Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.757
Filtrar
1.
Med ; 5(5): 380-382, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38733970

RESUMO

Wagenlehner and colleagues1 demonstrated non-inferiority and superiority with respect to a primary endpoint of composite success (microbiological plus clinical) of cefepime/taniborbactam vs. meropenem in treating complicated urinary tract infections and acute pyelonephritis caused by carbapenem-susceptible gram-negative bacteria in adults. A major area of interest in real-world application of cefepime/taniborbactam is its potential role in treating carbapenem-resistant infections, which deserves further investigation.


Assuntos
Antibacterianos , Carbapenêmicos , Cefepima , Infecções Urinárias , Cefepima/uso terapêutico , Cefepima/farmacologia , Humanos , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Carbapenêmicos/uso terapêutico , Carbapenêmicos/farmacologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Cefalosporinas/uso terapêutico , Cefalosporinas/farmacologia , Pielonefrite/tratamento farmacológico , Pielonefrite/microbiologia , Combinação de Medicamentos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Meropeném/uso terapêutico , Meropeném/farmacologia , Ácidos Borínicos , Ácidos Carboxílicos
2.
Appl Environ Microbiol ; 90(5): e0026424, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38695519

RESUMO

The emergence of foodborne Salmonella strains carrying antimicrobial resistance (AMR) in mobile genetic elements (MGE) is a significant public health threat in a One Health context requiring continuous surveillance. Resistance to ciprofloxacin and cephalosporins is of particular concern. Since pigs are a relevant source of foodborne Salmonella for human beings, we studied transmissible AMR genes and MGE in a collection of 83 strains showing 9 different serovars and 15 patterns of multidrug resistant (MDR) previously isolated from pigs raised in the conventional breeding system of Northern Spain. All isolates were susceptible to ciprofloxacin and three isolates carried blaCMY-2 or blaCTX-M-9 genes responsible for cefotaxime resistance. Filter mating experiments showed that the two plasmids carrying blaCTX-M-9 were conjugative while that carrying blaCMY-2 was self-transmissible by transformation. Whole-genome sequencing and comparative analyses were performed on the isolates and plasmids. The IncC plasmid pSB109, carrying blaCMY-2, was similar to one found in S. Reading from cattle, indicating potential horizontal transfer between serovars and animal sources. The IncHI2 plasmids pSH102 in S. Heidelberg and pSTM45 in S. Typhimurium ST34, carrying blaCTX-M-9, shared similar backbones and two novel "complex class 1 integrons" containing different AMR and heavy metal genes. Our findings emphasize the importance of sequencing techniques to identify emerging AMR regions in conjugative and stable plasmids from livestock production. The presence of MGE carrying clinically relevant AMR genes raises public health concerns, requiring monitoring to mitigate the emergence of bacteria carrying AMR genes and subsequent spread through animals and food.IMPORTANCEThe emergence of foodborne Salmonella strains carrying antimicrobial resistance (AMR) in mobile genetic elements (MGE) is a significant public health threat in a One Health context. Since pigs are a relevant source of foodborne Salmonella for humans, in this study, we investigate different aspects of AMR in a collection of 83 Salmonella showing nine different serovars and 15 patterns of multidrug resistant (MDR) isolated from pigs raised in the conventional breeding system. Our findings emphasize the importance of sequencing techniques to identify emerging AMR regions in conjugative and stable plasmids from livestock production. The presence of MGE carrying clinically relevant AMR genes raises public health concerns, requiring monitoring to mitigate the emergence of bacteria carrying AMR genes and subsequent spread through animals and food.


