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Open accessJournal ArticleDOI: 10.1016/J.JGAR.2021.02.020

A global perspective on the convergence of hypervirulence and carbapenem resistance in Klebsiella pneumoniae.

02 Mar 2021-Journal of global antimicrobial resistance (Elsevier)-Vol. 25, pp 26-34
Abstract: Hypervirulence and carbapenem resistance have emerged as two distinct evolutionary directions for Klebsiella pneumoniae, which pose a great threat in clinical settings. Multiple virulence factors contribute to hypervirulence, and the mechanisms of carbapenem resistance are complicated. However, more and more K. pneumoniae strains have been identified in recent years integrating both phenotypes, resulting in devastating clinical outcomes. Hypervirulent and carbapenem-resistant K. pneumoniae (CR-hvKP) emerged in the early 2010s and thereafter have become increasingly prevalent. CR-hvKP are primarily prevalent in Asia, especially China, but are reported all over the world. Mechanisms for the emergence of CR-hvKP can be summarised by three patterns: (i) carbapenem-resistant K. pneumoniae (CRKP) acquiring a hypervirulent phenotype; (ii) hypervirulent K. pneumoniae (hvKP) acquiring a carbapenem-resistant phenotype; and (iii) K. pneumoniae acquiring both a carbapenem resistance and hypervirulence hybrid plasmid. With their global dissemination, continued surveillance of the emergence of CR-hvKP should be more highly prioritised.

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5 results found


Open accessJournal ArticleDOI: 10.3390/ANTIBIOTICS10040415
10 Apr 2021-Antibiotics
Abstract: Multidrug-resistant bacteria have on overwhelming impact on human health, as they cause over 670,000 infections and 33,000 deaths annually in the European Union alone. Of these, the vast majority of infections and deaths are caused by only a handful of species—multi-drug resistant Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus spp., Acinetobacter spp. and Klebsiella pneumoniae. These pathogens employ a multitude of antibiotic resistance mechanisms, such as the production of antibiotic deactivating enzymes, changes in antibiotic targets, or a reduction of intracellular antibiotic concentration, which render them insusceptible to multiple antibiotics. The purpose of this review is to summarize in a clinical manner the resistance mechanisms of each of these 6 pathogens, as well as the mechanisms of recently developed antibiotics designed to overcome them. Through a basic understanding of the mechanisms of antibiotic resistance, the clinician can better comprehend and predict resistance patterns even to antibiotics not reported on the antibiogram and can subsequently select the most appropriate antibiotic for the pathogen in question.

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Topics: Antibiotic resistance (61%), Antibiotics (55%), Pseudomonas aeruginosa (54%) ... show more

7 Citations


Open accessJournal ArticleDOI: 10.1371/JOURNAL.PBIO.3001276
06 Jul 2021-PLOS Biology
Abstract: Mobile genetic elements (MGEs) drive genetic transfers between bacteria using mechanisms that require a physical interaction with the cellular envelope. In the high-priority multidrug-resistant nosocomial pathogens (ESKAPE), the first point of contact between the cell and virions or conjugative pili is the capsule. While the capsule can be a barrier to MGEs, it also evolves rapidly by horizontal gene transfer (HGT). Here, we aim at understanding this apparent contradiction by studying the covariation between the repertoire of capsule genes and MGEs in approximately 4,000 genomes of Klebsiella pneumoniae (Kpn). We show that capsules drive phage-mediated gene flow between closely related serotypes. Such serotype-specific phage predation also explains the frequent inactivation of capsule genes, observed in more than 3% of the genomes. Inactivation is strongly epistatic, recapitulating the capsule biosynthetic pathway. We show that conjugative plasmids are acquired at higher rates in natural isolates lacking a functional capsular locus and confirmed experimentally this result in capsule mutants. This suggests that capsule inactivation by phage pressure facilitates its subsequent reacquisition by conjugation. Accordingly, capsule reacquisition leaves long recombination tracts around the capsular locus. The loss and regain process rewires gene flow toward other lineages whenever it leads to serotype swaps. Such changes happen preferentially between chemically related serotypes, hinting that the fitness of serotype-swapped strains depends on the host genetic background. These results enlighten the bases of trade-offs between the evolution of virulence and multidrug resistance and caution that some alternatives to antibiotics by selecting for capsule inactivation may facilitate the acquisition of antibiotic resistance genes (ARGs).

