scholarly journals CRISPR-Cas9-Mediated Carbapenemase Gene and Plasmid Curing in Carbapenem-Resistant Enterobacteriaceae

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Mingju Hao ◽  
Yuzhang He ◽  
Haifang Zhang ◽  
Xiao-Ping Liao ◽  
Ya-Hong Liu ◽  
...  
Keyword(s):  
Clinical Intervention ◽  
Carbapenem Resistance ◽  
Plasmid Curing ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Fold Reduction ◽  
Carbapenemase Gene ◽  
Enterobacter Hormaechei ◽  
Generation Sequencing ◽  
Carbapenem Resistant Enterobacteriaceae

ABSTRACT Combating plasmid-mediated carbapenem resistance is essential to control and prevent the dissemination of carbapenem-resistant Enterobacteriaceae (CRE). Here, we conducted a proof-of-concept study to demonstrate that CRISPR-Cas9-mediated resistance gene and plasmid curing can effectively resensitize CRE to carbapenems. A novel CRISPR-Cas9-mediated plasmid-curing system (pCasCure) was developed and electrotransferred into various clinical CRE isolates. The results showed that pCasCure can effectively cure blaKPC, blaNDM, and blaOXA-48 in various Enterobacteriaceae species of Klebsiella pneumoniae, Escherichia coli, Enterobacter hormaechei, Enterobacter xiangfangensis, and Serratia marcescens clinical isolates, with a >94% curing efficiency. In addition, we also demonstrated that pCasCure can efficiently eliminate several epidemic carbapenem-resistant plasmids, including the blaKPC-harboring IncFIIK-pKpQIL and IncN pKp58_N plasmids, the blaOXA-48-harboring pOXA-48-like plasmid, and the blaNDM-harboring IncX3 plasmid, by targeting their replication and partitioning (parA in pKpQIL) genes. However, curing the blaOXA-48 gene failed to eliminate its corresponding pOXA-48-like plasmid in clinical K. pneumoniae isolate 49210, while further next-generation sequencing revealed that it was due to IS1R-mediated recombination outside the CRISPR-Cas9 cleavage site resulting in blaOXA-48 truncation and, therefore, escaped plasmid curing. Nevertheless, the curing of carbapenemase genes or plasmids, including the truncation of blaOXA-48 in 49210, successfully restore their susceptibility to carbapenems, with a >8-fold reduction of MIC values in all tested isolates. Taken together, our study confirmed the concept of using CRISPR-Cas9-mediated carbapenemase gene and plasmid curing to resensitize CRE to carbapenems. Further work is needed to integrate pCasCure in an optimal delivery system to make it applicable for clinical intervention.

scholarly journals High-Level Carbapenem Resistance in OXA-232-Producing Raoultella ornithinolytica Triggered by Ertapenem Therapy

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
Alina Iovleva ◽  
Roberta T. Mettus ◽  
Christi L. McElheny ◽  
Marissa P. Griffith ◽  
Mustapha M. Mustapha ◽  
...  
Keyword(s):  
Rapid Development ◽  
Carbapenem Resistance ◽  
Resistant Isolate ◽  
Clinical Microbiology Laboratory ◽  
Loss Of Function ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Class D ◽  
Fold Reduction ◽  
High Level

ABSTRACT OXA-232 is an OXA-48-group class D β-lactamase that hydrolyzes expanded-spectrum cephalosporins and carbapenems at low levels. Clinical strains producing OXA-232 are sometimes susceptible to carbapenems, making it difficult to identify them in the clinical microbiology laboratory. We describe the development of carbapenem resistance in sequential clinical isolates of Raoultella ornithinolytica carrying blaOXA-232 in a hospitalized patient, where the ertapenem MIC increased from 0.5 μg/ml to 512 μg/ml and the meropenem MIC increased from 0.125 μg/ml to 32 μg/ml during the course of ertapenem therapy. Whole-genome sequencing (WGS) analysis identified loss-of-function mutations in ompC and ompF in carbapenem-resistant isolates that were not present in the initial carbapenem-susceptible isolate. Complementation of a carbapenem-resistant isolate with an intact ompF gene resulted in 16- to 32-fold reductions in carbapenem MICs, whereas complementation with intact ompC resulted in a 2-fold reduction in carbapenem MICs. Additionally, blaOXA-232 expression increased 2.9-fold in a carbapenem-resistant isolate. Rapid development of high-level carbapenem resistance in initially carbapenem-susceptible OXA-232-producing R. ornithinolytica under selective pressure from carbapenem therapy highlights the diagnostic challenges in detecting Enterobacteriaceae strains producing this inefficient carbapenemase.