Assuntos
Antibacterianos , Farmacorresistência Bacteriana Múltipla , Sequências Repetitivas Dispersas , Plasmídeos , Salmonella , Animais , Suínos/microbiologia , Plasmídeos/genética , Salmonella/genética , Salmonella/efeitos dos fármacos , Salmonella/isolamento & purificação , Farmacorresistência Bacteriana Múltipla/genética , Antibacterianos/farmacologia , Humanos , Resistência às Cefalosporinas/genética , Salmonelose Animal/microbiologia , Espanha , Doenças dos Suínos/microbiologia , Cefalosporinas/farmacologia , Transferência Genética Horizontal
3.
EBioMedicine ; 103: 105097, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38608515

RESUMO

BACKGROUND: Extended-spectrum cephalosporins (ESCs) are third and fourth generation cephalosporin antimicrobials used in humans and animals to treat infections due to multidrug-resistant (MDR) bacteria. Resistance to ESCs (ESC-R) in Enterobacterales is predominantly due to the production of extended-spectrum ß-lactamases (ESBLs) and plasmid-mediated AmpC ß-lactamases (AmpCs). The dynamics of ESBLs and AmpCs are changing across countries and host species, the result of global transmission of ESC-R genes. Plasmids are known to play a key role in this dissemination, but the relative importance of different types of plasmids is not fully understood. METHODS: In this study, Escherichia coli with the major ESC-R genes blaCTX-M-1, blaCTX-M-15, blaCTX-M-14 (ESBLs) and blaCMY-2 (AmpC), were selected from diverse host species and other sources across Canada, France and Germany, collected between 2003 and 2017. To examine in detail the vehicles of transmission of the ESC-R genes, long- and short-read sequences were generated to obtain complete contiguous chromosome and plasmid sequences (n = 192 ESC-R E. coli). The types, gene composition and genetic relatedness of these plasmids were investigated, along with association with isolate year, source and geographical origin, and put in context with publicly available plasmid sequences. FINDINGS: We identified five epidemic resistance plasmid subtypes with distinct genetic properties that are associated with the global dissemination of ESC-R genes across multiple E. coli lineages and host species. The IncI1 pST3 blaCTX-M-1 plasmid subtype was found in more diverse sources than the other main plasmid subtypes, whereas IncI1 pST12 blaCMY-2 was more frequent in Canadian and German human and chicken isolates. Clonal expansion also contributed to the dissemination of the IncI1 pST12 blaCMY-2 plasmid in ST131 and ST117 E. coli harbouring this plasmid. The IncI1 pST2 blaCMY-2 subtype was predominant in isolates from humans in France, while the IncF F31:A4:B1 blaCTX-M-15 and F2:A-:B- blaCTX-M-14 plasmid subtypes were frequent in human and cattle isolates across multiple countries. Beyond their epidemic nature with respect to ESC-R genes, in our collection almost all IncI1 pST3 blaCTX-M-1 and IncF F31:A4:B1 blaCTX-M-15 epidemic plasmids also carried multiple antimicrobial resistance (AMR) genes conferring resistance to other antimicrobial classes. Finally, we found genetic signatures in the regions surrounding specific ESC-R genes, identifying the predominant mechanisms of ESC-R gene movement, and using publicly available databases, we identified these epidemic plasmids from widespread bacterial species, host species, countries and continents. INTERPRETATION: We provide evidence that epidemic resistance plasmid subtypes contribute to the global dissemination of ESC-R genes, and in addition, some of these epidemic plasmids confer resistance to multiple other antimicrobial classes. The success of these plasmids suggests that they may have a fitness advantage over other plasmid types and subtypes. Identification and understanding of the vehicles of AMR transmission are crucial to develop and target strategies and interventions to reduce the spread of AMR. FUNDING: This project was supported by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR), through the Medical Research Council (MRC, MR/R000948/1), the Canadian Institutes of Health Research (CFC-150770), and the Genomics Research and Development Initiative (Government of Canada), the German Federal Ministry of Education and Research (BMBF) grant no. 01KI1709, the French Agency for food environmental and occupational health & safety (Anses), and the French National Reference Center (CNR) for antimicrobial resistance. Support was also provided by the Biotechnology and Biological Sciences Research Council (BBSRC) through the BBSRC Institute Strategic Programme Microbes in the Food ChainBB/R012504/1 and its constituent project BBS/E/F/000PR10348 (Theme 1, Epidemiology and Evolution of Pathogens in the Food Chain).