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3 Citations


Open accessJournal ArticleDOI: 10.3390/ANTIBIOTICS10060691
Abstract: The emergence of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKp) is a new threat to healthcare. In this study, we analyzed nine CR-hvKp isolates of different sequence-types (ST) recovered from patients with nosocomial infections in two hospitals in Saint Petersburg. Whole-genome sequencing showed that eight of them harbored large mosaic plasmids carrying resistance to carbapenems and hypervirulence simultaneously, and four different types of hybrid plasmids were identified. BLAST analysis showed a high identity with two hybrid plasmids originating in the UK and Czech Republic. We demonstrated that hybrid plasmids emerged due to the acquisition of resistance genes by virulent plasmids. Moreover, one of the hybrid plasmids carried a novel New Delhi metallo-beta-lactamase (NDM) variant, differing from NDM-1 by one amino acid substitution (D130N), which did not provide significant evolutionary advantages compared to NDM-1. The discovery of structurally similar plasmids in geographically distant regions suggests that the actual distribution of hybrid plasmids carrying virulence and resistance genes is much wider than expected.

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Topics: Plasmid (53%), Virulence (52%), Klebsiella pneumoniae (51%)

3 Citations


Open accessJournal ArticleDOI: 10.3390/ANTIBIOTICS10080979
01 Jan 2020-Antibiotics
Abstract: The purpose of this study was the identification of genetic lineages and antimicrobial resistance (AMR) and virulence genes in Klebsiella pneumoniae isolates associated with severe infections in the neuro-ICU. Susceptibility to antimicrobials was determined using the Vitek-2 instrument. AMR and virulence genes, sequence types (STs), and capsular types were identified by PCR. Whole-genome sequencing was conducted on the Illumina MiSeq platform. It was shown that K. pneumoniae isolates of ST14K2, ST23K57, ST39K23, ST76K23, ST86K2, ST218K57, ST219KL125/114, ST268K20, and ST2674K47 caused severe systemic infections, including ST14K2, ST39K23, and ST268K20 that were associated with fatal incomes. Moreover, eight isolates of ST395K2 and ST307KL102/149/155 were associated with manifestations of vasculitis and microcirculation disorders. Another 12 K. pneumoniae isolates of ST395K2,KL39, ST307KL102/149/155, and ST147K14/64 were collected from patients without severe systemic infections. Major isolates (n = 38) were XDR and MDR. Beta-lactamase genes were identified: blaSHV (n = 41), blaCTX-M (n = 28), blaTEM (n = 21), blaOXA-48 (n = 21), blaNDM (n = 1), and blaKPC (n = 1). The prevalent virulence genes were wabG (n = 41), fimH (n = 41), allS (n = 41), and uge (n = 34), and rarer, detected only in the genomes of the isolates causing severe systemic infections—rmpA (n = 8), kfu (n = 6), iroN (n = 5), and iroD (n = 5) indicating high potential of the isolates for hypervirulence.

