The Global Spread of Healthcare-Associated Multidrug-Resistant Bacteria: a Perspective from Asia
TL;DR: The authors in this article found that metallo-β-lactamase enzymes are encoded on highly transmissible plasmids that spread rapidly between bacteria, rather than relying on clonal proliferation.
Abstract: Since antibiotics were first used, each new introduced class has been followed by a global wave of emergent resistance, largely originating in Europe and North America where they were first used. Methicillin-resistant Staphylococcus aureus spread from the United Kingdom and North America across Europe and then Asia over more than a decade. Vancomycin-resistant enterococci and Klebsiella pneumoniae carbapenemase-producing K. pneumoniae followed a similar path some 20 years later. Recently however, metallo-β-lactamases have originated in Asia. New Delhi metallo-β-lactamase-1 was found in almost every continent within a year of its emergence in India. Metallo-β-lactamase enzymes are encoded on highly transmissible plasmids that spread rapidly between bacteria, rather than relying on clonal proliferation. Global air travel may have helped facilitate rapid dissemination. As the antibiotic pipeline offers little in the short term, our most important tools against the spread of antibiotic resistant organisms are intensified infection control, surveillance, and antimicrobial stewardship.
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TL;DR: The data highlight the complex evolution of MDR and XDR K. pneumoniae, involving transfer and spread of ARGs, and epidemic plasmids in highly disseminating successful clones, and a need for future genomic and translational studies to decipher specific targets in HiR clones to design targeted prevention and treatment.
Abstract: Klebsiella pneumoniae is an important multidrug-resistant (MDR) pathogen affecting humans and a major source for hospital infections associated with high morbidity and mortality due to limited treatment options We summarize the wide resistome of this pathogen, which encompasses plentiful chromosomal and plasmid-encoded antibiotic resistance genes (ARGs) Under antibiotic selective pressure, K pneumoniae continuously accumulates ARGs, by de novo mutations, and via acquisition of plasmids and transferable genetic elements, leading to extremely drug resistant (XDR) strains harboring a 'super resistome' In the last two decades, numerous high-risk (HiR) MDR and XDR K pneumoniae sequence types have emerged showing superior ability to cause multicontinent outbreaks, and continuous global dissemination The data highlight the complex evolution of MDR and XDR K pneumoniae, involving transfer and spread of ARGs, and epidemic plasmids in highly disseminating successful clones With the worldwide catastrophe of antibiotic resistance and the urgent need to identify the main pathogens that pose a threat on the future of infectious diseases, further studies are warranted to determine the epidemic traits and plasmid acquisition in K pneumoniae There is a need for future genomic and translational studies to decipher specific targets in HiR clones to design targeted prevention and treatment
654 citations
TL;DR: This work attempts to define the ecological and evolutionary environmental factors that contribute to resistance development and transmission and investigates under what conditions and to what extent environmental selection for resistance takes place.
Abstract: Antibiotic resistance and its wider implications present us with a growing healthcare crisis. Recent research points to the environment as an important component for the transmission of resistant bacteria and in the emergence of resistant pathogens. However, a deeper understanding of the evolutionary and ecological processes that lead to clinical appearance of resistance genes is still lacking, as is knowledge of environmental dispersal barriers. This calls for better models of how resistance genes evolve, are mobilized, transferred and disseminated in the environment. Here, we attempt to define the ecological and evolutionary environmental factors that contribute to resistance development and transmission. Although mobilization of resistance genes likely occurs continuously, the great majority of such genetic events do not lead to the establishment of novel resistance factors in bacterial populations, unless there is a selection pressure for maintaining them or their fitness costs are negligible. To enable preventative measures it is therefore critical to investigate under what conditions and to what extent environmental selection for resistance takes place. In addition, understanding dispersal barriers is not only key to evaluate risks, but also to prevent resistant pathogens, as well as novel resistance genes, from reaching humans.
606 citations
TL;DR: It seems that ST258 is a hybrid clone that was created by a large recombination event between ST11 and ST442, and incompatibility group F plasmids with blaKPC have contributed significantly to the success of ST258.
Abstract: The management of infections due to Klebsiella pneumoniae has been complicated by the emergence of antimicrobial resistance, especially to carbapenems. Resistance to carbapenems in K. pneumoniae involves multiple mechanisms, including the production of carbapenemases (e.g., KPC, NDM, VIM, OXA-48-like), as well as alterations in outer membrane permeability mediated by the loss of porins and the upregulation of efflux systems. The latter two mechanisms are often combined with high levels of other types of β-lactamases (e.g., AmpC). K. pneumoniae sequence type 258 (ST258) emerged during the early to mid-2000s as an important human pathogen and has spread extensively throughout the world. ST258 comprises two distinct lineages, namely, clades I and II, and it seems that ST258 is a hybrid clone that was created by a large recombination event between ST11 and ST442. Incompatibility group F plasmids with blaKPC have contributed significantly to the success of ST258. The optimal treatment of infections due to carbapenemase-producing K. pneumoniae remains unknown. Some newer agents show promise for treating infections due to KPC producers; however, effective options for the treatment of NDM producers remain elusive.
