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Background: Carbapenem-resistant Klebsiella pneumoniae (CRKp) is the most prevalent carbapenem-resistant Enterobacterales in the United States. We evaluated CRKp clustering in patients in US hospitals., Methods: From April 2016 to August 2017, 350 patients with clonal group 258 CRKp were enrolled in the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae, a prospective, multicenter, cohort study. A maximum likelihood tree was constructed using RAxML. Static clusters shared ≤21 single-nucleotide polymorphisms (SNP) and a most recent common ancestor. Dynamic clusters incorporated SNP distance, culture timing, and rates of SNP accumulation and transmission using the R program TransCluster., Results: Most patients were admitted from home (n = 150, 43%) or long-term care facilities (n = 115, 33%). Urine (n = 149, 43%) was the most common isolation site. Overall, 55 static and 47 dynamics clusters were identified involving 210 of 350 (60%) and 194 of 350 (55%) patients, respectively. Approximately half of static clusters were identical to dynamic clusters. Static clusters consisted of 33 (60%) intrasystem and 22 (40%) intersystem clusters. Dynamic clusters consisted of 32 (68%) intrasystem and 15 (32%) intersystem clusters and had fewer SNP differences than static clusters (8 vs 9; P = .045; 95% confidence interval [CI]: -4 to 0). Dynamic intersystem clusters contained more patients than dynamic intrasystem clusters (median [interquartile range], 4 [2, 7] vs 2 [2, 2]; P = .007; 95% CI: -3 to 0)., Conclusions: Widespread intrasystem and intersystem transmission of CRKp was identified in hospitalized US patients. Use of different methods for assessing genetic similarity resulted in only minor differences in interpretation., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Carbapenem-resistant Klebsiella pneumoniae (CR Kp ) is an urgent public health threat. Worldwide dissemination of CR Kp has been largely attributed to clonal group (CG) 258. However, recent evidence indicates the global emergence of a CR Kp CG307 lineage. Houston, TX, is the first large city in the United States with detected cocirculation of both CR Kp CG307 and CG258. We sought to characterize the genomic and clinical factors contributing to the parallel endemic spread of CG258 and CG307. CR Kp isolates were collected as part of the prospective, Consortium on Resistance against Carbapenems in Klebsiella and other Enterobacterales 2 (CRACKLE-2) study. Hybrid short-read and long-read genome assemblies were generated from 119 CR Kp isolates (95 originated from Houston hospitals). A comprehensive characterization of phylogenies, gene transfer, and plasmid content with pan-genome analysis was performed on all CR Kp isolates. Plasmid mating experiments were performed with CG307 and CG258 isolates of interest. Dissection of the accessory genomes suggested independent evolution and limited horizontal gene transfer between CG307 and CG258 lineages. CG307 contained a diverse repertoire of mobile genetic elements, which were shared with other non-CG258 K. pneumoniae isolates. Three unique clades of Houston CG307 isolates clustered distinctly from other global CG307 isolates, indicating potential selective adaptation of particular CG307 lineages to their respective geographical niches. CG307 strains were often isolated from the urine of hospitalized patients, likely serving as important reservoirs for genes encoding carbapenemases and extended-spectrum β-lactamases. Our findings suggest parallel cocirculation of high-risk lineages with potentially divergent evolution. IMPORTANCE The prevalence of carbapenem-resistant Klebsiella pneumoniae (CR Kp ) infections in nosocomial settings remains a public health challenge. High-risk clones such as clonal group 258 (CG258) are particularly concerning due to their association with bla KPC carriage, which can severely complicate antimicrobial treatments. There is a recent emergence of clonal group 307 (CG307) worldwide with little understanding of how this successful clone has been able to adapt while cocirculating with CG258. We provide the first evidence of potentially divergent evolution between CG258 and CG307 with limited sharing of adaptive genes. Houston, TX, is home to the largest medical center in the world, with a large influx of domestic and international patients. Thus, our unique geographical setting, where two pandemic strains of CR Kp are circulating, provides an indication of how differential accessory genome content can drive stable, endemic populations of CR Kp . Pan-genomic analyses such as these can reveal unique signatures of successful CR Kp dissemination, such as the CG307-associated plasmid (pCG307_HTX), and provide invaluable insights into the surveillance of local carbapenem-resistant Enterobacterales (CRE) epidemiology.