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1.
Microb Genom ; 7(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33843573

RESUMO

Cefotaxime (CTX) is a third-generation cephalosporin (3GC) commonly used to treat infections caused by Escherichia coli. Two genetic mechanisms have been associated with 3GC resistance in E. coli. The first is the conjugative transfer of a plasmid harbouring antibiotic-resistance genes. The second is the introduction of mutations in the promoter region of the ampC ß-lactamase gene that cause chromosome-encoded ß-lactamase hyperproduction. A wide variety of promoter mutations related to AmpC hyperproduction have been described. However, their link to CTX resistance has not been reported. We recultured 172 cefoxitin-resistant E. coli isolates with known CTX minimum inhibitory concentrations and performed genome-wide analysis of homoplastic mutations associated with CTX resistance by comparing Illumina whole-genome sequencing data of all isolates to a PacBio sequenced reference chromosome. We mapped the mutations on the reference chromosome and determined their occurrence in the phylogeny, revealing extreme homoplasy at the -42 position of the ampC promoter. The 24 occurrences of a T at the -42 position rather than the wild-type C, resulted from 18 independent C>T mutations in five phylogroups. The -42 C>T mutation was only observed in E. coli lacking a plasmid-encoded ampC gene. The association of the -42 C>T mutation with CTX resistance was confirmed to be significant (false discovery rate <0.05). To conclude, genome-wide analysis of homoplasy in combination with CTX resistance identifies the -42 C>T mutation of the ampC promotor as significantly associated with CTX resistance and underlines the role of recurrent mutations in the spread of antibiotic resistance.


Assuntos
Antibacterianos/farmacologia , Cefotaxima/farmacologia , Farmacorresistência Bacteriana , Infecções por Escherichia coli/microbiologia , Escherichia coli/genética , Genoma Bacteriano , Heteroplasmia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Escherichia coli/classificação , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Humanos , Testes de Sensibilidade Microbiana , Mutação , Plasmídeos/genética , Regiões Promotoras Genéticas , beta-Lactamases/genética , beta-Lactamases/metabolismo
3.
J Antimicrob Chemother ; 74(12): 3481-3488, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504559

RESUMO

OBJECTIVES: AmpC-ß-lactamase production is an under-recognized antibiotic resistance mechanism that renders Gram-negative bacteria resistant to common ß-lactam antibiotics, similar to the well-known ESBLs. For infection control purposes, it is important to be able to discriminate between plasmid-mediated AmpC (pAmpC) production and chromosomal-mediated AmpC (cAmpC) hyperproduction in Gram-negative bacteria as pAmpC requires isolation precautions to minimize the risk of horizontal gene transmission. Detecting pAmpC in Escherichia coli is challenging, as both pAmpC production and cAmpC hyperproduction may lead to third-generation cephalosporin resistance. METHODS: We tested a collection of E. coli strains suspected to produce AmpC. Elaborate susceptibility testing for third-generation cephalosporins, WGS and machine learning were used to develop an algorithm to determine ampC genotypes in E. coli. WGS was applied to detect pampC genes, cAmpC hyperproducers and STs. RESULTS: In total, 172 E. coli strains (n=75 ST) were divided into a training set and two validation sets. Ninety strains were pampC positive, the predominant gene being blaCMY-2 (86.7%), followed by blaDHA-1 (7.8%), and 59 strains were cAmpC hyperproducers. The algorithm used a cefotaxime MIC value above 6 mg/L to identify pampC-positive E. coli and an MIC value of 0.5 mg/L to discriminate between cAmpC-hyperproducing and non-cAmpC-hyperproducing E. coli strains. Accuracy was 0.88 (95% CI=0.79-0.94) on the training set, 0.79 (95% CI=0.64-0.89) on validation set 1 and 0.85 (95% CI=0.71-0.94) on validation set 2. CONCLUSIONS: This approach resulted in a pragmatic algorithm for differentiating ampC genotypes in E. coli based on phenotypic susceptibility testing.


