scholarly journals Synergistic Combination of AS101 and Azidothymidine against Clinical Isolates of Carbapenem-Resistant Klebsiella pneumoniae

Pathogens ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1552
Author(s):  
Chung-Lin Sung ◽  
Wei-Chun Hung ◽  
Po-Liang Lu ◽  
Lin Lin ◽  
Liang-Chun Wang ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Carbapenem Resistance ◽  
Antibacterial Activities ◽  
Clinical Isolates ◽  
World Health ◽  
Synergistic Activity ◽  
Antibiotic Development ◽  
Carbapenem Resistant ◽  
Health Organization ◽  
Carbapenem Resistant Enterobacteriaceae

Owing to the over usage of carbapenems, carbapenem resistance has become a vital threat worldwide, and, thus, the World Health Organization announced the carbapenem-resistant Enterobacteriaceae (CRE) as the critical priority for antibiotic development in 2017. In the current situation, combination therapy would be one solution against CRE. Azidothymidine (AZT), a thymidine analog, has demonstrated its synergistically antibacterial activities with other antibiotics. The unexpected antimicrobial activity of the immunomodulator ammonium trichloro(dioxoethylene-o,o’)tellurate (AS101) has been reported against carbapenem-resistant Klebsiella pneumoniae (CRKP). Here, we sought to investigate the synergistic activity between AS101 and AZT against 12 CRKP clinical isolates. According to the gene detection results, the blaOXA-1 (7/12, 58.3%), blaDHA (7/12, 58.3%), and blaKPC (7/12, 58.3%) genes were the most prevalent ESBL, AmpC, and carbapenemase genes, respectively. The checkerboard analysis demonstrated the remarkable synergism between AS101 and AZT, with the observable decrease in the MIC value for two agents and the fractional inhibitory concentration (FIC) index ≤0.5 in all strains. Hence, the combination of AS101 and azidothymidine could be a potential treatment option against CRKP for drug development.

scholarly journals Stepwise evolution of carbapenem-resistance, captured in patient samples and evident in global genomics of Klebsiella pneumoniae

2021 ◽  
Author(s):  
Laura Perlaza-Jimenez ◽  
Jonathan J. Wilksch ◽  
christopher J. Stubenrauch ◽  
Tao Chen ◽  
Yajie Zhao ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Efflux Pump ◽  
Carbapenem Resistance ◽  
Forensic Analysis ◽  
World Health ◽  
Beta Lactamases ◽  
Carbapenem Resistant ◽  
Large Numbers ◽  
Plasmid Genes ◽  
Health Organization

The World Health Organization ranks Klebsiella pneumoniae as a priority antimicrobial-resistant (AMR) pathogen requiring urgent study. New strategies for diagnosis and treatment, particularly for those Klebsiella that are classified as carbapenem-resistant Enterobacteriaceae (CRE) need to recognize the increased prevalence of non-carbapenemase producing CRE (non-CP CRE). By integrating diverse Klebsiella genomes with known CRE phenotypes, we successfully identified a synchronized presence of CRE phenotype-related genes in plasmids and chromosomes in comparison to strains with carbapenem susceptible phenotypes. The data revealed a major contribution to CRE comes from the combined effect of chromosome and plasmid genes potentiated by modifications of outer membrane porins. Our computational workflow identified key gene contributors to the non-CP CRE phenotype, including those that lead to an increase of antibiotic expulsion by enhanced efflux pump activity and mobile elements that reduce antibiotic intake, such as IS1 and Tn3-like elements. These findings are consistent with a new model wherein a change to the balance in drug influx and efflux potentiates the ability of some beta-lactamases to enable survival in the presence of carbapenems. Analysis of the large numbers of documented CRE infections, as well as forensic analysis of a case study, showed that this potentiation can occur in short timeframes to deliver a non-CP CRE infection. Our results suggest that the multiple genes that function to build an AMR phenotype can be diagnosed, so that strains that will resist treatment with carbapenem treatment will be evident if a comprehensive genome-based diagnostic for CRE considers all of these sequence-accessible features.