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global threat. We therefore analysed the bacterial characteristics of CRKP infections and the clinical outcomes of patients with CRKP infections across different countries., Methods: In this prospective, multicentre, cohort study (CRACKLE-2), hospitalised patients with cultures positive for CRKP were recruited from 71 hospitals in Argentina, Australia, Chile, China, Colombia, Lebanon, Singapore, and the USA. The first culture positive for CRKP was included for each unique patient. Clinical data on post-hospitalisation death and readmission were collected from health records, and whole genome sequencing was done on all isolates. The primary outcome was a desirability of outcome ranking at 30 days after the index culture, and, along with bacterial characteristics and 30-day all-cause mortality (a key secondary outcome), was compared between patients from China, South America, and the USA. The desirability of outcome ranking was adjusted for location before admission, Charlson comorbidity index, age at culture, Pitt bacteremia score, and anatomical culture source through inverse probability weighting; mortality was adjusted for the same confounders, plus region where relevant, through multivariable logistic regression. This study is registered at ClinicalTrials.gov, NCT03646227, and is complete., Findings: Between June 13, 2017, and Nov 30, 2018, 991 patients were enrolled, of whom 502 (51%) met the criteria for CRKP infection and 489 (49%) had positive cultures that were considered colonisation. We observed little intra-country genetic variation in CRKP. Infected patients from the USA were more acutely ill than were patients from China or South America (median Pitt bacteremia score 3 [IQR 2-6] vs 2 [0-4] vs 2 [0-4]) and had more comorbidities (median Charlson comorbidity index 3 [IQR 2-5] vs 1 [0-3] vs 1 [0-2]). Adjusted desirability of outcome ranking outcomes were similar in infected patients from China (n=246), South America (n=109), and the USA (n=130); the estimates were 53% (95% CI 42-65) for China versus South America, 50% (41-61) for the USA versus China, and 53% (41-66) for the USA versus South America. In patients with CRKP infections, unadjusted 30-day mortality was lower in China (12%, 95% CI 8-16; 29 of 246) than in the USA (23%, 16-30; 30 of 130) and South America (28%, 20-37; 31 of 109). Adjusted 30-day all-cause mortality was higher in South America than in China (adjusted odds ratio [aOR] 4·82, 95% CI 2·22-10·50) and the USA (aOR 3·34, 1·50-7·47), with the mortality difference between the USA and China no longer being significant (aOR 1·44, 0·70-2·96)., Interpretation: Global CRKP epidemics have important regional differences in patients' baseline characteristics and clinical outcomes, and in bacterial characteristics. Research findings from one region might not be generalisable to other regions., Funding: The National Institutes of Health., Competing Interests: Declaration of interests MW, ME, LC, YY, ZL, SS, EC, LL, SSK, HG, KM, LK, SDR, SHM, CM, JR, MVV, CH, RA, KB, BCF, BNK, and RAB report funding support from the ARLG of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID; UM1AI104681) during the conduct of this study. BMH reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681), during the conduct of this study, and a grants from the NIH and the NIAID (K01AI148593–01), outside the submitted work. JMM reports funding support from the ALRG of the NIH and the NIAID (UM1AI104681) during the conduct of this study and grants from Pfizer, MSD, and bioMerieux, outside the submitted work. KO reports funding support from the ALRG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; payments for educational events and presentations from Pfizer, MSD, AstraZeneca, and Farma de Colombia; and meeting support from Pfizer, MSD, and Gilead, outside the submitted work. GW reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681), and from Allergan. MJS reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; contracts payments, to his institution, from Merck, Allergan, BioFire Diagnostics, and Affinity Biosensors; personal consulting fees from Achaogen and Shionogi; and board participation for Spero Therapeutics, outside the submitted work. SLV-B reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study and personal fees from MSD and Biotoscana, outside the submitted work. MES reports grants from the NIH during the conduct of the study; speaker fees from Pfizer (Argentina); advisory board participation for Wockhardt; and consultancy for Basilea, outside the submitted work. CL reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study and salary support from the National Institute of General Medical Sciences of the NIH (award number T32GM086330) outside the submitted work. DLP reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; grants and contracts with MERCK, Pfizer, and Shionogi; consulting fees from Merck, Shionogi, and Qpex; payments and financial support from Sumitomo, Merck, Pfizer, bioMerieux, and Shionogi; and board participation for Symvivo, outside the submitted work. SE reports grants from the NIAID and the NIH and Degruter (Editor in Chief for Statistical Communications in Infectious Diseases); royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Cardinal Health, Microbiotix, Stryker, Atricure, Roivant, Neovasc, Nobel Pharma, Horizon, the International Drug Development Institute, and SVB Leerink; payments from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, Osaka University, and the National Cerebral and Cardiovascular Center of Japan; meeting support from the US Food and Drug Administration, the Deming Conference on Applied Statistics, the Clinical Trial Transformation Initiative, the Council for International Organizations of Medical Sciences, and the Antimicrobial Resistance and Stewardship Conference; and board member participation for the NIH, the Breast International Group, the University of Pennsylvania, Duke