Detection and treatment options for Klebsiella pneumoniae carbapenemases (KPCs): an emerging cause of multidrug-resistant infection

Klebsiella pneumoniae is a frequent cause of nosocomial and severe community-acquired infections. Multidrug-resistant (MDR) and hypervirulent (hv) strains represent major threats, and tracking their emergence, evolution and the emerging convergence of MDR and hv traits is of major importance. We employed whole-genome sequencing (WGS) to study the evolution and epidemiology of a large longitudinal collection of clinical K. pneumoniae isolates from the H301 hospital in Beijing, China. Overall, the population was highly diverse, although some clones were predominant. Strains belonging to clonal group (CG) 258 were dominant, and represented the majority of carbapenemase-producers. While CG258 strains showed high diversity, one clone, ST11-KL47, represented the majority of isolates, and was highly associated with the KPC-2 carbapenemase and several virulence factors, including a virulence plasmid. The second dominant clone was CG23, which is the major hv clone globally. While it is usually susceptible to multiple antibiotics, we found some isolates harbouring MDR plasmids encoding for ESBLs and carbapenemases. We also reported the local emergence of a recently described high-risk clone, ST383. Conversely to strains belonging to CG258, which are usually associated to KPC-2, ST383 strains seem to readily acquire carbapenemases of different types. Moreover, we found several ST383 strains carrying the hypervirulence plasmid. Overall, we detected about 5 % of simultaneous carriage of AMR genes (ESBLs or carbapenemases) and hypervirulence genes. Tracking the emergence and evolution of such strains, causing severe infections with limited treatment options, is fundamental in order to understand their origin and evolution and to limit their spread. This article contains data hosted by Microreact.

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EVALUATION OF EFFLUX PUMP ACTIVITY AND BIOFILM FORMATION IN MULTIDRUG RESISTANT KLEBSIELLA PNEUMONIAE ISOLATES IN TANTA, EGYPT

International Research Journal of Pharmacy ◽

10.7897/2230-8407.1203123 ◽

2021 ◽

Vol 12 (3) ◽

pp. 1-5

Author(s):

Tarek El-Said El-Banna ◽

Fatma Ibrahim Sonbol ◽

Heba M El-Dawy ◽

Lamiaa A Al-Madboly

Keyword(s):

Drug Resistance ◽

Klebsiella Pneumoniae ◽

Biofilm Formation ◽

Efflux Pump ◽

Treatment Options ◽

Multidrug Resistant ◽

High Morbidity ◽

Biochemical Tests ◽

Antibiotic Resistance Profile ◽

Pump Activity

Nosocomial and community acquired infections that caused by multidrug-resistant (MDR) Klebsiella pneumoniae isolates are widespread recently resulting in high morbidity and mortality due to limited number of treatment options with effective antibiotics. The aim of this study is to evaluate the antibiotic resistance profile, biofilm formation and efflux pump activity of MDR K. pneumoniae isolates collected from different hospitals in Tanta, Egypt. A total of 70 K. pneumoniae isolates characterized by standard biochemical tests and confirmed by MALDI-TOF/MS were screened for antibiotic susceptibility, efflux pump activity and biofilm formation. Isolates displayed high resistance to penicillins, cephalosporins, trimethoprim-sulfamethoxazole and the majority of tested fluoro/-quinolones and decreased resistance to imipenem, amikacin, chloramphenicol, tigecycline and colistin. Out of 70 K. pneumoniae isolates, 2 isolates exhibited Pan Drug-Resistance (PDR) profile while 57 (81.4%) and 11 (15.7%) exhibited MDR and Extensively drug-resistance (XDR) profiles, respectively. Sixty-four (91.4%) isolates exhibited efflux pump activity while all tested isolates had the ability to form biofilm with varied degrees as 40 (57.1%), 26 (37.1%), and 4 (5.7%) isolates were strong, moderate and weak biofilm producers, respectively. Also, a strong relation between efflux pump activity and biofilm formation per isolate was detected. In conclusion, Multidrug resistance, biofilm formation and efflux pump capabilities in K. pneumoniae have serious public health implications in the management and control of infections caused by this bacterium. Therefore, a multifaceted approach and precise planning are recommended in controlling these infections