Assuntos
Resistência às Cefalosporinas , Infecções por Escherichia coli , Escherichia coli , Plasmídeos , Plasmídeos/genética , Escherichia coli/genética , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/epidemiologia , Infecções por Escherichia coli/transmissão , Humanos , Resistência às Cefalosporinas/genética , Animais , beta-Lactamases/genética , Cefalosporinas/farmacologia , Antibacterianos/farmacologia , Alemanha/epidemiologia , Testes de Sensibilidade Microbiana , França/epidemiologia
4.
BMC Infect Dis ; 24(1): 434, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38654148

RESUMO

BACKGROUND: The problem of resistance to beta-lactam antibiotics, which is caused by ESBL and AmpC ß-lactamases, is getting worse globally. Infections caused by bacterial isolates harboring these enzymes are difficult to treat with carbapenems being the sole effective treatment option for such infections. The objective of this study was to determine the frequency of ESBLs and AmpC-producing Gram-negative bacilli isolated from clinical specimens and to evaluate the sensitivity of cefepime-tazobactam combination against them. METHODS: This is an observational cross-sectional study carried out on 100 Gram-negative bacilli at Theodor Bilharz Research Institute Hospital during the period from February 2015 to January 2016. ESBL production was screened by using the disc diffusion test followed by confirmation by the combined disc confirmatory test, the screening for AmpC production was conducted using the cefoxitin disc test, which was subsequently confirmed by the AmpC disc test. Isolates confirmed positive for ESBL and/ or AmpC production were investigated for their susceptibility to antibiotics. RESULTS: Among 100 Gram-negative bacilli, 44 isolates were confirmed as ESBL producers by the combined disc confirmatory test out of 56 isolates that tested positive for ESBL production through the disc diffusion test. The presence of AmpC production was assessed using the cefoxitin disc test, 32 isolates were screened to be AmpC producers, and the AmpC disc test confirmed AmpC production in 9 isolates of them. Using the Mast® D68C set, 32 isolates were ESBL producers, 3 were AmpC producers, and 4 isolates were ESBL/AmpC co-producers. The highest sensitivity was to cefepime-tazobactam (91.48%) followed by the carbapenems. CONCLUSION: Cefepime-tazobactam showed remarkable activity against ESBL and/or AmpC-producing Gram-negative bacilli and may be considered as a therapeutic alternative to carbapenems.


Assuntos
Antibacterianos , Proteínas de Bactérias , Cefepima , Bactérias Gram-Negativas , Infecções por Bactérias Gram-Negativas , Testes de Sensibilidade Microbiana , Tazobactam , beta-Lactamases , beta-Lactamases/metabolismo , Cefepima/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/enzimologia , Bactérias Gram-Negativas/isolamento & purificação , Humanos , Estudos Transversais , Antibacterianos/farmacologia , Tazobactam/farmacologia , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Cefalosporinas/farmacologia , Masculino , Feminino , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacologia
5.
Front Cell Infect Microbiol ; 14: 1345935, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38572315