University, Roche, Pfizer, Takeda, Novartis, Amgen, Teva, Vir, Shire, Alexion, Gilead, Tracon, Rakuten, Abbvie, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, the American Statistical Association, the Society for Clinical Trials, and the Frontier Science Foundation, outside the submitted work. YD reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; grants from Janssen, Pfizer, MSD, Shionogi, Astellas, and Kanto Chemical, outside the submitted work; and personal fees from Janssen, MSD, Entasis, VenatoRx, AstraZeneca, Gilead, FUJIFILM Toyama Chemical, bioMerieux, and Meiji Seika Pharma, outside the submitted work. RP reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; reports grants from Merck, ContraFect, TenNor Therapeutics, and Shionogi; is a consultant to Curetis, Specific Technologies, Next Gen Diagnostics, PathoQuest, Selux Diagnostics, 1928 Diagnostics, PhAST, and Qvella, for which monies are paid to Mayo Clinic; is a consultant to Netflix; has a patent on Bordetella pertussis (parapertussis) PCR issued, a patent on a device and method for sonication (with royalties paid by Samsung to Mayo Clinic), and a patent on an anti-biofilm substance issued; receives an editor's stipend from the Infectious Diseases Society of America; and receives honoraria from the National Board of Medical Examiners, UpToDate, and the Infectious Diseases Board Review Course, outside the submitted work. HFC reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; personal fees from Merck; and stock ownership from Moderna, outside the submitted work. VGF reports personal Fees from Novartis, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines, Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Basilea, Affinergy, Janssen, xBiotech, Contrafect, Regeneron, Basilea, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, and Aridis; grants to his institution from the NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Basilea, and Janssen; educational fees from Green Cross, Cubist, Cerexa, Durata, Theravance, and Debiopharm; royalties from UpToDate; and stock options in Valanbio. CAA is employed at the University of Texas Health Science Center in Houston, TX, USA; declares money paid to the University of Texas as part of a grant from Merck, MeMed Diagnostics, Entasis Therapeutics, and the ARLG of the NIH and the NIAID (UM1AI104681); reports royalties paid as personal fees from UptoDate (Harrison Principles of Internal Medicine and Mandell Principles and Practice of Infectious Diseases); reports personal fees from the NIH and the NIAID for being a study section member and grant reviewer; reports an editor-in-chief stipend from the American Society for Microbiology for Antimicrobial Agents and Chemotherapy; reports reimbursement for travel to Infectious Disease Week and Infectious Disease programme committee meetings as Infectious Disease chair from the Infectious Disease Society of America; and reports reimbursement for traveling to the American Society for Microbiology Microbe conference from the American Society for Microbiology. DvD reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; is a consultant for Actavis, Tetraphase, Sanofi Pasteur, MedImmune, Astellas, Merck, Allergan, T2Biosystems, Roche, Achaogen, Neumedicine, Shionogi, Pfizer, Entasis, QPex, Wellspring, Karius, and Utility; receives an editor's stipend from the British Society for Antimicrobial Chemotherapy; and reports grants from the NIH, outside the submitted work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Carbapenem-resistant Enterobacterales (CRE) pose a significant threat to global public health. The most important mechanism for carbapenem resistance is the production of carbapenemases. Klebsiella pneumoniae carbapenemase (KPC) represents one of the main carbapenemases worldwide. Complex mechanisms of bla KPC dissemination have been reported in Colombia, a country with a high endemicity of carbapenem resistance. Here, we characterized the dynamics of dissemination of bla KPC gene among CRE infecting and colonizing patients in three hospitals localized in a highly endemic area of Colombia (2013 and 2015). We identified the genomic characteristics of KPC-producing Enterobacterales recovered from patients infected/colonized and reconstructed the dynamics of dissemination of bla KPC-2 using both short and long read sequencing. We found that spread of bla KPC-2 among Enterobacterales in the participating hospitals was due to intra- and interspecies horizontal gene transfer (HGT) mediated by promiscuous plasmids associated with transposable elements that was originated from a multispecies outbreak of KPC-producing Enterobacterales in a neonatal intensive care unit. The plasmids were detected in isolates recovered in other units within the same hospital and nearby hospitals. The gene "epidemic" was driven by IncN-pST15-type plasmids carrying a novel Tn 4401 b structure and non-Tn 4401 elements (NTE KPC ) in Klebsiella spp., Escherichia coli , Enterobacter spp., and Citrobacter spp. Of note, mcr-9 was found to coexist with bla KPC-2 in species of the Enterobacter cloacae complex. Our findings suggest that the main mechanism for dissemination of bla KPC-2 is HGT mediated by highly transferable plasmids among species of Enterobacterales in infected/colonized patients, presenting a major challenge for public health interventions in developing countries such as Colombia., (Copyright © 2020 American Society for Microbiology.)