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Treatment Options for Colistin Resistant Klebsiella pneumoniae: Present and Future

Journal of Clinical Medicine ◽

10.3390/jcm8070934 ◽

2019 ◽

Vol 8 (7) ◽

pp. 934 ◽

Cited By ~ 25

Author(s):

Petrosillo ◽

Taglietti ◽

Granata

Keyword(s):

Monoclonal Antibodies ◽

Side Effects ◽

Mortality Rate ◽

Klebsiella Pneumoniae ◽

Treatment Options ◽

Multidrug Resistant ◽

Limited Range ◽

Therapeutic Strategies ◽

Colistin Resistance ◽

Carbapenem Resistant

Multidrug-resistant (MDR) Klebsiella pneumoniae represents an increasing threat to human health, causing difficult-to-treat infections with a high mortality rate. Since colistin is one of the few treatment options for carbapenem-resistant K. pneumoniae infections, colistin resistance represents a challenge due to the limited range of potentially available effective antimicrobials, including tigecycline, gentamicin, fosfomycin and ceftazidime/avibactam. Moreover, the choice of these antimicrobials depends on their pharmacokinetics/pharmacodynamics properties, the site of infection and the susceptibility profile of the isolated strain, and is sometimes hampered by side effects. This review describes the features of colistin resistance in K. pneumoniae and the characteristics of the currently available antimicrobials for colistin-resistant MDR K. pneumoniae, as well as the characteristics of novel antimicrobial options, such as the soon-to-be commercially available plazomicin and cefiderocol. Finally, we consider the future use of innovative therapeutic strategies in development, including bacteriophages therapy and monoclonal antibodies.

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Convergence of virulence and multidrug resistance in a single plasmid vector in multidrug-resistant Klebsiella pneumoniae ST15

10.1101/463406 ◽

2018 ◽

Cited By ~ 1

Author(s):

Margaret M. C. Lam ◽

Kelly L. Wyres ◽

Ryan R. Wick ◽

Louise M. Judd ◽

Aasmund Fostervold ◽

...

Keyword(s):

Multidrug Resistance ◽

Klebsiella Pneumoniae ◽

Treatment Options ◽

Plasmid Vector ◽

Multidrug Resistant ◽

Virulence Plasmid ◽

Genetic Determinants ◽

Oxford Nanopore ◽

Invasive Infections ◽

Rapid Emergence

SYNOPSISBackgroundMultidrug resistance (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.ObjectivesTo characterize the genetic determinants of virulence and antimicrobial resistance (AMR) in two ESBL-producing K. pneumoniae isolates belonging to the international MDR clone ST15.MethodsThe complete genome sequences of both isolates, including their plasmids, were resolved using Illumina and Oxford Nanopore sequencing.ResultsBoth 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 IncFIIK conjugative AMR plasmids. One hv-MDR plasmid carried three MDR elements encoding the ESBL gene blaCTX-M-15 and eight other AMR genes (blaTEM, aac3’-IIa, aph3’-Ia, dfrA1, satA2, blaSHV, sul1, aadA1). The other carried remnants of these elements encoding blaTEM and aac3’-IIa, and blaCTX-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.ConclusionsThe 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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Innate Host Defense against Klebsiella pneumoniae and the Outlook for Development of Immunotherapies

Journal of Innate Immunity ◽

10.1159/000518679 ◽

2021 ◽

pp. 1-15

Author(s):

Clement Opoku-Temeng ◽

Natalia Malachowa ◽

Scott D. Kobayashi ◽

Frank R. DeLeo

Keyword(s):