scholarly journals Plasmidome analysis of carbapenem-resistant Enterobacteriaceae isolated in Vietnam

2020 ◽  
Author(s):  
Aki Hirabayashi ◽  
Koji Yahara ◽  
Satomi Mitsuhashi ◽  
So Nakagawa ◽  
Tadashi Imanishi ◽  
...  
Keyword(s):  
Carbapenem Resistance ◽  
Genomic Epidemiology ◽  
Carbapenem Resistant ◽  
Oxford Nanopore ◽  
Carbapenemase Gene ◽  
Long Read ◽  
Severe Infections ◽  
Oxford Nanopore Technologies ◽  
Carbapenem Resistant Enterobacteriaceae

Carbapenem-resistant Enterobacteriaceae (CRE) represent a serious threat to public health due to limited management of severe infections and high mortality. The rate of resistance of Enterobacteriaceae isolates to major antimicrobials, including carbapenems, is much higher in Vietnam than in Western countries, but the reasons remain unknown due to the lack of genomic epidemiology research. A previous study suggested that carbapenem resistance genes, such as the carbapenemase gene bla NDM-1 , spread via plasmids among Enterobacteriaceae in Vietnam. In this study, we performed detection and molecular characterization of bla NDM-1 -carrying plasmids in CRE isolated in Vietnam, and identified several possible cases of horizontal transfer of plasmids both within and among species of bacteria. Twenty-five carbapenem-resistant isolates from Enterobacteriaceae clinically isolated in a reference medical institution in Hanoi were sequenced on Illumina short-read sequencers, and 12 isolates harboring bla NDM-1 were sequenced on an Oxford Nanopore Technologies long-read sequencer to obtain complete plasmid sequences. Most of the plasmids co-carried genes conferring resistance to clinically relevant antimicrobials, including third-generation cephalosporins, aminoglycosides, and fluoroquinolones, in addition to bla NDM-1 , leading to multidrug resistance of their bacterial hosts. These results provide insight into the genetic basis of CRE in Vietnam, and could help control nosocomial infections.

scholarly journals Co-occurrence of Plasmid-Mediated Tigecycline and Carbapenem Resistance in Acinetobacter spp. from Waterfowls and Their Neighboring Environment

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Chao-Yue Cui ◽  
Chong Chen ◽  
Bao-Tao Liu ◽  
Qian He ◽  
Xiao-Ting Wu ◽  
...  
Keyword(s):  
Sequence Comparison ◽  
Resistance Mechanism ◽  
Carbapenem Resistance ◽  
Multidrug Resistant ◽  
Inverse Pcr ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Carbapenemase Gene ◽  
Acinetobacter Spp ◽  
Plasmid Backbone

ABSTRACT Tigecycline serves as one of the antibiotics of last resort to treat multidrug-resistant (including carbapenem-resistant) pathogens. However, the recently emerged plasmid-mediated tigecycline resistance mechanism, Tet(X), challenges the clinical efficacy of this class of antibiotics. In this study, we detected 180 tet(X)-harboring Acinetobacter isolates (8.9%, n = 180) from 2,018 samples collected from avian farms and adjacent environments in China. Eighteen tet(X)-harboring isolates (10.0%) were found to cocarry the carbapenemase gene blaNDM-1, mostly from waterfowl samples (94.4%, 17/18). Interestingly, among six Acinetobacter strains, tet(X) and blaNDM-1 were found to colocalize on the same plasmids. Moreover, whole-genome sequencing (WGS) revealed a novel orthologue of tet(X) in the six isolates coharboring tet(X) and blaNDM-1. Inverse PCR suggested that the two tet(X) genes form a single transposable unit and may be cotransferred. Sequence comparison between six tet(X)- and blaNDM-1-coharboring plasmids showed that they shared a highly homologous plasmid backbone even though they were isolated from different Acinetobacter species (three from Acinetobacter indicus, two from Acinetobacter schindleri, and one from Acinetobacter lwoffii) from various sources and from different geological regions, suggesting the horizontal genetic transfer of a common tet(X)- and blaNDM-1-coharboring plasmid among Acinetobacter species in China. Emergence and spread of such plasmids and strains are of great clinical concern, and measures must be implemented to avoid their dissemination.

