scholarly journals Identifying Spectra of Activity and Therapeutic Niches for Ceftazidime-Avibactam and Imipenem-Relebactam against Carbapenem-Resistant Enterobacteriaceae

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Ghady Haidar ◽  
Cornelius J. Clancy ◽  
Liang Chen ◽  
Palash Samanta ◽  
Ryan K. Shields ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Extended Spectrum ◽  
Independent Association ◽  
Carbapenem Resistant Enterobacteriaceae

ABSTRACT We determined imipenem, imipenem-relebactam, ceftazidime, and ceftazidime-avibactam MICs against 100 CRE isolates that underwent whole-genome sequencing. Klebsiella pneumoniae carbapenemases (KPCs) were the most common carbapenemases. Forty-six isolates carried extended-spectrum β-lactamases (ESBLs). With the addition of relebactam, imipenem susceptibility increased from 8% to 88%. With the addition of avibactam, ceftazidime susceptibility increased from 0% to 85%. Neither imipenem-relebactam nor ceftazidime-avibactam was active against metallo-β-lactamase (MBL) producers. Ceftazidime-avibactam (but not imipenem-relebactam) was active against OXA-48-like producers, including a strain not harboring any ESBL. Major OmpK36 porin mutations were independently associated with higher imipenem-relebactam MICs (P < 0.0001) and showed a trend toward independent association with higher ceftazidime-avibactam MICs (P = 0.07). The presence of variant KPC-3 was associated with ceftazidime-avibactam resistance (P < 0.0001). In conclusion, imipenem-relebactam and ceftazidime-avibactam had overlapping spectra of activity and niches in which each was superior. Major OmpK36 mutations in KPC-K. pneumoniae may provide a foundation for stepwise emergence of imipenem-relebactam and ceftazidime-avibactam resistance.

scholarly journals MCR-1 and OXA-48 In Vivo Acquisition in KPC-Producing Escherichia coli after Colistin Treatment

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Racha Beyrouthy ◽  
Frederic Robin ◽  
Aude Lessene ◽  
Igor Lacombat ◽  
Laurent Dortet ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Content Type ◽  
First Report ◽  
E Coli ◽  
Carbapenem Resistant

ABSTRACT The spread of mcr-1-encoding plasmids into carbapenem-resistant Enterobacteriaceae raises concerns about the emergence of untreatable bacteria. We report the acquisition of mcr-1 in a carbapenem-resistant Escherichia coli strain after a 3-week course of colistin in a patient repatriated to France from Portugal. Whole-genome sequencing revealed that the Klebsiella pneumoniae carbapenemase-producing E. coli strain acquired two plasmids, an IncL OXA-48-encoding plasmid and an IncX4 mcr-1-encoding plasmid. This is the first report of mcr-1 in carbapenemase-encoding bacteria in France.

scholarly journals Whole-Genome Sequencing To Identify Drivers of Carbapenem-Resistant Klebsiella pneumoniae Transmission within and between Regional Long-Term Acute-Care Hospitals

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Jennifer H. Han ◽  
Zena Lapp ◽  
Frederic Bushman ◽  
Ebbing Lautenbach ◽  
Ellie J. C. Goldstein ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Treatment Options ◽  
Health Care Facilities ◽  
Resistant Organism ◽  
Whole Genome ◽  
Content Type ◽  
Transmission Rates ◽  
Carbapenem Resistant

