SUMMARY β-Lactam antibiotics have been widely used as therapeutic agents for the past 70 years, resulting in emergence of an abundance of β-lactam-inactivating β-lactamases. Although penicillinases in Staphylococcus aureus challenged the initial uses of penicillin, β-lactamases are most important in Gram-negative bacteria, particularly in enteric and nonfermentative pathogens, where collectively they confer resistance to all β-lactam-containing antibiotics. Critical β-lactamases are those enzymes whose genes are encoded on mobile elements that are transferable among species. Major β-lactamase families include plasmid-mediated extended-spectrum β-lactamases (ESBLs), AmpC cephalosporinases, and carbapenemases now appearing globally, with geographic preferences for specific variants. CTX-M enzymes include the most common ESBLs that are prevalent in all areas of the world. In contrast, KPC serine carbapenemases are present more frequently in the Americas, the Mediterranean countries, and China, whereas NDM metallo-β-lactamases are more prevalent in the Indian subcontinent and Eastern Europe. As selective pressure from β-lactam use continues, multiple β-lactamases per organism are increasingly common, including pathogens carrying three different carbapenemase genes. These organisms may be spread throughout health care facilities as well as in the community, warranting close attention to increased infection control measures and stewardship of the β-lactam-containing drugs in an effort to control selection of even more deleterious pathogens.

Epidemiology of β-Lactamase-Producing Pathogens.

SUMMARY Surveillance studies have shown that OXA-48-like carbapenemases are the most common carbapenemases in Enterobacterales in certain regions of the world and are being introduced on a regular basis into regions of nonendemicity, where they are responsible for nosocomial outbreaks. OXA-48, OXA-181, OXA-232, OXA-204, OXA-162, and OXA-244, in that order, are the most common enzymes identified among the OXA-48-like carbapenemase group. OXA-48 is associated with different Tn1999 variants on IncL plasmids and is endemic in North Africa and the Middle East. OXA-162 and OXA-244 are derivatives of OXA-48 and are present in Europe. OXA-181 and OXA-232 are associated with ISEcp1, Tn2013 on ColE2, and IncX3 types of plasmids and are endemic in the Indian subcontinent (e.g., India, Bangladesh, Pakistan, and Sri Lanka) and certain sub-Saharan African countries. Overall, clonal dissemination plays a minor role in the spread of OXA-48-like carbapenemases, but certain high-risk clones (e.g., Klebsiella pneumoniae sequence type 147 [ST147], ST307, ST15, and ST14 and Escherichia coli ST38 and ST410) have been associated with the global dispersion of OXA-48, OXA-181, OXA-232, and OXA-204. Chromosomal integration of blaOXA-48 within Tn6237 occurred among E. coli ST38 isolates, especially in the United Kingdom. The detection of Enterobacterales with OXA-48-like enzymes using phenotypic methods has improved recently but remains challenging for clinical laboratories in regions of nonendemicity. Identification of the specific type of OXA-48-like enzyme requires sequencing of the corresponding genes. Bacteria (especially K. pneumoniae and E. coli) with blaOXA-48, blaOXA-181, and blaOXA-232 are emerging in different parts of the world and are most likely underreported due to problems with the laboratory detection of these enzymes. The medical community should be aware of the looming threat that is posed by bacteria with OXA-48-like carbapenemases.

The Global Ascendency of OXA-48-Type Carbapenemases.

Background Klebsiella species, including the notable pathogen K. pneumoniae, are increasingly associated with antimicrobial resistance (AMR). Genome-based surveillance can inform interventions aimed at controlling AMR. However, its widespread implementation requires tools to streamline bioinformatic analyses and public health reporting. Methods We developed the web application Pathogenwatch, which implements analytics tailored to Klebsiella species for integration and visualization of genomic and epidemiological data. We populated Pathogenwatch with 16 537 public Klebsiella genomes to enable contextualization of user genomes. We demonstrated its features with 1636 genomes from 4 low- and middle-income countries (LMICs) participating in the NIHR Global Health Research Unit (GHRU) on AMR. Results Using Pathogenwatch, we found that GHRU genomes were dominated by a small number of epidemic drug-resistant clones of K. pneumoniae. However, differences in their distribution were observed (eg, ST258/512 dominated in Colombia, ST231 in India, ST307 in Nigeria, ST147 in the Philippines). Phylogenetic analyses including public genomes for contextualization enabled retrospective monitoring of their spread. In particular, we identified hospital outbreaks, detected introductions from abroad, and uncovered clonal expansions associated with resistance and virulence genes. Assessment of loci encoding O-antigens and capsule in K. pneumoniae, which represent possible vaccine candidates, showed that 3 O-types (O1-O3) represented 88.9% of all genomes, whereas capsule types were much more diverse. Conclusions Pathogenwatch provides a free, accessible platform for real-time analysis of Klebsiella genomes to aid surveillance at local, national, and global levels. We have improved representation of genomes from GHRU participant countries, further facilitating ongoing surveillance.