Klebsiella Pneumoniae ◽

Host Defense ◽

Severe Disease ◽

Treatment Options ◽

Opportunistic Pathogen ◽

Multidrug Resistant ◽

Severe Illness ◽

Preventative Measures ◽

Number Of Treatment ◽

Healthcare Associated

Klebsiella pneumoniae (K. pneumoniae) is a Gram-negative commensal bacterium and opportunistic pathogen. In healthy individuals, the innate immune system is adept at protecting against K. pneumoniae infection. Notably, the serum complement system and phagocytic leukocytes (e.g., neutrophils) are highly effective at eliminating K. pneumoniae and thereby preventing severe disease. On the other hand, the microbe is a major cause of healthcare-associated infections, especially in individuals with underlying susceptibility factors, such as pre-existing severe illness or immune suppression. The burden of K. pneumoniae infections in hospitals is compounded by antibiotic resistance. Treatment of these infections is often difficult largely because the microbes are usually resistant to multiple antibiotics (multidrug resistant [MDR]). There are a limited number of treatment options for these infections and new therapies, and preventative measures are needed. Here, we review host defense against K. pneumoniae and discuss recent therapeutic measures and vaccine approaches directed to treat and prevent severe disease caused by MDR K. pneumoniae.

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Tracking Nosocomial Klebsiella pneumoniae Infections and Outbreaks by Whole-Genome Analysis: Small-Scale Italian Scenario within a Single Hospital

Journal of Clinical Microbiology ◽

10.1128/jcm.00545-15 ◽

2015 ◽

Vol 53 (9) ◽

pp. 2861-2868 ◽

Cited By ~ 31

Author(s):

Raffaella Onori ◽

Stefano Gaiarsa ◽

Francesco Comandatore ◽

Stefano Pongolini ◽

Sylvain Brisse ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Treatment Options ◽

Multidrug Resistant ◽

Small Scale ◽

Phylogenomic Analysis ◽

Whole Genome ◽

Whole Genome Analysis ◽

Content Type ◽

Carbapenem Resistant ◽

Single Clone

Multidrug-resistant (MDR)Klebsiella pneumoniaeis one of the most important causes of nosocomial infections worldwide. After the spread of strains resistant to beta-lactams at the end of the previous century, the diffusion of isolates resistant to carbapenems and colistin is now reducing treatment options and the containment of infections. Carbapenem-resistantK. pneumoniaestrains have spread rapidly among Italian hospitals, with four subclades of pandemic clonal group 258 (CG258). Here we show that a single Italian hospital has been invaded by three of these subclades within 27 months, thus replicating on a small scale the “Italian scenario.” We identified a single clone responsible for an epidemic outbreak involving seven patients, and we reconstructed its star-like pattern of diffusion within the intensive care unit. This epidemiological picture was obtained through phylogenomic analysis of 16 carbapenem-resistantK. pneumoniaeisolates collected in the hospital during a 27-month period, which were added to a database of 319 genomes representing the available global diversity ofK. pneumoniaestrains. Phenotypic and molecular assays did not reveal virulence or resistance determinants specific for the outbreak isolates. Other factors, rather than selective advantages, might have caused the outbreak. Finally, analyses allowed us to identify a major subclade of CG258 composed of strains bearing the yersiniabactin virulence factor. Our work demonstrates how the use of combined phenotypic, molecular, and whole-genome sequencing techniques can help to identify quickly and to characterize accurately the spread of MDR pathogens.

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Klebsiella pneumoniae reduces SUMOylation to limit host defence responses

10.1101/2020.06.29.179275 ◽

2020 ◽

Author(s):

Joana Sá-Pessoa ◽

Kornelia Przybyszewska ◽

Filipe Nuno Vasconcelos ◽

Amy Dumigan ◽

Christian G. Frank ◽

...

