Increased Expression Levels of Chromosomal AmpC β-Lactamase in Clinical<i>Escherichia coli</i>Isolates and Their Effect on Susceptibility to Extended-Spectrum Cephalosporins

Paltansing, Sunita; Kraakman, M. E. M.; Boxtel, Ria van; Kors, Ivo; Wessels, Els; Goessens, W. H. F.; Tommassen, Jan; Bernards, A.T.

doi:10.1089/mdr.2014.0108

Cited by 13 publications

(10 citation statements)

References 29 publications

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“…Our study demonstrated that mutation at position −32 increased AmpC expression by 5.98 folds based on RT–qPCR assay. Similarly, mutations at positions −11, −20, −21, −42, −1 and +58 cause increased AmpC expression in the range of 1.39 to 13.87 folds, which is in agreement with the previously reported studies 37–39 . Hyper-production of AmpC leads to increased resistance to cephalosporins as corroborated in our DEC isolates.…”

Section: Discussionsupporting

confidence: 93%

Transcriptome analysis of beta-lactamase genes in diarrheagenic Escherichia coli

Singh

Wani

et al. 2019

Sci Rep

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Beta (β)-lactamases are the most important agents that confer drug resistance among gram-negative bacteria. Continuous mutations in β-lactamases make them remarkably diverse. We carried out the transcriptome analysis of 10 β-lactamase genes of Extended-Spectrum β-lactamases (ESBL), Metallo β-lactamases (MBL), and AmpC β-lactamases (ABL) in drug-resistant and sensitive diarrheagenic E. coli (DEC) isolates obtained from children up to 5 years of age. Out of the 10 β-lactamase genes, four belonged to ESBL ( TEM , SHV , CTX, and OXA ); three to MBL ( NDM -1, IMP , and VIM ); and three to ABL ( ACT , DHA and CMY ) class of genes. The different categories of DEC were estimated for β-lactamases production using a set of conventional phenotypic tests, followed by detection of their messenger RNA (mRNA) expression. The study revealed a direct correlation between mRNA expression of these genes and the presence of antibiotic resistance; also corroborated by mutation analysis of the AmpC promoter region. All the 10 β-lactamase genes showed a significant increase in their expression levels in resistant isolates, compared to those of the sensitive isolates, indicating their possible role in the disease pathogenesis. Increase in mRNA expression of β-lactamase genes, and thereby virulence, may be due to multifactorial parameters causing phenotypic as well as genotypic changes. Our study highlights the necessity of instantaneous detection of β-lactamase gene expression to curb the overwhelming threat posed by emergence of drug resistance amongst the commensal E. coli strains in children from developing countries for larger public health interest.

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Section: Discussionsupporting

confidence: 93%

Transcriptome analysis of beta-lactamase genes in diarrheagenic Escherichia coli

Singh

Wani

et al. 2019

Sci Rep

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“…This may also have been the cause of the greater variability in CFU counts at levels around the static dose level than at other levels of exposure. Another explanation could be that there were diverse levels of transcription of beta-lactamases, given the differential levels of expression of beta-lactamase enzymes in bacteria (19,20), and the presence of various beta-lactamase variants may indicate the reason for the differential C T s of tazobactam (16).…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamics of Ceftolozane Combined with Tazobactam against Enterobacteriaceae in a Neutropenic Mouse Thigh Model