ABSTRACT Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an antibiotic resistance threat of the highest priority. Given the limited treatment options for this multidrug-resistant organism (MDRO), there is an urgent need for targeted strategies to prevent transmission. Here, we applied whole-genome sequencing to a comprehensive collection of clinical isolates to reconstruct regional transmission pathways and analyzed this transmission network in the context of statewide patient transfer data and patient-level clinical data to identify drivers of regional transmission. We found that high regional CRKP burdens were due to a small number of regional introductions, with subsequent regional proliferation occurring via patient transfers among health care facilities. While CRKP was predicted to have been imported into each facility multiple times, there was substantial variation in the ratio of intrafacility transmission events per importation, indicating that amplification occurs unevenly across regional facilities. While myriad factors likely influence intrafacility transmission rates, an understudied one is the potential for clinical characteristics of colonized and infected patients to influence their propensity for transmission. Supporting the contribution of high-risk patients to elevated transmission rates, we observed that patients colonized and infected with CRKP in high-transmission facilities had higher rates of carbapenem use, malnutrition, and dialysis and were older. This report highlights the potential for regional infection prevention efforts that are grounded in genomic epidemiology to identify the patients and facilities that make the greatest contribution to regional MDRO prevalence, thereby facilitating the design of precision interventions of maximal impact.

scholarly journals Whole Genome Sequencing detects Inter-Facility Transmission of Carbapenem-resistant Klebsiella pneumoniae

2019 ◽  
Vol 78 (3) ◽  
pp. 187-199 ◽  
Author(s):  
Melanie D. Spencer ◽  
Kathryn Winglee ◽  
Catherine Passaretti ◽  
Ashlee M. Earl ◽  
Abigail L. Manson ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Carbapenem Resistant

scholarly journals 677. Activity of Novel β-Lactamase Inhibitor QPX7728 Combined with β-Lactam Agents When Tested Against Carbapenem-Resistant Enterobacteriaceae (CRE) Isolates

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S309-S309 ◽  
Author(s):  
Mariana Castanheira ◽  
Jill Lindley ◽  
Holly Huynh ◽  
Rodrigo E Mendes ◽  
Olga Lomovskaya
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Inhibitory Activity ◽  
Multidrug Resistant ◽  
Whole Genome ◽  
Broth Microdilution ◽  
Carbapenem Resistant ◽  
Further Development ◽  
Lactamase Inhibitor ◽  
Carbapenem Resistant Enterobacteriaceae

Abstract Background CREs have been described worldwide and these isolates are often multidrug resistant with few therapeutic options remaining active against them. New β-lactam (BL)/β-lactamase inhibitor (BLI) combinations recently approved are active against KPC and some OXA-48 producers, but not against isolates producing metallo-β-lactamases (MBLs). We evaluated the activity of QPX7728 (QPX), a novel BLI paired with various BLs against a collection of CRE isolates characterized for the presence of carbapenemases. Methods A total of 508 CRE clinical isolates were susceptibility (S) tested by reference broth microdilution methods against meropenem (MER), tebipenem (TEB), cefepime (FEP), ceftolozane (TOL), and ertapenem (ETP), and meropenem (MEM) combined with QPX at fixed 2, 4, and 8 mg/L. Agents were provided by Qpex Biopharma except for FEP, ETP, and MEM. Carbapenemases were detected using PCR/sequencing or whole-genome sequencing. Results All BLs had limited activity against CRE isolates (MIC50/90, ≥32/ >32 mg/L) and QPX lowered the MIC for all agents (figure). Against 157 isolates carrying serine-carbapenemase (SCarb) genes (153 KPC-producers), MEM or ETP plus QPX at fixed 4 or 8 mg/L displayed MIC50 at ≤ 0.03 mg/L and MIC90 ranging from 0.12 to 0.5 mg/L. QPX lowered the FEP or TOL MIC50 to ≤ 0.25 mg/L and MIC90 to 0.25, 0.5 or 1 mg/L depending on the BLI concentration. Over 98.0% of the 150 isolates harboring OXA-48-like genes were inhibited by FEP, TOL, ETP or MEM plus QPX at ≤2 mg/L. Similarly, MEM, FEP, TOL and ETP + QPX inhibited >98.0% of the 51 CREs that did not carry carbapenemases at ≤2 mg/L when using a higher BLI concentration. The activity of FEP (MIC50/90, 0.06/1 mg/L), ETP (MIC50/90, 0.03/4 mg/L), and MEM (MIC50/90, ≤ 0.015/2 mg/L) was mostly restored when 8 mg/L of QPX was combined with these agents and tested against 150 MBL-producing isolates. Conclusion QPX restored the activity of several BLs when tested against 508 CRE isolates that include 157 harboring SCarb, 150 OXA-48-like-producers, and 150 MBL-producing isolates. Further development of this BLI with inhibitory activity against all carbapenemase types seems warranted. Disclosures All authors: No reported disclosures.

