Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP), a type of Klebsiella pneumoniae (KP) that exhibits hypervirulence and carbapenem resistance phenotypes, can cause severe infections, both hospital- and community-acquired infections. CR-hvKP has brought great challenges to global public health and is associated with significant morbidity and mortality. There are many mechanisms responsible for the evolution of the hypervirulence and carbapenem resistance phenotypes, such as the horizontal transfer of the plasmid carrying the carbapenem resistance gene to hypervirulent Klebsiella pneumoniae (hvKP) or carbapenemase-producing Klebsiella pneumoniae (CRKP) acquiring a hypervirulence plasmid carrying a virulence-encoding gene. Notably, KP can evolve into CR-hvKP by acquiring a hybrid plasmid carrying both the carbapenem resistance and hypervirulence genes. In this review, we summarize the evolutionary mechanisms of resistance and plasmid-borne virulence as well as the prevalence of CR-hvKP.

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Epidemiological characteristics and molecular evolution mechanisms of carbapenem-resistant hypervirulent Klebsiella pneumoniae

The skin is the largest organ in the human body, acting as a physical and immunological barrier against pathogenic microorganisms The cutaneous lesions constitute a gateway for microbial contamination that can lead to chronic wounds and other invasive infections Chronic wounds are considered as serious public health problems due the related social, psychological and economic consequences The group of bacteria known as ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter sp) are among the most prevalent bacteria in cutaneous infections These pathogens have a high level of incidence in hospital environments and several strains present phenotypes of multidrug resistance In this review, we discuss some important aspects of skin immunology and the involvement of ESKAPE in wound infections First, we introduce some fundamental aspects of skin physiology and immunology related to cutaneous infections Following this, the major virulence factors involved in colonization and tissue damage are highlighted, as well as the most frequently detected antimicrobial resistance genes ESKAPE pathogens express several virulence determinants that overcome the skin’s physical and immunological barriers, enabling them to cause severe wound infections The high ability these bacteria to acquire resistance is alarming, particularly in the hospital settings where immunocompromised individuals are exposed to these pathogens Knowledge about the virulence and resistance markers of these species is important in order to develop new strategies to detect and treat their associated infections

Interplay between ESKAPE Pathogens and Immunity in Skin Infections: An Overview of the Major Determinants of Virulence and Antibiotic Resistance.

Although hypervirulent Klebsiella pneumoniae (hvKP) can produce community-acquired infections that are fatal in young and adult hosts, such as pyogenic liver abscess, endophthalmitis, and meningitis, it has historically been susceptible to antibiotics. Carbapenem-resistant K. pneumoniae (CRKP) is usually associated with urinary tract infections acquired in hospitals, pneumonia, septicemias, and soft tissue infections. Outbreaks and quick spread of CRKP in hospitals have become a major challenge in public health due to the lack of effective antibacterial treatments. In the early stages of K. pneumoniae development, HvKP and CRKP first appear as distinct routes. However, the lines dividing the two pathotypes are vanishing currently, and the advent of carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKP) is devastating as it is simultaneously multidrug-resistant, hypervirulent, and highly transmissible. Most CR-hvKP cases have been reported in Asian clinical settings, particularly in China. Typically, CR-hvKP develops when hvKP or CRKP acquires plasmids that carry either the carbapenem-resistance gene or the virulence gene. Alternatively, classic K. pneumoniae (cKP) may acquire a hybrid plasmid carrying both genes. In this review, we provide an overview of the key antimicrobial resistance mechanisms, virulence factors, clinical presentations, and outcomes associated with CR-hvKP infection. Additionally, we discuss the possible evolutionary processes and prevalence of CR-hvKP in China. Given the wide occurrence of CR-hvKP, continued surveillance and control measures of such organisms should be assigned a higher priority. 

"Superbugs" with hypervirulence and carbapenem resistance in Klebsiella pneumoniae: the rise of such emerging nosocomial pathogens in China.

