lineages from a background of ESBL-producingKlebsiella pneumoniaeandK. quasipneumoniaehighlights different evolutionary mechanisms

Cited by 5 publications

References 94 publications

Convergence of virulence and MDR in a single plasmid vector in MDR Klebsiella pneumoniae ST15

Convergence of virulence and MDR in a single plasmid vector in MDR Klebsiella pneumoniae ST15

Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria

Distinct evolutionary dynamics of horizontal gene transfer in drug resistant and virulent clones of Klebsiella pneumoniae

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