scholarly journals Detection of carbapenem-resistant Escherichia coli and Klebsiella pneumoniae producing NDM-1 in Lebanon

2012 ◽  
Vol 6 (05) ◽  
pp. 457-461 ◽  
Author(s):  
Rima I El-Herte ◽  
George F Araj ◽  
Ghassan M Matar ◽  
Maysa Baroud ◽  
Zeina A Kanafani ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Carbapenem Resistance ◽  
New Delhi ◽  
Beta Lactamase ◽  
The Novel ◽  
First Report ◽  
Carbapenem Resistant ◽  
Lactamase Gene ◽  
Carbapenem Resistant Enterobacteriaceae

Carbapenem resistance has been encountered globally with poor outcome of infected patients. NDM-1 (New Delhi metallo-beta-lactamase) gene containing organisms have emerged and are now spreading in all continents. This is the first report of Iraqi patients referred to Lebanon from whom carbapenem resistant Enterobacteriaceae were recovered. The genes involved in carbapenem resistance were bla-OXA-48   and the novel NDM-1. This report highlights the alarming introduction of such resistance among Enterobacteriaecae to this country.

Risk Factors and Molecular Epidemiology of Complicated Intra-Abdominal Infections With Carbapenem-Resistant Enterobacteriaceae: A Multicenter Study in China

2020 ◽  
Vol 221 (Supplement_2) ◽  
pp. S156-S163 ◽  
Author(s):  
Jiao Liu ◽  
Lidi Zhang ◽  
Jingye Pan ◽  
Man Huang ◽  
Yingchuan Li ◽  
...  
Keyword(s):  
Risk Factors ◽  
Klebsiella Pneumoniae ◽  
Hospital Mortality ◽  
Molecular Epidemiology ◽  
Carbapenem Resistance ◽  
Resistance Mechanisms ◽  
Carbapenem Resistant ◽  
Abdominal Infections ◽  
Hospital Acquired ◽  
Carbapenem Resistant Enterobacteriaceae

Abstract Background Carbapenem-resistant Enterobacteriaceae (CRE) infections are associated with poor patient outcomes. Data on risk factors and molecular epidemiology of CRE in complicated intra-abdominal infections (cIAI) in China are limited. This study examined the risk factors of cIAI with CRE and the associated mortality based on carbapenem resistance mechanisms. Methods In this retrospective analysis, we identified 1024 cIAI patients hospitalized from January 1, 2013 to October 31, 2018 in 14 intensive care units in China. Thirty CRE isolates were genotyped to identify β-lactamase-encoding genes. Results Escherichia coli (34.5%) and Klebsiella pneumoniae (21.2%) were the leading pathogens. Patients with hospital-acquired cIAI had a lower rate of E coli (26.0% vs 49.1%; P < .001) and higher rate of carbapenem-resistant Gram-negative bacteria (31.7% vs 18.8%; P = .002) than those with community-acquired cIAI. Of the isolates, 16.0% and 23.4% of Enterobacteriaceae and K pneumoniae, respectively, were resistant to carbapenem. Most carbapenemase-producing (CP)-CRE isolates carried blaKPC (80.9%), followed by blaNMD (19.1%). The 28-day mortality was 31.1% and 9.0% in patients with CRE vs non-CRE (P < .001). In-hospital mortality was 4.7-fold higher for CP-CRE vs non-CP-CRE infection (P = .049). Carbapenem-containing combinations did not significantly influence in-hospital mortality of CP and non-CP-CRE. The risk factors for 28-day mortality in CRE-cIAI included septic shock, antibiotic exposure during the preceding 30 days, and comorbidities. Conclusions Klebsiella pneumoniae had the highest prevalence in CRE. Infection with CRE, especially CP-CRE, was associated with increased mortality in cIAI.