Melchers

Mavridou

Mil

et al. 2016

Antimicrob Agents Chemother

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Ceftolozane is a new broad-spectrum cephalosporin and is combined with tazobactam to broaden the activity of ceftolozane against strains producing extended-spectrum beta-lactamases (ESBLs). We determined the pharmacodynamics (PD) of the combination in the neutropenic mouse thigh model to determine the optimal exposure of tazobactam. Treatment of CD-1 neutropenic mice was started 2 h after infection with ceftolozane every 2 h (q2h) alone or in combination with tazobactam at different dosing frequencies for 24 h, and the number of CFU in the thighs was determined before and after treatment. The maximum effect model was fit to the dose-response and the pharmacokinetic/PD index (PDI)-response to determine the PDI values for ceftolozane alone and ceftolozane in combination with tazobactam resulting in a static effect and a 1-log kill. The effect of tazobactam was dependent on the percentage of time that the free drug concentration remained above the concentration threshold (percent fT ϾC T ), whereby dosing q2h was more efficacious than dosing every 8 h (q8h), reducing the tazobactam daily dose by a factor 6.9 to 59.0 (n ‫؍‬ 3 strains) to obtain a static effect. Using R 2 as an indicator of the best fit of the percent fT ϾC T -response relationships, the concentration threshold best correlating with the response varied from 0.5 to 2 mg/liter, depending on the strain. A similar result was obtained when the q2h and q8h regimens were analyzed. For all isolates tested, the mean fT ϾC T for 0.5 mg/ liter tazobactam was 28.2% (range, 17.5 to 45.8%) and 44.4% (range, 26.6 to 54.7%) for a static effect and a 1-log kill, respectively, at ceftolozane exposures that produced a ceftolozane concentration of 4 mg/liter (a concentration greater than the MIC) for 33.9 to 63.3% of a 24-h period under steady-state pharmacokinetic conditions. The main PDI that correlated with the effect of tazobactam was the fT ϾC T achieved with a C T of 0.5 mg/liter tazobactam. Resistance to beta-lactam antibiotics and the rapid spread thereof are major concerns and are likely to remain so. In particular, infections caused by beta-lactamase-producing bacteria present a therapeutic dilemma when the beta-lactam antibiotic alone is ineffective (1-4). Ceftolozane is a novel cephalosporin that has activity against Pseudomonas aeruginosa and other Gramnegative bacteria as well as certain Gram-positive bacteria. However, the drug is susceptible to degradation by extended-spectrum beta-lactamases (ESBLs). In vitro studies have shown that elevated MICs of ceftolozane against resistant strains of the Enterobacteriaceae or Pseudomonas strains were restored to the levels for susceptible strains in the presence of the beta-lactamase inhibitor tazobactam (5, 6). This increase of drug efficacy after addition of tazobactam has been confirmed in a murine thigh infection model (7). However, the optimal tazobactam dosing regimen for the treatment of infections caused by ESBL producers still needs to be verified.Little is known about the antimicrobial effect of ceftoloz...

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“…Colistin resistance has been associated with mutations in the genes coding for the PmrAB two-component regulatory system that regulates the addition of aminoarabinose to lipid A [207]. Additionally, mutations resulting in increased production of β-lactamases, e.g., by mutations in the promoter of the chromosomal ampC gene [208] or by increase of plasmid copy number [150] have been described, among others. In addition, the genes have evolved over the years, showing a large number of β-lactamase variants with point mutations in the gene resulting in changes in the amino-acid sequence [209].…”

Section: Mutation and Biofilmsmentioning

confidence: 99%

Biofilms as Promoters of Bacterial Antibiotic Resistance and Tolerance

et al. 2020

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Multidrug resistant bacteria are a global threat for human and animal health. However, they are only part of the problem of antibiotic failure. Another bacterial strategy that contributes to their capacity to withstand antimicrobials is the formation of biofilms. Biofilms are associations of microorganisms embedded a self-produced extracellular matrix. They create particular environments that confer bacterial tolerance and resistance to antibiotics by different mechanisms that depend upon factors such as biofilm composition, architecture, the stage of biofilm development, and growth conditions. The biofilm structure hinders the penetration of antibiotics and may prevent the accumulation of bactericidal concentrations throughout the entire biofilm. In addition, gradients of dispersion of nutrients and oxygen within the biofilm generate different metabolic states of individual cells and favor the development of antibiotic tolerance and bacterial persistence. Furthermore, antimicrobial resistance may develop within biofilms through a variety of mechanisms. The expression of efflux pumps may be induced in various parts of the biofilm and the mutation frequency is induced, while the presence of extracellular DNA and the close contact between cells favor horizontal gene transfer. A deep understanding of the mechanisms by which biofilms cause tolerance/resistance to antibiotics helps to develop novel strategies to fight these infections.

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Increased Expression Levels of Chromosomal AmpC β-Lactamase in ClinicalEscherichia coliIsolates and Their Effect on Susceptibility to Extended-Spectrum Cephalosporins

Cited by 13 publications

References 29 publications

Transcriptome analysis of beta-lactamase genes in diarrheagenic Escherichia coli

Transcriptome analysis of beta-lactamase genes in diarrheagenic Escherichia coli

Pharmacodynamics of Ceftolozane Combined with Tazobactam against Enterobacteriaceae in a Neutropenic Mouse Thigh Model

Biofilms as Promoters of Bacterial Antibiotic Resistance and Tolerance

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