scholarly journals Food Workers as a Reservoir of Extended-Spectrum-Cephalosporin-Resistant Salmonella Strains in Japan

2020 ◽  
Vol 86 (13) ◽  
Author(s):  
Hiroaki Shigemura ◽  
Eri Sakatsume ◽  
Tsuyoshi Sekizuka ◽  
Hiroshi Yokoyama ◽  
Kunihiko Hamada ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Bacterial Species ◽  
Diffusion Method ◽  
Whole Genome ◽  
Disk Diffusion Method ◽  
Content Type ◽  
Extended Spectrum ◽  
Food Workers ◽  
M 14

ABSTRACT Dissemination of extended-spectrum-cephalosporin (ESC)-resistant Salmonella, especially extended-spectrum-β-lactamase (ESBL)-producing Salmonella, is a concern worldwide. Here, we assessed Salmonella carriage by food workers in Japan to clarify the prevalence of ESC-resistant Salmonella harboring blaCTX-M. We then characterized the genetic features, such as transposable elements, of blaCTX-M-harboring plasmids using whole-genome sequencing. A total of 145,220 stool samples were collected from food workers, including cooks and servers from several restaurants, as well as food factory workers, from January to October 2017. Isolated salmonellae were subjected to antimicrobial susceptibility testing (disk diffusion method), and whole-genome sequencing was performed for Salmonella strains harboring blaCTX-M. Overall, 164 Salmonella isolates (0.113%) were recovered from 164 samples, from which we estimated that at least 0.113% (95% confidence interval [CI]: 0.096 to 0.132%) of food workers may carry Salmonella. Based on this estimation, 3,473 (95% CI = 2,962 to 4,047) individuals among the 3,075,330 Japanese food workers are likely to carry Salmonella. Of the 158 culturable isolates, seven showed resistance to ESCs: three isolates harbored blaCMY-2 and produced AmpC β-lactamase, while four ESBL-producing isolates harbored blaCTX-M-14 (n = 1, Salmonella enterica serovar Senftenberg) or blaCTX-M-15 (n = 3, S. enterica serovar Haardt). blaCTX-M-15 was chromosomally located in the S. Haardt isolates, which also contained ISEcp1, while the S. Senftenberg isolate contained an IncFIA(HI1)/IncHI1A/IncHI1B(R27) hybrid plasmid carrying blaCTX-M-14 along with ISEcp1. This study indicates that food workers may be a reservoir of ESBL-producing Salmonella and associated genes. Thus, these workers may contribute to the spread of blaCTX-M via plasmids or mobile genetic elements such as ISEcp1. IMPORTANCE Antimicrobial-resistant Salmonella bacteria arise in farm environments through imprudent use of antimicrobials. Subsequently, these antimicrobial-resistant strains, such as extended-spectrum-β-lactamase (ESBL)-producing Salmonella, may be transmitted to humans via food animal-derived products. Here, we examined Salmonella carriage among food handlers in Japan. Overall, 164 of 145,220 fecal samples (0.113%) were positive for Salmonella. Among the 158 tested isolates, four were identified as ESBL-producing isolates carrying ESBL determinants blaCTX-M-15 or blaCTX-M-14. In all cases, the genes coexisted with ISEcp1, regardless of whether they were located on the chromosome or on a plasmid. Our findings suggest that food workers may be a reservoir of ESBL-producing strains and could contribute to the spread of resistance genes from farm-derived Salmonella to other bacterial species present in the human gut.

