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The dramatic increase in the prevalence and clinical impact of infections caused by bacteria producing carbapenemases is a global health concern. Carbapenemase production is especially problematic when encountered in members of the family Enterobacteriaceae. Due to their ability to readily spread and colonize patients in healthcare environments, preventing the transmission of these organisms is a major public health initiative and coordinated international effort are needed. Central to the treatment and control of carbapenemase-producing organisms (CPOs) are phenotypic (growth-/biochemical-dependent) and nucleic acid-based carbapenemase detection tests that identify carbapenemase activity directly or their associated molecular determinants. Importantly, bacterial isolates harboring carbapenemases are often resistant to multiple antibiotic classes, resulting in limited therapy options. Emerging agents, novel antibiotic combinations and treatment regimens offer promise for management of these infections. This review highlights our current understanding of CPOs with emphasis on their epidemiology, detection, treatment, and control.

Carbapenem-resistant Enterobacterales (CRE) are a global threat. We aimed to describe the clinical and molecular characteristics of Centers for Disease Control and Prevention (CDC)-defined CRE in the USA. CRACKLE-2 is a prospective, multicentre, cohort study. Patients hospitalised in 49 US hospitals, with clinical cultures positive for CDC-defined CRE between April 30, 2016, and Aug 31, 2017, were included. There was no age exclusion. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after index culture. Clinical data and bacteria were collected, and whole genome sequencing was done. This trial is registered with ClinicalTrials.gov, number NCT03646227. 1040 patients with unique isolates were included, 449 (43%) with infection and 591 (57%) with colonisation. The CDC-defined CRE admission rate was 57 per 100 000 admissions (95% CI 45–71). Three subsets of CDC-defined CRE were identified: carbapenemase-producing Enterobacterales (618 [59%] of 1040), non-carbapenemase-producing Enterobacterales (194 [19%]), and unconfirmed CRE (228 [22%]; initially reported as CRE, but susceptible to carbapenems in two central laboratories). Klebsiella pneumoniae carbapenemase-producing clonal group 258 K pneumoniae was the most common carbapenemase-producing Enterobacterales. In 449 patients with CDC-defined CRE infections, DOOR outcomes were not significantly different in patients with carbapenemase-producing Enterobacterales, non-carbapenemase-producing Enterobacterales, and unconfirmed CRE. At 30 days 107 (24%, 95% CI 20–28) of these patients had died. Among patients with CDC-defined CRE, similar outcomes were observed among three subgroups, including the novel unconfirmed CRE group. CDC-defined CRE represent diverse bacteria, whose spread might not respond to interventions directed to carbapenemase-producing Enterobacterales. National Institutes of Health.

Colistin represents one of the few available drugs for treating infections caused by carbapenem-resistant Enterobacteriaceae . As such, the recent plasmid-mediated spread of the colistin resistance gene mcr-1 poses a significant public health threat, requiring global monitoring and surveillance. Here, we characterize the global distribution of mcr-1 using a data set of 457 mcr-1- positive sequenced isolates. We find mcr-1 in various plasmid types but identify an immediate background common to all mcr-1 sequences. Our analyses establish that all mcr-1 elements in circulation descend from the same initial mobilization of mcr-1 by an IS A pl1 transposon in the mid 2000s (2002–2008; 95% highest posterior density), followed by a marked demographic expansion, which led to its current global distribution. Our results provide the first systematic phylogenetic analysis of the origin and spread of mcr-1 , and emphasize the importance of understanding the movement of antibiotic resistance genes across multiple levels of genomic organization. The recent plasmid-mediated spread of the mobilized colistin resistance gene mcr-1 poses a significant public health threat, requiring worldwide monitoring and surveillance. Here, Wang et al. compile and analyze a data set of 457 mcr-1 -positive sequenced isolates to investigate the origin and global distribution of mcr-1 .

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.