scholarly journals Complete Nucleotide Sequence of the IncN Plasmid Encoding IMP-6 and CTX-M-2 from Emerging Carbapenem-Resistant Enterobacteriaceae in Japan

2014 ◽  
Vol 59 (2) ◽  
pp. 1356-1359 ◽  
Author(s):  
Shizuo Kayama ◽  
Norifumi Shigemoto ◽  
Ryuichi Kuwahara ◽  
Kenshiro Oshima ◽  
Hideki Hirakawa ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Nucleotide Sequence ◽  
Klebsiella Pneumoniae ◽  
Dna Sequence ◽  
Complete Nucleotide Sequence ◽  
Carbapenem Resistance ◽  
Content Type ◽  
Carbapenem Resistant ◽  
The Family ◽  
Carbapenem Resistant Enterobacteriaceae

ABSTRACTWe have determined the DNA sequence ofKlebsiella pneumoniaemultidrug resistance plasmid pKPI-6, which is a self-transmissible IncN-type plasmid. pKPI-6 harboringblaIMP-6andblaCTX-M-2confers a stealth-type carbapenem resistance phenotype on members of the familyEnterobacteriaceaethat is not detectable with imipenem. pKPI-6 is already epidemic in Japan, favoring the dissemination of IMP-6 and CTX-M-2 in members of the familyEnterobacteriaceae.

scholarly journals Diverse Mechanisms of Resistance in Carbapenem-Resistant Enterobacteriaceae at a Health Care System in Silicon Valley, California

2018 ◽  
Author(s):  
Fiona Senchyna ◽  
Rajiv Gaur ◽  
Johanna Sandlund ◽  
Cynthia Truong ◽  
Guillaume Tremintin ◽  
...  
Keyword(s):  
Health System ◽  
Silicon Valley ◽  
Carbapenem Resistance ◽  
Gene Encoding ◽  
Major Health ◽  
Mechanism Of Resistance ◽  
Carbapenem Resistant ◽  
Carbapenemase Gene ◽  
Underlying Mechanisms ◽  
Carbapenem Resistant Enterobacteriaceae

AbstractCarbapenem-resistant Enterobacteriaceae (CRE) are emerging as a major health threat in North America. The mechanism of resistance to carbapenems has therapeutic and public health implications. We comprehensively characterized the underlying mechanisms of carbapenem resistance in CRE isolates recovered between 2013 and 2016 at a health system in Northern California. Genotypic methods were used to detect carbapenemases and plasmid-encoded cephalosporinases, and mass spectrometry was used to quantify relative porin levels for OmpC and OmpF and their analogs. MICs for imipenem-relebactam, meropenem-vaborbactam, ceftazidime-avibactam, and ceftolozane-tazobactam were measured. Whole genome sequencing was used for strain typing. A carbapenemase gene encoding blaOXA-48 like, blaNDM, blaKPC, blaSME, blaIMP, and blaVIM was detected in 38.7% (24/62) of CRE isolates. Porin levels was down at least 2-fold in 91.9% (57/62) of isolates. Including carbapenemase genes and porin loss, the mechanism of resistance was identified in 95.2% (59/62) of CRE isolates. Of the carbapenemase gene-positive isolates, blaKPC -positive isolates were 100% susceptible to ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam; blaOXA-48 like-positive isolates were 100% susceptible to ceftazidime-avibactam; and blaSME-positive isolates were 100% susceptible to meropenem-vaborbactam and ceftolozane-tazobactam. 100% (38/38), 92.1% (35/38), 89.5% (34/38), and 31.6% (12/38) of carbapenemase gene-negative CRE isolates were susceptible to ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, and ceftolozane-tazobactam, respectively. None of the CRE strains were genetically identical. In conclusion, at this health system in Silicon Valley, carbapenemase-producing CRE occurred sporadically and were mediated by diverse mechanisms. Nucleic acid testing for blaOXA-48 like, blaNDM, blaKPC, blaIMP, and blaVIM was sufficient to distinguish between carbapenemase-producing and non-producing CRE and accurately predicted susceptibility to ceftazidime-avibactam, meropenem-vaborbactam and imipenem-relebactam.