Rapid Genomic Characterization and Global Surveillance of Klebsiella Using Pathogenwatch.

Background Klebsiella species, including the notable pathogen K. pneumoniae, are increasingly associated with antimicrobial resistance (AMR). Genome-based surveillance can inform interventions aimed at controlling AMR. However, its widespread implementation requires tools to streamline bioinformatic analyses and public health reporting. Methods We developed the web application Pathogenwatch, which implements analytics tailored to Klebsiella species for integration and visualization of genomic and epidemiological data. We populated Pathogenwatch with 16,537 public Klebsiella genomes to enable contextualization of user genomes. We demonstrated its features with 1,636 genomes from four low- and middle-income countries (LMICs) participating in the NIHR Global Health Research Unit (GHRU) on AMR. Results Using Pathogenwatch, we found that GHRU genomes were dominated by a small number of epidemic drug-resistant clones of K. pneumoniae. However, differences in their distribution were observed (e.g. ST258/512 dominated in Colombia, ST231 in India, ST307 in Nigeria, ST147 in the Philippines). Phylogenetic analyses including public genomes for contextualization enabled retrospective monitoring of their spread. In particular, we identified hospital outbreaks, detected introductions from abroad, and uncovered clonal expansions associated with resistance and virulence genes. Assessment of loci encoding O-antigens and capsule in K. pneumoniae, which represent possible vaccine candidates, showed that three O-types (O1-O3) represented 88.9% of all genomes, whereas capsule types were much more diverse. Conclusions Pathogenwatch provides a free, accessible platform for real-time analysis of Klebsiella genomes to aid surveillance at local, national and global levels. We have improved representation of genomes from GHRU participant countries, further facilitating ongoing surveillance. summary Pathogenwatch is a free web-application for analysis of Klebsiella genomes to aid surveillance at local, national and global levels. We improved the representation of genomes from middle-income countries through the Global Health Research Unit on AMR, further facilitating ongoing surveillance.

/pdf/rapid-genomic-characterization-and-global-surveillance-of-3fnzz3aaiy.pdf

Rapid Genomic Characterization and Global Surveillance of Klebsiella Using Pathogenwatch

The spread and outbreak of Enterobacteriaceae producing OXA-48-like carbapenemases have become more and more prevalent in China. A total of 62 non-duplicated OXA-232-producing K. pneumoniae (OXA232Kp) were isolated between 2015 and 2017. An outbreak of OXA232Kp was observed in burn ICU. The 62 OXA232Kp isolates were all belongs to ST15 and categorized into two PFGE types (A and B). Type A was dominated of the isolates, which contained 61 clinical isolates and divided into 10 subtypes (A1-A10). In addition, most of OXA232Kp strains exhibited low-level carbapenems resistance. All strains carried a 6141 bp ColKP3 plasmid harboring the blaOXA-232 gene which is highly homologous to other blaOXA-232-bearing plasmids involved in other studies in eastern China. In this study, clone transmission of OXA232Kp ST15was observed. Highly significant homology among the blaOXA-232-bearing plasmids indicated the important role of the 6.1 kb ColE-like plasmid on the prevalence of blaOXA-232 gene in China.

/pdf/nosocomial-spread-of-oxa-232-producing-klebsiella-pneumoniae-12ucz5clme.pdf

V. Biscaro

Papers

Genomics of Klebsiella pneumoniae ST16 producing NDM-1, CTX-M-15, and OXA-232