Background. Gut colonization is a risk factor for infections with extended-spectrum beta-lactamase (ESBL)–producing organisms. We aimed to determine the ESBL class A reservoir among healthy individuals. Methods. We searched PubMed and EMBASE (through 10 July 2015) looking for studies that contained data for fecal colonization with ESBL class A bacteria among healthy individuals for each World Health Organization–defined region. Distribution of isolates among cefotaximase (CTX-M), sulfhydryl variable, and temoneira enzymes and data on previous antibiotic use, international travel, previous hospitalization, and animal contacts were extracted. Results. Sixty-six of 17 479 studies on 28 909 healthy individuals were included. The pooled prevalence of ESBL class A colonization was 14% (95% confidence interval [CI], 9, 20), with an increasing trend of 5.38% annually (P = .003). The pooled prevalence was higher in Asia and Africa (ranging from 46%, 95% CI, 29, 63 to 15%, 95% CI, 4, 31) and lower but still significant in central (3%, 95% CI, 1, 5), northern (4%, 95% CI, 2, 6), and southern Europe (6%, 95% CI, 1, 12) and the Americas (2%, 95% CI, 0, 5). CTX-Ms were the prevalent ESBL enzyme (69%). Antibiotic use for the prior 4 or 12 months was associated with a high colonization risk (risk ratio [RR] = 1.63; 95% CI, 1.19, 2.24 and RR = 1.58; 95% CI, 1.16, 2.16, respectively). International travel was also correlated with ESBL colonization [(RR = 4.06, (95% CI, 1.33, 12.41)]. Conclusions. The ESBL colonization rate among healthy individuals is significant worldwide. This should be taken into consideration in infection control and antibiotic management decisions.

The mcr-1 gene confers transferable colistin resistance. mcr-1-positive Enterobacteriaceae (MCRPE) have attracted substantial medical, media, and political attention; however, so far studies have not addressed their clinical impact. Herein, we report the prevalence of MCRPE in human infections and carriage, clinical associations of mcr-1-positive Escherichia coli (MCRPEC) infection, and risk factors for MCRPEC carriage. We undertook this study at two hospitals in Zhejiang and Guangdong, China. We did a retrospective cross-sectional assessment of prevalence of MCRPE infection from isolates of Gram-negative bacteria collected at the hospitals from 2007 to 2015 (prevalence study). We did a retrospective case-control study of risk factors for infection and mortality after infection, using all MCRPEC from infection isolates and a random sample of mcr-1-negative E coli infections from the retrospective collection between 2012 and 2015 (infection study). We also did a prospective case-control study to assess risk factors for carriage of MCRPEC in rectal swabs from inpatients with MCRPEC and mcr-1 negative at the hospitals and collected between May and December, 2015, compared with mcr-1-negative isolates from rectal swabs of inpatients (colonisation study). Strains were analysed for antibiotic resistance, plasmid typing, and transfer analysis, and strain relatedness. We identified 21 621 non-duplicate isolates of Enterobacteriaceae, Acinetobacter spp, and Pseudomonas aeruginosa from 18 698 inpatients and 2923 healthy volunteers. Of 17 498 isolates associated with infection, mcr-1 was detected in 76 (1%) of 5332 E coli isolates, 13 (<1%) of 348 Klebsiella pneumoniae, one (<1%) of 890 Enterobacter cloacae, and one (1%) of 162 Enterobacter aerogenes. For the infection study, we included 76 mcr-1-positive clinical E coli isolates and 508 mcr-1-negative isolates. Overall, MCRPEC infection was associated with male sex (209 [41%] vs 47 [63%], adjusted p=0·011), immunosuppression (30 [6%] vs 11 [15%], adjusted p=0·011), and antibiotic use, particularly carbapenems (45 [9%] vs 18 [24%], adjusted p=0·002) and fluoroquinolones (95 [19%] vs 23 [30%], adjusted p=0·017), before hospital admission. For the colonisation study, we screened 2923 rectal swabs from healthy volunteers, of which 19 were MCRPEC, and 1200 rectal swabs from patients, of which 35 were MCRPEC. Antibiotic use before hospital admission (p<0·0001) was associated with MCRPEC carriage in 35 patients compared with 378 patients with mcr-1-negative E coli colonisation, whereas living next to a farm was associated with mcr-1-negative E coli colonisation (p=0·03, univariate test). mcr-1 could be transferred between bacteria at high frequencies (10−1 to 10−3), and plasmid types and MCRPEC multi-locus sequence types (MLSTs) were more variable in Guangdong than in Zhejiang and included the human pathogen ST131. MCRPEC also included 17 unreported ST clades. In 2017, colistin will be formally banned from animal feeds in China and switched to human therapy. Infection with MRCPEC is associated with sex, immunosuppression, and previous antibiotic exposure, while colonisation is also associated with antibiotic exposure. MLST and plasmid analysis shows that MCRPEC are diversely spread throughout China and pervasive in Chinese communities. National Key Basic Research Program of China, National Natural Science Foundation of China/Zhejiang, National Key Research and Development Program, and MRC, UK.

