OXA-48-like carbapenemases: the phantom menace
01 Jul 2012-Journal of Antimicrobial Chemotherapy (Oxford University Press)-Vol. 67, Iss: 7, pp 1597-1606
TL;DR: Since many OXA-48-like producers do not exhibit resistance to broad-spectrum cephalosporins, or only decreased susceptibility to carbapenems, their recognition and detection can be challenging.
Abstract: OXA-48-type carbapenem-hydrolysing class D β-lactamases are increasingly reported in enterobacterial species. To date, six OXA-48-like variants have been identified, with OXA-48 being the most widespread. They differ by a few amino acid substitutions or deletions (one to five amino acids). The enzymes hydrolyse penicillins at a high level and carbapenems at a low level, sparing broad-spectrum cephalosporins, and are not susceptible to β-lactamase inhibitors. When combining permeability defects, OXA-48-like producers may exhibit a high level of resistance to carbapenems. OXA-163 is an exception, hydrolysing broad-spectrum cephalosporins but carbapenems at a very low level, and being susceptible to β-lactamase inhibitors. The bla(OXA-48)-type genes are always plasmid-borne and have been identified in association with insertion sequences involved in their acquisition and expression. The current spread of the bla(OXA-48) gene is mostly linked to the dissemination of a single IncL/M-type self-transferable plasmid of 62 kb that does not carry any additional resistance gene. OXA-48-type carbapenemases have been identified mainly from North African countries, the Middle East, Turkey and India, those areas constituting the most important reservoirs; however, occurrence of OXA-48 producers in European countries is now well documented, with some reported hospital outbreaks. Since many OXA-48-like producers do not exhibit resistance to broad-spectrum cephalosporins, or only decreased susceptibility to carbapenems, their recognition and detection can be challenging. Adequate screening and detection methods are therefore required to prevent and control their dissemination.
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University of Miami1, Jackson Memorial Hospital2, University of Paris-Sud3, United States Department of Veterans Affairs4, Case Western Reserve University5, Israel Ministry of Health6, National and Kapodistrian University of Athens7, National University of Ireland, Galway8, University of Verona9, University of Barcelona10, Rush University Medical Center11, University of Madras12, Public Health England13, University of East Anglia14, Centers for Disease Control and Prevention15, Royal Brisbane and Women's Hospital16, University of Calgary17, Peking University18, AstraZeneca19
TL;DR: The epidemiology of Klebsiella pneumoniae carbapenemases across continents is summarized, issues around detection, present antibiotic options and those in development, treatment outcome and mortality, and infection control are discussed.
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.
1,314 citations
TL;DR: The concept of the resistome is discussed, examples of HGT of clinically relevant ARGs are provided and an overview of the current knowledge of the contributions the various HGT mechanisms make to the spread of antibiotic resistance is presented.
Abstract: The emergence and spread of antibiotic resistance among pathogenic bacteria has been a rising problem for public health in recent decades. It is becoming increasingly recognized that not only antibiotic resistance genes (ARGs) encountered in clinical pathogens are of relevance, but rather, all pathogenic, commensal as well as environmental bacteria-and also mobile genetic elements and bacteriophages-form a reservoir of ARGs (the resistome) from which pathogenic bacteria can acquire resistance via horizontal gene transfer (HGT). HGT has caused antibiotic resistance to spread from commensal and environmental species to pathogenic ones, as has been shown for some clinically important ARGs. Of the three canonical mechanisms of HGT, conjugation is thought to have the greatest influence on the dissemination of ARGs. While transformation and transduction are deemed less important, recent discoveries suggest their role may be larger than previously thought. Understanding the extent of the resistome and how its mobilization to pathogenic bacteria takes place is essential for efforts to control the dissemination of these genes. Here, we will discuss the concept of the resistome, provide examples of HGT of clinically relevant ARGs and present an overview of the current knowledge of the contributions the various HGT mechanisms make to the spread of antibiotic resistance.
996 citations
Cites background from "OXA-48-like carbapenemases: the pha..."
...The OXA-48-type carbapenem-hydrolyzing β-lactamase genes, which are increasingly reported in enterobacterial species worldwide, were also found to originate from the chromosomes of waterborne, environmental Shewanella species (Poirel et al., 2012)....