Aim To describe the occurrence of carbapenem resistance among multidrug-resistant (MDR) Escherichia coli and Klebsiella pneumoniae isolated from clinical specimens in Accra using phenotypic and genotypic methods. Methodology The study was cross-sectional, involving 144 clinical MDR E. coli and K. pneumoniae isolates recovered from the Central Laboratory of the Korle Bu Teaching Hospital (KBTH). The isolates were re-cultured bacteriologically, identified using standard biochemical tests, and subjected to antibiotic susceptibility testing using the Kirby-Bauer method. Carbapenem resistance was determined based on imipenem, meropenem, and ertapenem zones of inhibition, as well as minimum inhibitory concentrations (MICs). Carbapenemase production was determined phenotypically by modified Hodge test (MHT) and modified carbapenem inactivation method (mCIM), and genotypically with multiplex PCR targeting the blaKPC, blaIMP, blaNDM, blaVIM, and blaOXA-48 genes. Results Of the 144 MDR isolates, 69.4% were E. coli, and 30.6% were K. pneumoniae. The distribution of antimicrobial resistance rates among them was ampicillin (97.2%), cefuroxime (93.1%), sulfamethoxazole-trimethoprim (86.8%), tetracycline (85.4%), cefotaxime and cefpodoxime (77.1% each), amoxicillin-clavulanate (75%), ceftriaxone (73.6%), ciprofloxacin (70.8%), levofloxacin (66.0%), cefepime (65.3%), ceftazidime (64.6%), gentamicin (48.6), piperacillin-tazobactam (40.3%), cefoxitin (14.6%), amikacin (13.9%), ertapenem and meropenem (5.6% each), and imipenem (2.8%). In total, 5.6% (8/144) of them were carbapenem-resistant (carbapenem MIC range = 0.094–32.0 μg/ml), with 75% (6/8) of these testing positive by the phenotypic tests and 62.5% (5/8) by the genotypic test (of which 80% [4/5] carried blaOXA-48 and 20% (1/5) blaNDM). The blaVIM, blaIMP, and blaKPC genes were not detected. Conclusion Although the rates of antibiotic resistance among the isolates were high, the prevalence of carbapenemase producers was low. The finding of blaOXA-48 and blaNDM warrants upscaling of antimicrobial resistance surveillance programmes and fortification of infection prevention and control programmes in the country.

Phenotypic and genotypic detection of carbapenemase-producing Escherichia coli and Klebsiella pneumoniae in Accra, Ghana

The burden of Hospital care-associated infections (HCAIs) is becoming a global concern. This is compounded by the emergence of virulent and high-risk bacterial strains such as "ESKAPE" pathogens - (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species), especially within Intensive care units (ICUs) that house high-risk and immunocompromised patients. In this review, we discuss the contributions of AMR pathogens to the increasing burden of HCAIs and provide insights into AMR mechanisms, with a particular focus on last-resort antibiotics like polymyxins. We extensively discuss how structural modifications of surface-membrane lipopolysaccharides and cationic interactions influence and inform AMR, and subsequent severity of HCAIs. We highlight some bacterial phenotypic survival mechanisms against polymyxins. Lastly, we discuss the emergence of plasmid-mediated resistance as a phenomenon making mitigation of AMR difficult, especially within the ICUs. This review provides a balanced perspective on the burden of HCAIs, associated pathogens, implication of AMR and factors influencing emerging AMR mechanisms. 