RESUMO

Introduction: Bacterial resistance is a major threat to public health worldwide. To gain an understanding of the clinical infection distribution, drug resistance information, and genotype of CRE in Dongguan, China, as well as the resistance of relevant genotypes to CAZ-AVI, this research aims to improve drug resistance monitoring information in Dongguan and provide a reliable basis for the clinical control and treatment of CRE infection. Methods: VITEK-2 Compact automatic analyzer was utilized to identify 516 strains of CRE collected from January 2017 to June 2023. To determine drug sensitivity, the K-B method, E-test, and MIC methods were used. From June 2022 to June 2023, 80 CRE strains were selected, and GeneXpert Carba-R was used to detect and identify the genotype of the carbapenemase present in the collected CRE strains. An in-depth analysis was conducted on the CAZ-AVI in vitro drug sensitivity activity of various genotypes of CRE, and the results were statistically evaluated using SPSS 23.0 and WHONET 5.6 software. Results: This study identified 516 CRE strains, with the majority (70.16%) being K.pneumoniae, followed by E.coli (18.99%). Respiratory specimens had highest detection rate with 53.77% identified, whereas urine specimens had the second highest detection rate with 17.99%. From June 2022 to June 2023, 95% of the strains tested using the CRE GeneXpert Carba-R assay possessed carbapenemase genes, of which 32.5% were blaNDM strains and 61.25% blaKPC strains. The results showed that CRE strains containing blaKPC had a significantly higher rate of resistance to amikacin, cefepime, and aztreonam than those harboring blaNDM. Conclusions: The CRE strains isolated from Dongguan region demonstrated a high resistance rate to various antibiotics used in clinical practice but a low resistance rate to tigecycline. These strains produce Class A serine carbapenemases and Class B metals ß-lactamases, with the majority of them carrying blaNDM and blaKPC. Notably, CRE strains with blaKPC and blaNDM had significantly lower resistance rates to tigecycline. CAZ-AVI showed a good sensitivity rate with no resistance to CRE strains carrying blaKPC. Therefore, CAZ-AVI and tigecycline should be used as a guide for rational use of antibiotics in clinical practice to effectively treat CRE.


Assuntos
Compostos Azabicíclicos , Carbapenêmicos , Ceftazidima , Enterobacteriaceae , Enterobacteriaceae/genética , Carbapenêmicos/farmacologia , Tigeciclina/farmacologia , Sistemas de Distribuição no Hospital , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Combinação de Medicamentos , beta-Lactamases/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/farmacologia , Cefalosporinas/farmacologia , Klebsiella pneumoniae/genética , Genótipo , Testes de Sensibilidade Microbiana
6.
J Antimicrob Chemother ; 79(5): 1176-1181, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38562061

RESUMO

BACKGROUND: Patients infected with difficult-to-treat Pseudomonas aeruginosa are likely to receive meropenem (MEM) empirically before escalation to ceftolozane/tazobactam (C/T). We assessed whether pre-exposure to MEM affected C/T resistance development on C/T exposure. MATERIALS AND METHODS: Nine clinical P. aeruginosa isolates were exposed to MEM 16 mg/L for 72 h. Then, isolates were serially passaged in the presence of C/T (concentration of 10 mg/L) for 72 h as two groups: an MEM-exposed group inoculated with MEM pre-exposed isolates and a non-MEM control group. At 24 h intervals, samples were plated on drug-free and drug-containing agar (C/T concentration 16/8 mg/L) and incubated to quantify bacterial densities (log10 cfu/mL). Growth on C/T agar indicated resistance development, and resistant population was calculated by dividing the cfu/mL on C/T plates by the cfu/mL on drug-free agar. RESULTS: At 72 h, resistant populations were detected in 6/9 isolates. In five isolates, MEM exposure significantly increased the prevalence of ceftolozane/tazobactam-resistance development; the percentages of resistance population were 100%, 100%, 53.5%, 31% and 3% for the MEM-exposed versus 0%, 0%, 2%, 0.35% and ≤0.0003% in the unexposed groups. One isolate had a similar resistant population at 72 h between the two groups. The remaining isolates showed no development of resistance, regardless of previous MEM exposure. CONCLUSIONS: MEM exposure may pre-dispose to C/T resistance development and thus limit the therapeutic utility of this ß-lactam/ß-lactamase inhibitor. Resistance may be a result of stress exposure or molecular-level mutations conferring cross-resistance. Further in vivo studies are needed to assess clinical implications of these findings.