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TL;DR: The evolution of CRE is discussed, with a focus on the epidemiology of the CPE pandemic; risk factors for colonization and infection with the most common transmissible CPE worldwide, Klebsiella pneumoniae carbapenemase-producing K. pneumoniae are reviewed; and strategies used to halt the striking spread of these deadly pathogens are presented.
Abstract: Carbapenem-resistant Enterobacteriaceae (CRE) are a serious public health threat. Infections due to these organisms are associated with significant morbidity and mortality. Mechanisms of drug resistance in gram-negative bacteria (GNB) are numerous; β-lactamase genes carried on mobile genetic elements are a key mechanism for the rapid spread of antibiotic-resistant GNB worldwide. Transmissible carbapenem-resistance in Enterobacteriaceae has been recognized for the last 2 decades, but global dissemination of carbapenemase-producing Enterobacteriaceae (CPE) is a more recent problem that, once initiated, has been occurring at an alarming pace. In this article, we discuss the evolution of CRE, with a focus on the epidemiology of the CPE pandemic; review risk factors for colonization and infection with the most common transmissible CPE worldwide, Klebsiella pneumoniae carbapenemase-producing K. pneumoniae; and present strategies used to halt the striking spread of these deadly pathogens.
944 citations
Cites background from "OXA-48-like carbapenemases: the pha..."
...spectrum cephalosporins; however, strains may express multiple ESBLs, rendering them resistant to all β-lactams [12]....
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TL;DR: Escherichia coli sequence type 131 (ST131) and Klebsiella pneumoniae ST258 emerged in the 2000s as important human pathogens, have spread extensively throughout the world, and are responsible for the rapid increase in antimicrobial resistance among E. coli and K. pneumoniae strains.
Abstract: SUMMARY Escherichia coli sequence type 131 (ST131) and Klebsiella pneumoniae ST258 emerged in the 2000s as important human pathogens, have spread extensively throughout the world, and are responsible for the rapid increase in antimicrobial resistance among E. coli and K. pneumoniae strains, respectively. E. coli ST131 causes extraintestinal infections and is often fluoroquinolone resistant and associated with extended-spectrum β-lactamase production, especially CTX-M-15. K. pneumoniae ST258 causes urinary and respiratory tract infections and is associated with carbapenemases, most often KPC-2 and KPC-3. The most prevalent lineage within ST131 is named fimH30 because it contains the H30 variant of the type 1 fimbrial adhesin gene, and recent molecular studies have demonstrated that this lineage emerged in the early 2000s and was then followed by the rapid expansion of its sublineages H30-R and H30-Rx. K. pneumoniae ST258 comprises 2 distinct lineages, namely clade I and clade II. Moreover, it seems that ST258 is a hybrid clone that was created by a large recombination event between ST11 and ST442. Epidemic plasmids with blaCTX-M and blaKPC belonging to incompatibility group F have contributed significantly to the success of these clones. E. coli ST131 and K. pneumoniae ST258 are the quintessential examples of international multidrug-resistant high-risk clones.
597 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
Cites background from "OXA-48-like carbapenemases: the pha..."
...The only class D carbapenem-hydrolyzing -lactamase found in K. pneumoniae isolates is OXA-48 (and derivatives), which was first reported in a Turkish MDR K. pneumoniae isolate in Paris, France (25)....
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...pneumoniae isolate in Paris, France (25)....
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..., Morocco, Tunisia, Spain, Belgium) and shows a wide range of susceptibility profiles (25)....
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References
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TL;DR: These resistance traits have been identified among nosocomial and community-acquired infections and are being investigated for use in drug discovery and development.
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2,044 citations
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1,438 citations
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1,093 citations
TL;DR: The high-level resistance to β-lactams of this clinical isolate resulted from peculiar β- lactamases and modification of outer membrane proteins.
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886 citations
TL;DR: New Delhi metallo-β-lactamase (NDM) enzymes are the latest carbapenemases to be recognized and since 2008 have been reported worldwide, mostly in bacteria from patients epidemiologically linked to the Indian subcontinent, where they occur widely in hospital and community infections, and also in contaminated urban water.
574 citations