scholarly journals Antecedent Carbapenem Exposure as a Risk Factor for Non-Carbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae and Carbapenemase-Producing Enterobacteriaceae

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Kalisvar Marimuthu ◽  
Oon Tek Ng ◽  
Benjamin Pei Zhi Cherng ◽  
Raymond Kok Choon Fong ◽  
Surinder Kaur Pada ◽  
...  
Keyword(s):  
Risk Factor ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
First Episode ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Carbapenemase Gene ◽  
Antibiotic Selection Pressure ◽  
Phenotypic Tests ◽  
Carbapenem Resistant Enterobacteriaceae

ABSTRACT Carbapenem-resistant Enterobacteriaceae (CRE) can be mechanistically classified into carbapenemase-producing Enterobacteriaceae (CPE) and non-carbapenemase-producing carbapenem nonsusceptible Enterobacteriaceae (NCPCRE). We sought to investigate the effect of antecedent carbapenem exposure as a risk factor for NCPCRE versus CPE. Among all patients with CRE colonization and infection, we conducted a case-control study comparing patients with NCPCRE (cases) and patients with CPE (controls). The presence of carbapenemases was investigated with phenotypic tests followed by PCR for predominant carbapenemase genes. We included 843 unique patients with first-episode CRE, including 387 (45.9%) NCPCRE and 456 (54.1%) CPE. The resistance genes detected in CPEs were blaNDM (42.8%), blaKPC (38.4%), and blaOXA-48-like (12.1%). After adjusting for confounders and clustering at the institutional level, the odds of prior 30-day carbapenem exposure was three times higher among NCPCRE than CPE patients (adjusted odds ratio [aOR], 3.48; 95% confidence interval [CI], 2.39 to 5.09; P < 0.001). The odds of prior carbapenem exposure and NCPCRE detection persisted in stratified analyses by Enterobacteriaceae species (Klebsiella pneumoniae and Escherichia coli) and carbapenemase gene (blaNDM and blaKPC). CPE was associated with male gender (aOR, 1.45; 95% CI, 1.07 to 1.97; P = 0.02), intensive care unit stay (aOR, 1.84; 95% CI, 1.24 to 2.74; P = 0.003), and hospitalization in the preceding 1 year (aOR, 1.42; 95% CI, 1.01 to 2.02; P = 0.05). In a large nationwide study, antecedent carbapenem exposure was a significant risk factor for NCPCRE versus CPE, suggesting a differential effect of antibiotic selection pressure.

scholarly journals Discovery of a Novel Metallo-β-Lactamase Inhibitor That Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacteriaceae

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Martin Everett ◽  
Nicolas Sprynski ◽  
Alicia Coelho ◽  
Jérôme Castandet ◽  
Maëlle Bayet ◽  
...  
Keyword(s):  
Carbapenem Resistance ◽  
New Drugs ◽  
Infection Model ◽  
Asian Countries ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Medical Need ◽  
Starting Point ◽  
Lactamase Inhibitor ◽  
Carbapenem Resistant Enterobacteriaceae

ABSTRACT Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent and have become a major worldwide threat to human health. Carbapenem resistance is driven primarily by the acquisition of β-lactamase enzymes, which are able to degrade carbapenem antibiotics (hence termed carbapenemases) and result in high levels of resistance and treatment failure. Clinically relevant carbapenemases include both serine β-lactamases (SBLs; e.g., KPC-2 and OXA-48) and metallo-β-lactamases (MBLs), such as NDM-1. MBL-producing strains are endemic within the community in many Asian countries, have successfully spread worldwide, and account for many significant CRE outbreaks. Recently approved combinations of β-lactam antibiotics with β-lactamase inhibitors are active only against SBL-producing pathogens. Therefore, new drugs that specifically target MBLs and which restore carbapenem efficacy against MBL-producing CRE pathogens are urgently needed. Here we report the discovery of a novel MBL inhibitor, ANT431, that can potentiate the activity of meropenem (MEM) against a broad range of MBL-producing CRE and restore its efficacy against an Escherichia coli NDM-1-producing strain in a murine thigh infection model. This is a strong starting point for a chemistry lead optimization program that could deliver a first-in-class MBL inhibitor-carbapenem combination. This would complement the existing weaponry against CRE and address an important and growing unmet medical need.