Keyword(s):

Epithelial Cells ◽

Klebsiella Pneumoniae ◽

Inflammatory Responses ◽

Treatment Options ◽

Multidrug Resistant ◽

Cellular Level ◽

Lung Epithelial Cells ◽

Type I ◽

Dependent Manner ◽

Medical Needs

ABSTRACTKlebsiella pneumoniae is an important cause of multidrug resistant infections worldwide. Understanding the virulence mechanisms of K. pneumoniae is a priority and timely to design new therapeutics. Here we demonstrate that K. pneumoniae limits the SUMOylation of host proteins in epithelial cells and macrophages (mouse and human) to subvert cell innate immunity. Mechanistically, in lung epithelial cells Klebsiella increases the levels of the deSUMOylase SENP2 in the cytosol by affecting its K48-ubiquitylation and its subsequent degradation by the ubiquitin proteasome. This is dependent on Klebsiella preventing the NEDDylation of the Cullin-1 subunit of the ubiquitin ligase complex E3-SCFβ-TrCP by exploiting the CSN5 deNEDDylase. Klebsiella induces the expression of CSN5 in an EGFR-PI3K-AKT-ERK-GSK3β signalling pathway dependent manner. In macrophages, TLR4-TRAM-TRIF induced type-I IFN via IFNAR1-controlled signalling mediates Klebsiella-triggered decrease in the levels of SUMOylation via let-7 miRNAs. Our results revealed the crucial role played by Klebsiella polysaccharides, the capsule and the LPS O-polysaccharide, to decrease the levels of SUMO-conjugated proteins in epithelial cells and macrophages. Klebsiella-induced decrease in SUMOylation promotes infection by limiting the activation of inflammatory responses and increasing intracellular survival in macrophages.IMPORTANCEKlebsiella pneumoniae has been singled out as an urgent threat to human health due to the increasing isolation of strains resistant to “last line” antimicrobials, narrowing the treatment options against Klebsiella infections. Unfortunately, at present, we cannot identify candidate compounds in late-stage development for treatment of multidrug Klebsiella infections; this pathogen is exemplary of the mismatch between unmet medical needs and the current antimicrobial research and development pipeline. Furthermore, there is still limited evidence on K. pneumoniae pathogenesis at the molecular and cellular level in the context of the interactions between bacterial pathogens and their hosts. In this research, we have uncovered a sophisticated strategy employed by Klebsiella to subvert the activation of immune defences by controlling the modification of proteins. Our research may open opportunities to develop new therapeutics based on counteracting this Klebsiella-controlled immune evasion strategy.

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Evidence of widespread endemic populations of highly multidrug-resistant Klebsiella pneumoniae seen concurrently through the lens of two hospital intensive care units in Vietnam

10.1101/2021.06.29.21259521 ◽

2021 ◽

Author(s):

My H. Pham ◽

Hoi Thi Le ◽

Mathew A. Beale ◽

Fahad A. Khokhar ◽

Hoa Thi Nguyen ◽

...

Keyword(s):

Intensive Care ◽

Klebsiella Pneumoniae ◽

Resistance Genes ◽

Phylogenetic Analyses ◽

Treatment Options ◽

Multidrug Resistant ◽

Healthcare Settings ◽

Carbapenem Resistant ◽

Antimicrobial Resistance Genes ◽

Extended Spectrum Beta Lactamases

Background: Extended spectrum beta-lactamases-producing (ESBL-P) and/or carbapenem-resistant (CR) Klebsiella pneumoniae have severely restricted available treatment options in healthcare settings in Vietnam. Understanding the diversity and transmission mechanisms of ESBL- and carbapenemase- encoding K. pneumoniae is important in both hospital and community settings for patient management. Methods: We conducted a 6-month prospective cohort study of 69 Intensive care unit (ICU) patients from two hospitals in Hanoi, Vietnam. Longitudinally collected samples from patients and the ICU environment were cultured on selective media, and 357 K. pneumoniae colonies were whole genome sequenced. We performed phylogenetic analyses, and correlated phenotypic antimicrobial susceptibility testing with genotypic features of K. pneumoniae isolates. We constructed transmission networks of patient samples, relating ICU admission times and locations with genetic similarity of infecting K. pneumoniae. Findings: Despite being geographically and clinically separated, the two hospitals shared closely related strains carrying the same array of antimicrobial resistance genes. Many patients carried the same resistant K. pneumoniae clone from admission to discharge. 45.9% of total isolates carried both ESBL- and carbapenemase- encoding genes, with high minimum inhibitory concentrations. We found a novel co-occurrence of blaKPC-2 and blaNDM 1 in 46. 6% of samples from the globally successful ST15 lineage. Interpretation: These results highlight the high prevalence of ESBL-positive carbapenem-resistant K. pneumoniae in Vietnamese ICUs. Through studying K. pneumoniae ST15 in detail, we illustrated how important resistance genes are coalescing in stains carried broadly by patients entering the two hospitals directly or through referral.