scholarly journals Combination of Colistin and Azidothymidine Demonstrates Synergistic Activity against Colistin-Resistant, Carbapenem-Resistant Klebsiella pneumoniae

2020 ◽  
Vol 8 (12) ◽  
pp. 1964
Author(s):  
Ya-Ting Chang ◽  
Tsung-Ying Yang ◽  
Po-Liang Lu ◽  
Shang-Yi Lin ◽  
Liang-Chun Wang ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Therapeutic Option ◽  
Rapid Evolution ◽  
Toxicity Testing ◽  
World Health ◽  
Synergistic Activity ◽  
Carbapenem Resistant

Carbapenem-resistant Enterobacteriaceae (CRE) is listed as an urgent threat by the World Health Organization because of the limited therapeutic options, rapid evolution of resistance mechanisms, and worldwide dissemination. Colistin is a common backbone agent among the “last-resort” antibiotics for CRE; however, its emerging resistance among CRE has taken the present dilemma to the next level. Azidothymidine (AZT), a thymidine analog used to treat human immunodeficiency virus/acquired immunodeficiency syndrome, has been known to possess antibacterial effects against Enterobacteriaceae. In this study, we investigated the combined effects of AZT and colistin in 40 clinical isolates of colistin-resistant, carbapenem-resistant K. pneumoniae (CCRKP). Eleven of the 40 isolates harbored Klebsiella pneumoniae carbapenemase. The in vitro checkerboard method and in vivo nematode killing assay both revealed synergistic activity between the two agents, with fractional inhibitory concentration indexes of ≤0.5 in every strain. Additionally, a significantly lower hazard ratio was observed for the nematodes treated with combination therapy (0.288; p < 0.0001) compared with either AZT or colistin treatment. Toxicity testing indicated potentially low toxicity of the combination therapy. Thus, the AZT–colistin combination could be a potentially favorable therapeutic option for treating CCRKP.

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 Polyphasic characterization of carbapenem-resistant Klebsiella pneumoniae clinical isolates suggests vertical transmission of the blaKPC-3 gene

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0247058
Author(s):  
Catarina Ferreira ◽  
Santosh K. Bikkarolla ◽  
Karolin Frykholm ◽  
Saga Pohjanen ◽  
Margarida Brito ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Vertical Transmission ◽  
Carbapenem Resistance ◽  
Clinical Isolates ◽  
Host Bacterium ◽  
Whole Genome ◽  
Healthcare Facilities ◽  
Genetic Elements ◽  
Dna Mapping ◽  
Carbapenem Resistant

Carbapenem-resistant Klebsiella pneumoniae are a major global threat in healthcare facilities. The propagation of carbapenem resistance determinants can occur through vertical transmission, with genetic elements being transmitted by the host bacterium, or by horizontal transmission, with the same genetic elements being transferred among distinct bacterial hosts. This work aimed to track carbapenem resistance transmission by K. pneumoniae in a healthcare facility. The study involved a polyphasic approach based on conjugation assays, resistance phenotype and genotype analyses, whole genome sequencing, and plasmid characterization by pulsed field gel electrophoresis and optical DNA mapping. Out of 40 K. pneumoniae clinical isolates recovered over two years, five were carbapenem- and multidrug-resistant and belonged to multilocus sequence type ST147. These isolates harboured the carbapenemase encoding blaKPC-3 gene, integrated in conjugative plasmids of 140 kbp or 55 kbp, belonging to replicon types incFIA/incFIIK or incN/incFIIK, respectively. The two distinct plasmids encoding the blaKPC-3 gene were associated with distinct genetic lineages, as confirmed by optical DNA mapping and whole genome sequence analyses. These results suggested vertical (bacterial strain-based) transmission of the carbapenem-resistance genetic elements. Determination of the mode of transmission of antibiotic resistance in healthcare facilities, only possible based on polyphasic approaches as described here, is essential to control resistance propagation.