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Topics: Klebsiella pneumoniae (52%)

1 Citations


Open accessJournal ArticleDOI: 10.3389/FMICB.2021.702956
Jiawei Chen1, Yu Zeng1, Rong Zhang1, Jiachang Cai1Institutions (1)
Abstract: Three carbapenem-resistant Klebsiella pneumoniae (CRKP; strains KP-426, KP-C76, and KP-CT77) were isolated from a patient with severe burns during the treatment of colistin and tigecycline. Single-nucleotide polymorphism typing showed that three ST11 CRKP were clonally related. Three isolates harbored the same set of antimicrobial resistance genes. blaKPC-2, blaSHV-12, blaTEM-1, and rmtB genes were located on the same 128,928-bp IncFII/IncR plasmid. Tet(A), catA2, sul2, and dfrA14 genes were located on a plasmid with an unknown Inc-type. blaSHV-11, fosA, and aadA2 were chromosomal genes. An IS1 and an ISKpn14 were found in the promoter region of the mgrB gene of two colistin-resistant CRKP, K. pneumoniae KP-C76, and KP-CT77, respectively. A novel amino acid substitution, G300E, was identified in the type 1 Tet(A) variant of K. pneumoniae KP-CT77 which exhibited high-level tigecycline resistance compared to strains KP-426 and KP-C76 (MIC of 32, 4, and 4mg/l, respectively). Conjugation and cloning experiments confirmed that the mutated Tet(A) resulted in a 4-fold increase in tigecycline minimal inhibitory concentration (MIC) of Escherichia coli. Three CRKP belonged to the K64 serotype and possessed a similar IncHI1B/repB virulence plasmid carrying rmpA, rmpA2, and iucABCDiutA. The survival rates of Galleria Mellonella injected with K. pneumoniae KP-426, KP-C76, and KP-CT77 were 4.2, 20.8, and 8.3%, respectively. The emergence of colistin and tigecycline resistance in carbapenem-resistant hypervirulent K. pneumoniae posed a serious threat to clinical anti-infective therapy. The type 1 Tet(A) variant carrying G300E mutation, which conferred significantly elevated tigecycline MIC and was located on a conjugative plasmid, needs attention.

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Topics: Colistin (55%), Tigecycline (54%), Klebsiella pneumoniae (54%) ... show more
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121 results found


Open accessJournal ArticleDOI: 10.1128/AAC.00774-09
Dongeun Yong1, Mark Toleman2, Christian G. Giske3, Hyun Sun Cho1  +3 moreInstitutions (4)
Abstract: A Swedish patient of Indian origin traveled to New Delhi, India, and acquired a urinary tract infection caused by a carbapenem-resistant Klebsiella pneumoniae strain that typed to the sequence type 14 complex. The isolate, Klebsiella pneumoniae 05-506, was shown to possess a metallo-β-lactamase (MBL) but was negative for previously known MBL genes. Gene libraries and amplification of class 1 integrons revealed three resistance-conferring regions; the first contained blaCMY-4 flanked by ISEcP1 and blc. The second region of 4.8 kb contained a complex class 1 integron with the gene cassettes arr-2, a new erythromycin esterase gene; ereC; aadA1; and cmlA7. An intact ISCR1 element was shown to be downstream from the qac/sul genes. The third region consisted of a new MBL gene, designated blaNDM-1, flanked on one side by K. pneumoniae DNA and a truncated IS26 element on its other side. The last two regions lie adjacent to one another, and all three regions are found on a 180-kb region that is easily transferable to recipient strains and that confers resistance to all antibiotics except fluoroquinolones and colistin. NDM-1 shares very little identity with other MBLs, with the most similar MBLs being VIM-1/VIM-2, with which it has only 32.4% identity. As well as possessing unique residues near the active site, NDM-1 also has an additional insert between positions 162 and 166 not present in other MBLs. NDM-1 has a molecular mass of 28 kDa, is monomeric, and can hydrolyze all β-lactams except aztreonam. Compared to VIM-2, NDM-1 displays tighter binding to most cephalosporins, in particular, cefuroxime, cefotaxime, and cephalothin (cefalotin), and also to the penicillins. NDM-1 does not bind to the carbapenems as tightly as IMP-1 or VIM-2 and turns over the carbapenems at a rate similar to that of VIM-2. In addition to K. pneumoniae 05-506, blaNDM-1 was found on a 140-kb plasmid in an Escherichia coli strain isolated from the patient's feces, inferring the possibility of in vivo conjugation. The broad resistance carried on these plasmids is a further worrying development for India, which already has high levels of antibiotic resistance.