Background: Carbapenem resistance is a critical healthcare challenge worldwide. Particularly concerning is the widespread dissemination of Klebsiella pneumoniae carbapenemase (KPC). Klebsiella pneumoniae harboring blaKPC (KPC-Kpn) is endemic in many areas including the United States, where the epidemic was primarily mediated by the clonal dissemination of Kpn ST258. We postulated that the spread of blaKPC in other regions occurs by different and more complex mechanisms. To test this, we investigated the evolution and dynamics of spread of KPC-Kpn in Colombia, where KPC became rapidly endemic after emerging in 2005., Methods: We sequenced the genomes of 133 clinical isolates recovered from 24 tertiary care hospitals located in 10 cities throughout Colombia, between 2002 (before the emergence of KPC-Kpn) and 2014. Phylogenetic reconstructions and evolutionary mapping were performed to determine temporal and genetic associations between the isolates., Results: Our results indicate that the start of the epidemic was driven by horizontal dissemination of mobile genetic elements carrying blaKPC-2, followed by the introduction and subsequent spread of clonal group 258 (CG258) isolates containing blaKPC-3., Conclusions: The combination of 2 evolutionary mechanisms of KPC-Kpn within a challenged health system of a developing country created the "perfect storm" for sustained endemicity of these multidrug-resistant organisms in Colombia., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

The association between persistent gram-negative bloodstream infection (GN-BSI), or ongoing positive cultures, and recurrent GN-BSI has not been investigated. Among 992 adults, persistent GN-BSI was associated with increased recurrent GN-BSI with the same bacterial species and strain (6% vs 2%; P =.04). Persistent GN-BSI may be a marker of complicated infection. [ABSTRACT FROM AUTHOR]

Background: Carbapenem resistance is a critical healthcare challenge worldwide. Particularly concerning is the widespread dissemination of Klebsiella pneumoniae carbapenemase (KPC). Klebsiella pneumoniae harboring blaKPC (KPC-Kpn) is endemic in many areas including the United States, where the epidemic was primarily mediated by the clonal dissemination of Kpn ST258. We postulated that the spread of blaKPC in other regions occurs by different and more complex mechanisms. To test this, we investigated the evolution and dynamics of spread of KPC-Kpn in Colombia, where KPC became rapidly endemic after emerging in 2005.Methods: We sequenced the genomes of 133 clinical isolates recovered from 24 tertiary care hospitals located in 10 cities throughout Colombia, between 2002 (before the emergence of KPC-Kpn) and 2014. Phylogenetic reconstructions and evolutionary mapping were performed to determine temporal and genetic associations between the isolates.Results: Our results indicate that the start of the epidemic was driven by horizontal dissemination of mobile genetic elements carrying blaKPC-2, followed by the introduction and subsequent spread of clonal group 258 (CG258) isolates containing blaKPC-3.Conclusions: The combination of 2 evolutionary mechanisms of KPC-Kpn within a challenged health system of a developing country created the "perfect storm" for sustained endemicity of these multidrug-resistant organisms in Colombia. [ABSTRACT FROM AUTHOR]