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Rapid increase of carbapenemase-producing Klebsiella pneumoniae strains in a large Italian hospital: surveillance period 1 March – 30 September 2010

Eurosurveillance ◽

10.2807/ese.16.08.19800-en ◽

2011 ◽

Vol 16 (8) ◽

Author(s):

P Gaibani ◽

S Ambretti ◽

A Berlingeri ◽

F Gelsomino ◽

A Bielli ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Infection Control ◽

Multidrug Resistant ◽

Northern Italy ◽

University Hospital ◽

Resistant Bacteria ◽

Surveillance Period ◽

Multidrug Resistant Bacteria ◽

First Case ◽

Klebsiella Pneumoniae Carbapenemases

The first case of carbapenemase-producing Enterobacteriaceae in Italy was reported in 2009. We performed a study over a period of seven months in 2010 to survey the circulation of Klebsiella pneumoniae carbapenemases (KPC) in a 1,500-bed university hospital in northern Italy and report the presence and rapid increase of these multidrug-resistant bacteria. The results raise a major concern about these pathogens and demonstrate the urgent need for infection control and antibiotic stewardship programmes.

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Innate Effector Systems in Primary Human Macrophages Sensitize Multidrug-Resistant Klebsiella pneumoniae to Antibiotics

Infection and Immunity ◽

10.1128/iai.00186-20 ◽

2020 ◽

Vol 88 (8) ◽

Author(s):

Rokeya Sultana Rekha ◽

Harpa Karadottir ◽

Sultan Ahmed ◽

Gudmundur H. Gudmundsson ◽

Birgitta Agerberth ◽

...

Keyword(s):

Vitamin D ◽

Klebsiella Pneumoniae ◽

Treatment Options ◽

Multidrug Resistant ◽

Human Macrophage ◽

Bacterial Killing ◽

Content Type ◽

Conventional Antibiotics ◽

Innate Effector ◽

In Cells

ABSTRACT Infections caused by multidrug-resistant (MDR) Klebsiella pneumoniae are difficult to treat with conventional antibiotics. Thus, alternative strategies to control the growth of MDR Klebsiella are warranted. We hypothesized that activation of innate effector systems could sensitize MDR K. pneumoniae to conventional antibiotics. Thus, human primary macrophages were stimulated with compounds known to activate innate immunity (vitamin D3, phenylbutyrate [PBA], and the aroylated phenylenediamine HO53) and then infected with MDR Klebsiella in the presence or absence of antibiotics. Antibiotics alone were ineffective against MDR Klebsiella in the cellular model, whereas vitamin D3, PBA, and HO53 reduced intracellular growth by up to 70%. The effect was further improved when the innate activators were combined with antibiotics. Vitamin D3- and PBA-induced bacterial killing was dependent on CAMP gene expression, whereas HO53 needed the production of reactive oxygen species (ROS), as shown in cells where the CYBB gene was silenced and in cells from a patient with reduced ROS production due to a deletion in the CYBB gene and skewed lyonization. The combination of innate effector activation by vitamin D3, PBA, and HO53 was effective in sensitizing MDR Klebsiella to conventional antibiotics in a primary human macrophage model. This study provides new evidence for future treatment options for K. pneumoniae.

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