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Topics: Integron (57%), Klebsiella pneumoniae (55%), New Delhi metallo-beta-lactamase 1 (54%) ... show more

1,940 Citations


Journal ArticleDOI: 10.1016/S1473-3099(09)70054-4
Abstract: Summary From early this decade, Enterobacteriaceae that produce Klebsiella pneumoniae carbapenemases (KPC) were reported in the USA and subsequently worldwide. These KPC-producing bacteria are predominantly involved in nosocomial and systemic infections; although they are mostly Enterobacteriaceae, they can also be, rarely, Pseudomonas aeruginosa isolates. KPC β lactamases (KPC-1 to KPC-7) confer decreased susceptibility or resistance to virtually all β lactams. Carbapenems (imipenem, meropenem, and ertapenem) may thus become inefficient for treating enterobacterial infections with KPC-producing bacteria, which are, in addition, resistant to many other non-β-lactam molecules, leaving few available therapeutic options. Detection of KPC-producing bacteria may be difficult based on routine antibiotic susceptibility testing. It is therefore crucial to implement efficient infection control measures to limit the spread of these pathogens.

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Topics: Ertapenem (59%), New Delhi metallo-beta-lactamase 1 (56%), Klebsiella pneumoniae (56%) ... show more

1,368 Citations


Open accessJournal ArticleDOI: 10.1016/S1473-3099(13)70190-7
Abstract: Klebsiella pneumoniae carbapenemases (KPCs) were originally identified in the USA in 1996. Since then, these versatile β-lactamases have spread internationally among Gram-negative bacteria, especially K pneumoniae, although their precise epidemiology is diverse across countries and regions. The mortality described among patients infected with organisms positive for KPC is high, perhaps as a result of the limited antibiotic options remaining (often colistin, tigecycline, or aminoglycosides). Triple drug combinations using colistin, tigecycline, and imipenem have recently been associated with improved survival among patients with bacteraemia. In this Review, we summarise the epidemiology of KPCs across continents, and discuss issues around detection, present antibiotic options and those in development, treatment outcome and mortality, and infection control. In view of the limitations of present treatments and the paucity of new drugs in the pipeline, infection control must be our primary defence for now.

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1,116 Citations


Open accessJournal ArticleDOI: 10.1128/CMR.05035-11
Abstract: Summary: The spread of Enterobacteriaceae, primarily Klebsiella pneumoniae, producing KPC, VIM, IMP, and NDM carbapenemases, is causing an unprecedented public health crisis. Carbapenemase-producing enterobacteria (CPE) infect mainly hospitalized patients but also have been spreading in long-term care facilities. Given their multidrug resistance, therapeutic options are limited and, as discussed here, should be reevaluated and optimized. Based on susceptibility data, colistin and tigecycline are commonly used to treat CPE infections. Nevertheless, a review of the literature revealed high failure rates in cases of monotherapy with these drugs, whilst monotherapy with either a carbapenem or an aminoglycoside appeared to be more effective. Combination therapies not including carbapenems were comparable to aminoglycoside and carbapenem monotherapies. Higher success rates have been achieved with carbapenem-containing combinations. Pharmacodynamic simulations and experimental infections indicate that modification of the current patterns of carbapenem use against CPE warrants further attention. Epidemiological data, though fragmentary in many countries, indicate CPE foci and transmission routes, to some extent, whilst also underlining the lack of international collaborative systems that could react promptly and effectively. Fortunately, there are sound studies showing successful containment of CPE by bundles of measures, among which the most important are active surveillance cultures, separation of carriers, and assignment of dedicated nursing staff.

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Topics: Carbapenem (54%), Tigecycline (50%)

861 Citations


Open accessJournal ArticleDOI: 10.1128/CMR.00117-14
Abstract: The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps.

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Topics: Efflux (56%), Antibiotic resistance (53%), Multiple drug resistance (52%) ... show more

785 Citations