583 citations
University of Padua1, Post Graduate Institute of Medical Education and Research2, University of Bologna3, University of Turin4, State University of Campinas5, Hallym University6, Sapienza University of Rome7, Autonomous University of Barcelona8, Odense University Hospital9, Austral University of Chile10, Hospital Italiano de Buenos Aires11, Ghent University Hospital12, University of Toronto13, University of Virginia14, Tel Aviv University15, The Catholic University of America16, Soonchunhyang University17, Ludwig Maximilian University of Munich18, Paris Diderot University19, University of Chile20, University of Miami21, University of Arizona22, Moscow State University23, Keimyung University24, University of Barcelona25
TL;DR: Differences in the prevalence of MDR bacterial infections in different global regions indicate the need for different empirical antibiotic strategies in different continents and countries.
259 citations
TL;DR: Considerable political will and effort are vital in order to reduce the prevalence of carbapenem-resistant Gram-negative bacteria in South and Southeast Asia and prevent their global spread.
Abstract: Carbapenem-resistant Gram-negative bacteria, in particular the Acinetobacter baumannii-calcoaceticus complex and Enterobacteriaceae, are escalating global public health threats. We review the epidemiology and prevalence of these carbapenem-resistant Gram-negative bacteria among countries in South and Southeast Asia, where the rates of resistance are some of the highest in the world. These countries house more than a third of the world's population, and several are also major medical tourism destinations. There are significant data gaps, and the almost universal lack of comprehensive surveillance programs that include molecular epidemiologic testing has made it difficult to understand the origins and extent of the problem in depth. A complex combination of factors such as inappropriate prescription of antibiotics, overstretched health systems, and international travel (including the phenomenon of medical tourism) probably led to the rapid rise and spread of these bacteria in hospitals in South and Southeast Asia. In India, Pakistan, and Vietnam, carbapenem-resistant Enterobacteriaceae have also been found in the environment and community, likely as a consequence of poor environmental hygiene and sanitation. Considerable political will and effort, including from countries outside these regions, are vital in order to reduce the prevalence of such bacteria in South and Southeast Asia and prevent their global spread.
223 citations
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TL;DR: The frequency of selected antimicrobial resistance patterns among pathogens causing device-associated and procedure-associated healthcare-associated infections reported by hospitals in the National Healthcare Safety Network (NHSN) is described.
Abstract: Objective. To describe antimicrobial resistance patterns for healthcare-associated infections (HAIs) reported to the National Healthcare Safety Network (NHSN) during 2009-2010. Methods. Central line-associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, and surgical site infections were included. Pooled mean proportions of isolates interpreted as resistant (or, in some cases, nonsusceptible) to selected antimicrobial agents were calculated by type of HAI and compared to historical data. Results. Overall, 2,039 hospitals reported 1 or more HAIs; 1,749 (86%) were general acute care hospitals, and 1,143 (56%) had fewer than 200 beds. There were 69,475 HAIs and 81,139 pathogens reported. Eight pathogen groups accounted for about 80% of reported pathogens: Staphylococcus aureus (16%), Enterococcus spp. (14%), Escherichia coli (12%), coagulase-negative staphylococci (11%), Candida spp. (9%), Klebsiella pneumoniae (and Klebsiella oxytoca; 8%), Pseudomonas aeruginosa (8%), and Enterobacter spp. (5%). The percentage of resistance was similar to that reported in the previous 2-year period, with a slight decrease in the percentage of S. aureus resistant to oxacillins (MRSA). Nearly 20% of pathogens reported from all HAIs were the following multidrug-resistant phenotypes: MRSA (8.5%); vancomycin-resistant Enterococcus (3%); extended-spectrum cephalosporin-resistant K. pneumoniae and K. oxytoca (2%), E. coli (2%), and Enterobacter spp. (2%); and carbapenem-resistant P. aeruginosa (2%), K. pneumoniae/oxytoca (<1%), E, coli (<1%), and Enterobacter spp. (<1%). Among facilities reporting HAIs with 1 of the above gram-negative bacteria, 20%-40% reported at least 1 with the resistant phenotype. Conclusion. While the proportion of resistant isolates did not substantially change from that in the previous 2 years, multidrug-resistant gram-negative phenotypes were reported from a moderate proportion of facilities.