The prevalence of carbapenemase genes and plasmid-mediated quinolone resistance determinants in carbapenem-resistant Enterobacteriaceae from five teaching hospitals in central China

2013 ◽  
Vol 142 (9) ◽  
pp. 1972-1977 ◽  
Author(s):  
L. HU ◽  
Q. ZHONG ◽  
Y. SHANG ◽  
H. WANG ◽  
C. NING ◽  
...  
Keyword(s):  
Klebsiella Oxytoca ◽  
Carbapenem Resistance ◽  
Quinolone Resistance ◽  
Central China ◽  
Teaching Hospitals ◽  
Resistance Determinants ◽  
Carbapenem Resistant ◽  
Carbapenemase Gene ◽  
High Prevalence ◽  
Carbapenem Resistant Enterobacteriaceae

SUMMARYWe investigated the prevalence of β-lactamase genes and plasmid-mediated quinolone resistance (PMQR) determinants in 51 carbapenem-resistant Enterobacteriaceae (CRE) from five teaching hospitals in central China. The prevalence of carbapenem resistance in Enterobacteriaceae was 1·0% (51/5012). Of 51 CRE, 31 (60·8%) isolates were positive for one tested carbapenemase gene, while 10 (19·6%) were simultaneously positive for two tested carbapenemase genes. The positive rates of blaKPC-2, blaNDM-1, blaIMP-4, blaIMP-26 and blaIMP-8 were 54·9%, 17·6%, 11·8%, 11·8% and 3·9%, respectively. Of 10 CRE with two carbapenemase genes, three, five, one and one were positive for blaKPC-2 and blaIMP-4, blaKPC-2 and blaIMP-26, blaKPC-2 and blaIMP-8, and blaKPC-2 and blaNDM-1, respectively. Eight of nine blaNDM-1-positive isolates lacked carbapenemases by the modified Hodge test, while 27/28 isolates harbouring blaKPC-2 were positive for carbapenemases determined by this test; 41·2% of the CRE-positive isolates also harboured ESBL genes in various combinations (three and two positive for blaKPC-2 also carried blaDHA-1 and blaCMY-2). The positive rates of qnrS1, qnrA1, qnrB and aac-(6/)-Ib-cr in CRE were 25·5%, 9·8%, 23·5% and 15·7%, respectively. In particular, 7/9 isolates harbouring blaNDM-1 were positive for these quinolone resistance genes, of which five carried qnrS1 and two carried qnrS1 and qnrB4. All but two of 29 Klebsiella pneumoniae isolates were grouped into 20 clonal clusters by PFGE, with the predominant cluster accounting for four blaKPC-2-positive isolates distributed in the same hospital. We conclude that there is a high prevalence of blaNDM-1 and PMQR determinants in CRE isolates in central China. Multiple resistance determinants in various combinations co-exist in these strains and we report for the first time the co-existence of blaKPC-2 and blaIMP-26 in a strain of Klebsiella oxytoca.

scholarly journals Phenotypic Detection of Carbapenemase Production in Carbapenem-Resistant Enterobacteriaceae by Modified Hodge Test and Modified Strip Carba NP Test

2021 ◽  
Author(s):  
Nisha Patidar ◽  
Nitya Vyas ◽  
Shanoo Sharma ◽  
Babita Sharma
Keyword(s):  
Carbapenem Resistance ◽  
Nonparametric Test ◽  
Multidrug Resistant ◽  
Clinical Samples ◽  
Chi Square ◽  
Carbapenem Resistant ◽  
The Social ◽  
Significant Difference ◽  
High Degree ◽  
Carbapenem Resistant Enterobacteriaceae