The burden of hospital acquired infections and antimicrobial resistance

Carbapenem-resistant hypervirulent Klebsiella pneumoniae strains have recently come into existence worldwide; however, researchers in northeast China are not aware of their clinical features and molecular characteristics. Here, the molecular and virulent characteristics of 44 carbapenem-resistant K. pneumoniae (CRKP) isolates collected from January 2015 to December 2017 were studied. Multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) were carried out to define the clonal relatedness among the isolates. PCR and capsular serotyping of the virulence-associated genes, as well as biofilm formation and serum complement-mediated killing assays, were employed to determine the virulent potential. The genomic features and associated mobile genetic elements of JmsCRE57 were detected by whole genome sequencing. The only positive isolate was JmsCRE57, which belonged to the ST375 serotype K2 that expressed uge, mrkD, fimH, kpn, aerobactin and rmpA virulence-associated genes and showed strong biofilm formation and serum sensitivity. Sequencing results showed that the JmsCRE57 genome mainly consisted of a circular chromosome, three antimicrobial resistant plasmids and a virulent plasmid. The antimicrobial resistant plasmid expressing blaKPC-2, blaCTX-M-15, aph(3″)-Ib, aph(6)-Id, qnrB1, aac(3)-IIa, aac(6′)-Ib-cr, blaOXA-1, blaTEM-1B, catB4, sul2, dfrA14 and blaSHV-99. The virulent plasmid belonged to the IncHI1B group, which is mainly composed of mucoid phenotype genes and siderophore-associated genes. The remaining CRKP strains that expressed uge, fimH, mrkD and kpn virulence-associated genes were not successfully typed. Our results provide new insights on the epidemiology of carbapenem-resistant K2 hypervirulent K. pneumoniae ST375 and CRKP ST76 strains in northeast China, which may help control their future outbreaks.

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Outbreak of KPC-2 Carbapenem-resistant Klebsiella pneumoniae ST76 and Carbapenem-resistant K2 Hypervirulent Klebsiella pneumoniae ST375 strains in Northeast China: molecular and virulent characteristics.

Background: The aim of this study was to investigate the characteristics of carbapenem-resistant Klebsiella pneumoniae (CRKP) ST76 isolates collected during an outbreak in a hospital's intensive ca...

Outbreak of KPC-2–Producing Klebsiella pneumoniae ST76 Isolates in an Intensive Care Unit and Neurosurgery Unit

Enterobacter cloacae complex (ECC) is one of the most common extended-spectrum β-lactamase and carbapenemase-producing pathogen that threatens millions of the elderly and vulnerable sick persons. The objective of this study was to perform the molecular characteristics of the carbapenem-resistant E. cloacae complex (CREC) emerged in Heilongjiang Province of China. Six CREC strains were isolated from the patients with infectious diseases. The identities of ECC isolates were confirmed by sequencing the polymerase chain reaction (PCR) products of 16S rRNA gene. The characterization of the CREC isolates were analyzed by sequencing PCR products of the carbapenemase, ampC and fluoroquinolone resistance genes and performing multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE) and whole genome sequencing. All 6 isolates harbored multiple resistance genes. Of them, 5 carried metallo-β-lactamases and one was blaKPC-2-positive. The levofloxacin and ciprofloxacin-resistant strains had substitutions of gyrA83, gyrA87, and parC80 in the quinolone-resistance determining regions. The MLST analyses revealed that 6 isolates belonged to five sequence types (ST520, ST528, ST1119, ST1120, and ST93) while the PFGE patterns of the isolates fallen into four clusters. The strain ST1120 was found to carry two separated plasmids that encode blaNDM-1 and blaIMP-4. Our study, for the first time, identified a CREC strain that co-produces blaNDM-1 and blaIMP-4 in the Northeast China. Our finding emphasizes an urgent need for more intensive surveillance and precaution measures to prevent the CERC spread.

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Molecular characterization of metallo- β -lactamase- producing carbapenem-resistant Enterobacter cloacae complex isolated in Heilongjiang Province of China

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Outbreak of KPC-2 Carbapenem-resistant Klebsiella pneumoniae ST76 and Carbapenem-resistant K2 Hypervirulent Klebsiella pneumoniae ST375 strains in Northeast China: molecular and virulent characteristics.

Outbreak of KPC-2–Producing Klebsiella pneumoniae ST76 Isolates in an Intensive Care Unit and Neurosurgery Unit

Molecular characterization of metallo- β -lactamase- producing carbapenem-resistant Enterobacter cloacae complex isolated in Heilongjiang Province of China