scholarly journals Whole-Genome Sequencing of Human ClinicalKlebsiella pneumoniaeIsolates Reveals Misidentification and Misunderstandings ofKlebsiella pneumoniae,Klebsiella variicola, andKlebsiella quasipneumoniae

mSphere ◽  
2017 ◽  
Vol 2 (4) ◽  
Author(s):  
S. Wesley Long ◽  
Sarah E. Linson ◽  
Matthew Ojeda Saavedra ◽  
Concepcion Cantu ◽  
James J. Davis ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Klebsiella Pneumoniae ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Clinical Microbiology ◽  
Whole Genome ◽  
Beta Lactamase ◽  
Opportunistic Pathogens ◽  
Content Type ◽  
Strain Collection

ABSTRACTKlebsiella pneumoniaeis a major threat to public health, causing significant morbidity and mortality worldwide. The emergence of highly drug-resistant strains is particularly concerning. There has been a recognition and division ofKlebsiella pneumoniaeinto three distinct phylogenetic groups:Klebsiella pneumoniae,Klebsiella variicola, andKlebsiella quasipneumoniae.K. variicolaandK. quasipneumoniaehave often been described as opportunistic pathogens that have less virulence in humans thanK. pneumoniaedoes. We recently sequenced the genomes of 1,777 extended-spectrum-beta-lactamase (ESBL)-producingK. pneumoniaeisolates recovered from human infections and discovered that 28 strains were phylogenetically related toK.variicolaandK. quasipneumoniae. Whole-genome sequencing of 95 additional non-ESBL-producingK. pneumoniaeisolates recovered from patients found 12K. quasipneumoniaestrains. Matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) analysis initially identified all patient isolates asK. pneumoniae, suggesting a potential pitfall in conventional clinical microbiology laboratory identification methods. Whole-genome sequence analysis revealed extensive sharing of core gene content and plasmid replicons among theKlebsiellaspecies. For the first time, strains of bothK. variicolaandK. quasipneumoniaewere found to carry theKlebsiella pneumoniaecarbapenemase (KPC) gene, while anotherK. variicolastrain was found to carry the New Delhi metallo-beta-lactamase 1 (NDM-1) gene.K. variicolaandK. quasipneumoniaeinfections were not less virulent thanK. pneumoniaeinfections, as assessed by in-hospital mortality and infection type. We also discovered evidence of homologous recombination in oneK. variicolastrain, as well as one strain from a novelKlebsiellaspecies, which challenge the current understanding of interrelationships between clades ofKlebsiella.IMPORTANCEKlebsiella pneumoniaeis a serious human pathogen associated with resistance to multiple antibiotics and high mortality.K. variicolaandK. quasipneumoniaeare closely related organisms that are generally considered to be less-virulent opportunistic pathogens. We used a large, comprehensive, population-based strain collection and whole-genome sequencing to investigate infections caused by these organisms in our hospital system. We discovered thatK. variicolaandK. quasipneumoniaeisolates are often misidentified asK. pneumoniaeby routine clinical microbiology diagnostics and frequently cause severe life-threatening infections similar toK. pneumoniae. The presence of KPC inK. variicolaandK. quasipneumoniaestrains as well as NDM-1 metallo-beta-lactamase in oneK. variicolastrain is particularly concerning because these genes confer resistance to many different beta-lactam antibiotics. The sharing of plasmids, as well as evidence of homologous recombination, between these three species ofKlebsiellais cause for additional concern.

Tracking the environmental dissemination of carbapenem-resistant Klebsiella pneumoniae using whole genome sequencing

2019 ◽  
Vol 691 ◽  
pp. 80-92 ◽  
Author(s):  
Mutshiene Deogratias Ekwanzala ◽  
John Barr Dewar ◽  
Ilunga Kamika ◽  
Maggy Ndombo Benteke Momba
Keyword(s):  
Klebsiella Pneumoniae ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Carbapenem Resistant
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