Assuntos
Proteínas de Bactérias/genética , Cromossomos Bacterianos , Escherichia coli/genética , Plasmídeos/genética , beta-Lactamases/genética , Algoritmos , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Genótipo , Testes de Sensibilidade Microbiana , Fenótipo , Sequenciamento Completo do Genoma
4.
PLoS One ; 13(10): e0204864, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30273375

RESUMO

OBJECTIVE: The objective of this study is to determine the prevalence of rectal carriage of plasmid- and chromosome-encoded AmpC ß-lactamase-producing Escherichia coli and Klebsiella spp. in patients in a Dutch teaching hospital between 2013 and 2016. METHODS: Between 2013 and 2016, hospital-wide yearly prevalence surveys were performed to determine the prevalence of AmpC ß-lactamase-producing E. coli and Klebsiella spp. rectal carriage. Rectal swabs were taken and cultured using an enrichment broth and selective agar plates. All E. coli and Klebsiella spp. isolates were screened for production of AmpC ß-lactamase using phenotypic confirmation tests and for the presence of plasmid-encoded AmpC (pAmpC) genes. E. coli isolates were screened for chromosome-encoded AmpC (cAmpC) promoter/attenuator alterations. RESULTS: Fifty (2.4%) of 2,126 evaluable patients were identified as rectal carrier of AmpC ß-lactamase-producing E. coli. No carriage of AmpC ß-lactamase producing Klebsiella spp. was found. Nineteen (0.9%) patients harboured isolates with pAmpC genes and 30 (1,4%) patients harboured isolates with cAmpC promoter/attenuator alterations associated with AmpC ß-lactamase overproduction. For one isolate, no pAmpC genes or cAmpC promotor/attenuator alterations could be identified. During the study period, a statistically significant decline in the prevalence of rectal carriage with E. coli with cAmpC promotor/attenuator alterations was found (p = 0.012). The prevalence of pAmpC remained stable over the years. CONCLUSIONS: The prevalence of rectal carriage of AmpC-producing E. coli and Klebsiella spp. in patients in Dutch hospitals is low and a declining trend was observed for E. coli with cAmpC promotor/attenuator alterations.


Assuntos
Proteínas de Bactérias/genética , Infecções por Escherichia coli/epidemiologia , Escherichia coli/crescimento & desenvolvimento , Infecções por Klebsiella/epidemiologia , beta-Lactamases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Proteínas de Bactérias/metabolismo , Criança , Pré-Escolar , Escherichia coli/enzimologia , Infecções por Escherichia coli/microbiologia , Feminino , Hospitais de Ensino , Humanos , Lactente , Recém-Nascido , Klebsiella/enzimologia , Klebsiella/crescimento & desenvolvimento , Infecções por Klebsiella/microbiologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Fenótipo , Prevalência , Regiões Promotoras Genéticas , Reto/microbiologia , Adulto Jovem , beta-Lactamases/metabolismo
5.
Am J Physiol Heart Circ Physiol ; 301(1): H241-6, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21515668

RESUMO

Episodic increases in shear stress have been proposed as a mechanism that induces training-induced adaptation in arterial wall remodeling in humans. To address this hypothesis in humans, we examined bilateral brachial artery wall thickness using high-resolution ultrasound in healthy men across an 8-wk period of bilateral handgrip training. Unilaterally, shear rate was attenuated by cuff inflation around the forearm to 60 mmHg. Grip strength, forearm volume, and girth improved similarly between the limbs. Acute bouts of handgrip exercise increased shear rate (P < 0.005) in the noncuffed limb, whereas cuff inflation successfully decreased exercise-induced increases in shear. Brachial blood pressure responses similarly increased during exercise in both the cuffed and noncuffed limbs. Handgrip training had no effect on baseline brachial artery diameter, blood flow, or shear rate but significantly decreased brachial artery wall thickness after 6 and 8 wk (ANOVA, P < 0.001) and wall-to-lumen ratio after week 8 (ANOVA, P = 0.005). The magnitude of decrease in brachial artery wall thickness and wall-to-lumen ratio after exercise training was similar in the noncuffed and cuffed arms. These results suggest that exercise-induced changes in shear rate are not obligatory for arterial wall remodeling during a period of 8 wk of exercise training in healthy humans.


Assuntos
Artérias/anatomia & histologia , Artérias/fisiologia , Exercício Físico/fisiologia , Estresse Mecânico , Adulto , Braço/irrigação sanguínea , Braço/fisiologia , Pressão Sanguínea/fisiologia , Artéria Braquial/diagnóstico por imagem , Artéria Braquial/fisiologia , Interpretação Estatística de Dados , Força da Mão/fisiologia , Humanos , Masculino , Aptidão Física/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Ultrassonografia , Adulto Jovem
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