Public health interventions to control the current epidemic of carbapenem-resistant Klebsiella pneumoniae rely on a comprehensive understanding of its emergence and spread over a wide range of geographical scales. We analysed the genome sequences and epidemiological data of >1,700 K. pneumoniae samples isolated from patients in 244 hospitals in 32 countries during the European Survey of Carbapenemase-Producing Enterobacteriaceae. We demonstrate that carbapenemase acquisition is the main cause of carbapenem resistance and that it occurred across diverse phylogenetic backgrounds. However, 477 of 682 (69.9%) carbapenemase-positive isolates are concentrated in four clonal lineages, sequence types 11, 15, 101, 258/512 and their derivatives. Combined analysis of the genetic and geographic distances between isolates with different β-lactam resistance determinants suggests that the propensity of K. pneumoniae to spread in hospital environments correlates with the degree of resistance and that carbapenemase-positive isolates have the highest transmissibility. Indeed, we found that over half of the hospitals that contributed carbapenemase-positive isolates probably experienced within-hospital transmission, and interhospital spread is far more frequent within, rather than between, countries. Finally, we propose a value of 21 for the number of single nucleotide polymorphisms that optimizes the discrimination of hospital clusters and detail the international spread of the successful epidemic lineage, ST258/512. Genomic and epidemiological analysis of carbapenem-resistant Klebsiella pneumoniae across Europe finds increased transmissibility of four clonal lineages, especially between hospitals within countries.

Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae present an ever-growing burden in the hospital and community settings, across all ages and demographics. Infections due to ESBL-containing pathogens continue to be associated with significant morbidity and mortality worldwide. With widespread empiric broad-spectrum β-lactam use creating selective pressure, and the resultant emergence of stable, rapidly proliferating ESBL-producing clones with continued horizontal gene transfer across genera, addressing this issue remains imperative. Although well characterized in adults, the epidemiology, risk factors, outcomes, therapies, and control measures for ESBL-producing bacteria are less appreciated in children. This analysis provides a brief summary of ESBL-producing Enterobacteriaceae in children, with a focus on recent clinical and molecular data regarding colonization and infection in nonoutbreak settings.

Despite being members of gut microbiota, Enterobacteriaceae are associated with many severe infections such as bloodstream infections. The β-lactam drugs have been the cornerstone of antibiotic therapy for such infections. However, the overuse of these antibiotics has contributed to select β-lactam-resistant Enterobacteriaceae isolates, so that β-lactam resistance is nowadays a major concern worldwide. The production of enzymes that inactivate β-lactams, mainly extended-spectrum β-lactamases and carbapenemases, can confer multidrug resistance patterns that seriously compromise therapeutic options. Further, β-lactam resistance may result in increases in the drug toxicity, mortality, and healthcare costs associated with Enterobacteriaceae infections. Here, we summarize the updated evidence about the molecular mechanisms and epidemiology of β-lactamase-mediated β-lactam resistance in Enterobacteriaceae, and their potential impact on clinical outcomes of β-lactam-resistant Enterobacteriaceae infections.

Carbapenem-resistant Enterobacteriaceae (CRE) are among the most severe threats to the antibiotic era. Multiple different species can exhibit resistance due to many different mechanisms, and many different mobile elements are capable of transferring resistance between lineages. We prospectively sampled CRE from hospitalized patients from three Boston-area hospitals, together with a collection of CRE from a single California hospital, to define the frequency and characteristics of outbreaks and determine whether there is evidence for transfer of strains within and between hospitals and the frequency with which resistance is transferred between lineages or species. We found eight species exhibiting resistance, with the majority of our sample being the sequence type 258 (ST258) lineage of Klebsiella pneumoniae. There was very little evidence of extensive hospital outbreaks, but a great deal of variation in resistance mechanisms and the genomic backgrounds carrying these mechanisms. Local transmission was evident in clear phylogeographic structure between the samples from the two coasts. The most common resistance mechanisms were KPC (K. pneumoniae carbapenemases) beta-lactamases encoded by bla KPC2, bla KPC3, and bla KPC4, which were transferred between strains and species by seven distinct subgroups of the Tn4401 element. We also found evidence for previously unrecognized resistance mechanisms that produced resistance when transformed into a susceptible genomic background. The extensive variation, together with evidence of transmission beyond limited clonal outbreaks, points to multiple unsampled transmission chains throughout the continuum of care, including asymptomatic carriage and transmission of CRE. This finding suggests that to control this threat, we need an aggressive approach to surveillance and isolation.