scholarly journals In Vitro Synergism of Azithromycin Combination with Antibiotics against OXA-48-Producing Klebsiella pneumoniae Clinical Isolates

Antibiotics ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1551
Author(s):  
Uthaibhorn Singkham-in ◽  
Netchanok Muhummudaree ◽  
Tanittha Chatsuwan
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Outer Membrane Proteins ◽  
Carbapenem Resistance ◽  
Resistance Mechanisms ◽  
In Vitro Activity ◽  
Bacterial Regrowth ◽  
Antibiotic Development ◽  
Carbapenem Resistant

Carbapenem-resistant Klebsiella pneumoniae has globally emerged as an urgent threat leading to the limitation for treatment. K. pneumoniae carrying blaOXA-48, which plays a broad magnitude of carbapenem susceptibility, is widely concerned. This study aimed to characterize related carbapenem resistance mechanisms and forage for new antibiotic combinations to combat blaOXA-48-carrying K. pneumoniae. Among nine isolates, there were two major clones and a singleton identified by ERIC-PCR. Most isolates were resistant to ertapenem (MIC range: 2–>256 mg/L), but two isolates were susceptible to imipenem and meropenem (MIC range: 0.5–1 mg/L). All blaOXA-48-carrying plasmids conferred carbapenem resistance in Escherichia coli transformants. Two ertapenem-susceptible isolates carried both outer membrane proteins (OMPs), OmpK35 and OmpK36. Lack of at least an OMP was present in imipenem-resistant isolates. We evaluated the in vitro activity of an overlooked antibiotic, azithromycin, in combination with other antibiotics. Remarkably, azithromycin exhibited synergism with colistin and fosfomycin by 88.89% and 77.78%, respectively. Bacterial regrowth occurred after exposure to colistin or azithromycin alone. Interestingly, most isolates were killed, reaching synergism by this combination. In conclusion, the combination of azithromycin and colistin may be an alternative strategy in dealing with blaOXA-48-carrying K. pneumoniae infection during a recent shortage of newly effective antibiotic development.

scholarly journals High-Level Carbapenem Resistance in a Klebsiella pneumoniae Clinical Isolate Is Due to the Combination of blaACT-1 β-Lactamase Production, Porin OmpK35/36 Insertional Inactivation, and Down-Regulation of the Phosphate Transport Porin PhoE

2006 ◽  
Vol 50 (10) ◽  
pp. 3396-3406 ◽  
Author(s):  
Frank M. Kaczmarek ◽  
Fadia Dib-Hajj ◽  
Wenchi Shang ◽  
Thomas D. Gootz
Keyword(s):  
New York ◽  
New York City ◽  
Klebsiella Pneumoniae ◽  
York City ◽  
Carbapenem Resistance ◽  
Clinical Isolates ◽  
Wild Type ◽  
Down Regulation ◽  
Carbapenem Resistant ◽  
Insertional Inactivation

ABSTRACT Clinical isolates of Klebsiella pneumoniae resistant to carbapenems and essentially all other antibiotics (multidrug resistant) are being isolated from some hospitals in New York City with increasing frequency. A highly related pair of K. pneumoniae strains isolated on the same day from one patient in a hospital in New York City were studied for antibiotic resistance. One (KP-2) was resistant to imipenem, meropenem, and sulopenem (MICs of 16 to 32 μg/ml) while the other (KP-1) was susceptible (MIC of 0.5 μg/ml); both contained the bla ACT-1, bla SHV-1, and bla TEM-1 β-lactamases. bla ACT-1 in both strains was encoded on a large ∼150-kb plasmid. Both isolates contained an identical class 1 integron encoding resistance to aminoglycosides and chloramphenicol. They each had identical insertions in ompK35 and ompK36, resulting in disruption of these key porin genes. The carbapenem-resistant and -susceptible isolates were extensively studied for differences in the structural and regulatory genes for the operons acrRAB, marORAB, romA-ramA, soxRS, micF, micC, phoE, phoBR, rpoS, and hfq. No changes were detected between the isolates except for a significant down-regulation of ompK37, phoB, and phoE in KP-2 as deduced from reverse transcription-PCR analysis of mRNA and polyacrylamide gel electrophoresis separation of outer membrane proteins. Backcross analysis was conducted using the wild-type phoE gene cloned into the vector pGEM under regulation of its native promoter as well as the lacZ promoter following transformation into the resistant KP-2 isolate. The wild-type gene reversed carbapenem resistance only when under control of the heterologous lacZ promoter. In the background of ompK35-ompK36 gene disruption, the up-regulation of phoE in KP-1 apparently compensated for porin loss and conferred carbapenem susceptibility. Down-regulation of phoE in KP-2 may represent the normal state of this gene, or it may have been selected from KP-1 in vivo under antibiotic pressure, generating the carbapenem-resistant clone. This is the first study in the Enterobacteriaceae where expression of the phosphate-regulated PhoE porin has been associated with resistance to antimicrobials. Our results with this pair of Klebsiella clinical isolates highlight the complex and evolving nature of multiple drug resistance in this species.