3,470 citations
University of Madras1, Cardiff University2, Health Protection Agency3, Karolinska University Hospital4, Aga Khan University5, Amrita Institute of Medical Sciences and Research Centre6, University of Queensland7, Gleneagles Hospital8, Northumbria Healthcare NHS Foundation Trust9, Apollo Hospitals10, Institute of Medical Sciences, Banaras Hindu University11
TL;DR: The prevalence of NDM-1, in multidrug-resistant Enterobacteriaceae in India, Pakistan, and the UK is investigated, and co-ordinated international surveillance is needed.
Abstract: Summary Background Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-β-lactamase 1 (NDM-1) are potentially a major global health problem. We investigated the prevalence of NDM-1, in multidrug-resistant Enterobacteriaceae in India, Pakistan, and the UK. Methods Enterobacteriaceae isolates were studied from two major centres in India—Chennai (south India), Haryana (north India)—and those referred to the UK's national reference laboratory. Antibiotic susceptibilities were assessed, and the presence of the carbapenem resistance gene bla NDM-1 was established by PCR. Isolates were typed by pulsed-field gel electrophoresis of XbaI-restricted genomic DNA. Plasmids were analysed by S1 nuclease digestion and PCR typing. Case data for UK patients were reviewed for evidence of travel and recent admission to hospitals in India or Pakistan. Findings We identified 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the UK, and 73 in other sites in India and Pakistan. NDM-1 was mostly found among Escherichia coli (36) and Klebsiella pneumoniae (111), which were highly resistant to all antibiotics except to tigecycline and colistin. K pneumoniae isolates from Haryana were clonal but NDM-1 producers from the UK and Chennai were clonally diverse. Most isolates carried the NDM-1 gene on plasmids: those from UK and Chennai were readily transferable whereas those from Haryana were not conjugative. Many of the UK NDM-1 positive patients had travelled to India or Pakistan within the past year, or had links with these countries. Interpretation The potential of NDM-1 to be a worldwide public health problem is great, and co-ordinated international surveillance is needed. Funding European Union, Wellcome Trust, and Wyeth.
2,680 citations
TL;DR: 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, showing broad resistance carried on these plasmids.
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.
2,144 citations
TL;DR: Therapy was resumed with the com -bination of arbekacin and ampicillin/sulbactam which has been shown to have synergic activity against MRSA.
Abstract: (MRSA) with reduced suscept-ibility to vancomycin (MIC 8 mg/L). The strain was isolated from a surgical wound infection which was refrac -tory to vancomycin therapy.In May 1996, a 4 month-old male infant underwent heartsurgery for pulmonary atresia. Two weeks followingsurgery, the infant became febrile and developed a purulent discharge from the sternal surgical incision site;culture of the purulent material yielded MRSA. The patientwas treated with vancomycin (45 mg/kg daily) for 29 days,but fever and discharge of pus continued, and the C-reactive protein (CRP) remained elevated (40 mg/L). Thetreatment was changed to a combination of vancomycin andarbekacin (an aminoglycoside approved for MRSA infec-tion in Japan). After 12 days of this regimen, the purulentdischarge subsided, the wound began to heal, and the CRPdeclined from 40 to 9 mg/L. The antimicrobial therapy wasdiscontinued. However, 12 days later the surgical siteappeared inflamed with the development of a subcutaneousabscess accompanied by a sudden onset of fever and a raised CRP level of 35 mg/L. Therapy was resumed with the com -bination of arbekacin and ampicillin/sulbactam which hasbeen shown to have synergic activity against MRSA.
2,023 citations
TL;DR: The substantial and expanding volume of evidence reporting animal-to-human spread of resistant bacteria, including that arising from use of NTAs, supports eliminating NTA use in order to reduce the growing environmental load of resistance genes.
Abstract: Antimicrobials are valuable therapeutics whose efficacy is seriously compromised by the emergence and spread of antimicrobial resistance. The provision of antibiotics to food animals encompasses a wide variety of nontherapeutic purposes that include growth promotion. The concern over resistance emergence and spread to people by nontherapeutic use of antimicrobials has led to conflicted practices and opinions. Considerable evidence supported the removal of nontherapeutic antimicrobials (NTAs) in Europe, based on the "precautionary principle." Still, concrete scientific evidence of the favorable versus unfavorable consequences of NTAs is not clear to all stakeholders. Substantial data show elevated antibiotic resistance in bacteria associated with animals fed NTAs and their food products. This resistance spreads to other animals and humans-directly by contact and indirectly via the food chain, water, air, and manured and sludge-fertilized soils. Modern genetic techniques are making advances in deciphering the ecological impact of NTAs, but modeling efforts are thwarted by deficits in key knowledge of microbial and antibiotic loads at each stage of the transmission chain. Still, the substantial and expanding volume of evidence reporting animal-to-human spread of resistant bacteria, including that arising from use of NTAs, supports eliminating NTA use in order to reduce the growing environmental load of resistance genes.
1,702 citations