Abstract Objective Carbapenems are last resort antibiotics for multidrug-resistant Enterobacteriaceae. However, resistance to carbapenem is increasing at an alarming rate worldwide leading to major therapeutic failures and increased mortality rate. Early and effective detection of carbapenemase producing carbapenem-resistant Enterobacteriaceae (CRE) is therefore key to control dissemination of carbapenem resistance in nosocomial as well as community-acquired infection. The aim of present study was to evaluate efficacy of Modified strip Carba NP (CNP) test against Modified Hodge test (MHT) for early detection of carbapenemase producing Enterobacteriaceae (CPE). Material and Methods Enterobacteriaceae isolated from various clinical samples were screened for carbapenem resistance. A total of 107 CRE were subjected to MHT and Modified strip CNP test for the detection of CPE. Statistical Analysis It was done on Statistical Package for the Social Sciences (SPSS) software, IBM India; version V26. Nonparametric test chi-square and Z-test were used to analyze the results within a 95% level of confidence. Results Out of 107 CRE, 94 (88%) were phenotypically confirmed as carbapenemase producer by Modified strip CNP test and 46 (43%) were confirmed by Modified Hodge Test (MHT). Thirty-eight (36%) isolates showed carbapenemase production by both MHT and CNP test, 56 isolates (52%) were CNP test positive but MHT negative, eight (7%) isolates were MHT positive but CNP test negative and five (5%) isolates were both MHT and CNP test negative. There is statistically significant difference in efficiency of Modified CNP test and MHT (p < 0.05). Conclusion Modified strip CNP test is simple and inexpensive test which is easy to perform and interpret and gives rapid results in less than 5 minutes. It has high degree of sensitivity and specificity. Modified strip CNP test shows significantly higher detection capacity for carbapenemase producers as compared with MHT.

scholarly journals Multicenter Clinical and Molecular Epidemiological Analysis of Bacteremia Due to Carbapenem-Resistant Enterobacteriaceae (CRE) in the CRE Epicenter of the United States

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Michael J. Satlin ◽  
Liang Chen ◽  
Gopi Patel ◽  
Angela Gomez-Simmonds ◽  
Gregory Weston ◽  
...  
Keyword(s):  
New York ◽  
Empirical Therapy ◽  
Carbapenem Resistance ◽  
The United States ◽  
Resistance Mechanisms ◽  
Rapid Diagnostics ◽  
Multicenter Studies ◽  
Content Type ◽  
Medical Centers ◽  
Carbapenem Resistant

ABSTRACT Although the New York/New Jersey (NY/NJ) area is an epicenter for carbapenem-resistant Enterobacteriaceae (CRE), there are few multicenter studies of CRE from this region. We characterized patients with CRE bacteremia in 2013 at eight NY/NJ medical centers and determined the prevalence of carbapenem resistance among Enterobacteriaceae bloodstream isolates and CRE resistance mechanisms, genetic backgrounds, capsular types (cps), and antimicrobial susceptibilities. Of 121 patients with CRE bacteremia, 50% had cancer or had undergone transplantation. The prevalences of carbapenem resistance among Klebsiella pneumoniae, Enterobacter spp., and Escherichia coli bacteremias were 9.7%, 2.2%, and 0.1%, respectively. Ninety percent of CRE were K. pneumoniae and 92% produced K. pneumoniae carbapenemase (KPC-3, 48%; KPC-2, 44%). Two CRE produced NDM-1 and OXA-48 carbapenemases. Sequence type 258 (ST258) predominated among KPC-producing K. pneumoniae (KPC-Kp). The wzi154 allele, corresponding to cps-2, was present in 93% of KPC-3-Kp, whereas KPC-2-Kp had greater cps diversity. Ninety-nine percent of CRE were ceftazidime-avibactam (CAZ-AVI)-susceptible, although 42% of KPC-3-Kp had an CAZ-AVI MIC of ≥4/4 μg/ml. There was a median of 47 h from bacteremia onset until active antimicrobial therapy, 38% of patients had septic shock, and 49% died within 30 days. KPC-3-Kp bacteremia (adjusted odds ratio [aOR], 2.58; P = 0.045), cancer (aOR, 3.61, P = 0.01), and bacteremia onset in the intensive care unit (aOR, 3.79; P = 0.03) were independently associated with mortality. Active empirical therapy and combination therapy were not associated with survival. Despite a decade of experience with CRE, patients with CRE bacteremia have protracted delays in appropriate therapies and high mortality rates, highlighting the need for rapid diagnostics and evaluation of new therapeutics.

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