scholarly journals Network Integrative Genomic and Transcriptomic Analysis of Carbapenem-ResistantKlebsiella pneumoniaeStrains Identifies Genes for Antibiotic Resistance and Virulence

mSystems ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
Muyoung Lee ◽  
Naina Adren Pinto ◽  
Chan Yeong Kim ◽  
Sunmo Yang ◽  
Roshan D’Souza ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Klebsiella Pneumoniae ◽  
Carbapenem Resistance ◽  
Clinical Isolates ◽  
Functional Modules ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Functional Association ◽  
Carbapenem Resistant ◽  
Tract Infections

ABSTRACTGlobal increases in the use of carbapenems have resulted in several strains of Gram-negative bacteria acquiring carbapenem resistance, thereby limiting treatment options.Klebsiella pneumoniaeis a common carbapenem-resistant pathogenic bacterium that is widely studied to identify novel antibiotic resistance mechanisms and drug targets. Antibiotic-resistant clinical isolates generally harbor many genetic alterations, and the identification of responsible mutations would provide insights into the molecular mechanisms of antibiotic resistance. We propose a method to prioritize mutated genes responsible for antibiotic resistance on the basis of expression changes in their local subnetworks, hypothesizing that mutated genes that show significant expression changes among the corresponding functionally associated genes are more likely to be involved in the carbapenem resistance. For network-based gene prioritization, we developed KlebNet (www.inetbio.org/klebnet), a genome-scale cofunctional network ofK. pneumoniaegenes. Using KlebNet, we reconstructed the functional modules for carbapenem resistance and virulence and identified the functional association between antibiotic resistance and virulence. Using complementation assays with the top candidate genes, we were able to validate a novel gene that negatively regulated carbapenem resistance and four novel genes that positively regulated virulence inGalleria mellonellalarvae. Therefore, our study demonstrated the feasibility of network-based identification of genes required for antibiotic resistance and virulence of human-pathogenic bacteria.IMPORTANCEKlebsiella pneumoniaeis a major bacterial pathogen that causes pneumonia and urinary tract infections in human.K. pneumoniaeinfections are treated with carbapenem, but carbapenem-resistantK. pneumoniaehas been spreading worldwide. We are able to identify antimicrobial-resistant genes among mutated genes of the antibiotic-resistant clinical isolates. However, they usually harbor many mutated genes, including those that cause weak or neutral functional effects. Therefore, we need to prioritize the mutated genes to identify the more likely candidates for the follow-up functional analysis. For this study, we present a functional network ofK. pneumoniaegenes and propose a network-based method of prioritizing the mutated genes of the resistant clinical isolates. We also reconstructed the network-based functional modules for carbapenem resistance and virulence and retrieved the functional association between antibiotic resistance and virulence. This study demonstrated the feasibility of network-based analysis of clinical genomics data for the study ofK. pneumoniaeinfection.

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