Assuntos
Antibacterianos , Cefalosporinas , Meropeném , Infecções por Pseudomonas , Pseudomonas aeruginosa , Tazobactam , Pseudomonas aeruginosa/efeitos dos fármacos , Cefalosporinas/farmacologia , Meropeném/farmacologia , Tazobactam/farmacologia , Antibacterianos/farmacologia , Humanos , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/tratamento farmacológico , Testes de Sensibilidade Microbiana , Inoculações Seriadas
7.
J Med Chem ; 67(8): 6705-6725, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38596897

RESUMO

Cefiderocol is the first approved catechol-conjugated cephalosporin against multidrug-resistant Gram-negative bacteria, while its application was limited by poor chemical stability associated with the pyrrolidinium linker, moderate potency against Klebsiella pneumoniae and Acinetobacter baumannii, intricate procedures for salt preparation, and potential hypersensitivity. To address these issues, a series of novel catechol-conjugated derivatives were designed, synthesized, and evaluated. Extensive structure-activity relationships and structure-metabolism relationships (SMR) were conducted, leading to the discovery of a promising compound 86b (Code no. YFJ-36) with a new thioether linker. 86b exhibited superior and broad-spectrum in vitro antibacterial activity, especially against A. baumannii and K. pneumoniae, compared with cefiderocol. Potent in vivo efficacy was observed in a murine systemic infection model. Furthermore, the physicochemical stability of 86b in fluid medium at pH 6-8 was enhanced. 86b also reduced potential the risk of allergy owing to the quaternary ammonium linker. The improved properties of 86b supported its further research and development.


Assuntos
Antibacterianos , Catecóis , Desenho de Fármacos , Bactérias Gram-Negativas , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Catecóis/química , Catecóis/farmacologia , Catecóis/síntese química , Animais , Relação Estrutura-Atividade , Camundongos , Bactérias Gram-Negativas/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Acinetobacter baumannii/efeitos dos fármacos , beta-Lactamas/farmacologia , beta-Lactamas/síntese química , beta-Lactamas/química , Cefalosporinas/farmacologia , Cefalosporinas/síntese química , Cefalosporinas/química , Descoberta de Drogas
8.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 32(2): 583-587, 2024 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-38660870

RESUMO

OBJECTIVE: To investigate distribution and drug resistance of pathogens of bloodstream infection in patients with hematological malignancies, in order to provide reference for clinical infection control and treatment. METHODS: The clinical information of blood culture patients in the hematology department of our hospital from January 2016 to December 2021 was reviewed. They were divided into transplantation group and non-transplantation group according to whether they had undergone hematopoietic stem cell transplantation. The types of pathogens and their drug resistance were analyzed. RESULTS: Two hundred and ninety-nine positive strains of pathogenic bacteria were detected. In the transplantation group, Gram-negative bacteria accounted for 68.5% (50/73), Gram-positive bacteria accounted for 6.8% (5/73), and fungi accounted for 24.7% (18/73). The resistance rate of Escherichia coli to the third-generation cephalosporins was 77.8%, and 11.5% to carbapenems. The resistance rate of Klebsiella pneumoniae to the third-generation cephalosporins was 50.0%, and 56.2% to carbapenems. In the non-transplantation group, Gram-negative bacteria accounted for 64.1% (145/226), Gram-positive bacteria accounted for 31.0% (70/226), and fungi accounted for 4.9% (11/226). Gram-positive bacteria were mainly Enterococcus faecium (6.6%, 15/226) and Coagulase-negative Staphylococci (6.2%, 14/226). The fungi were all Candida tropicalis. The resistance rate of Escherichia coli to the third-generation cephalosporins was 63.8%, and 10.3% to carbapenems. The resistance rate of Klebsiella pneumoniae to the third-generation cephalosporins was 46.3%, and 26.8% to carbapenems. CONCLUSION: The types of pathogenic bacteria in bloodstream infection in patients with hematological malignancies are varied. Gram-negative bacteria is the main pathogenic bacteria. The resistance of pathogenic bacteria to antibiotics is severe. Antibiotics should be used scientifically and reasonably according to the detection and resistance of pathogenic bacteria.


Assuntos
Antibacterianos , Escherichia coli , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Neoplasias Hematológicas , Humanos , Neoplasias Hematológicas/complicações , Bactérias Gram-Negativas/isolamento & purificação , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/isolamento & purificação , Bactérias Gram-Positivas/efeitos dos fármacos , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Farmacorresistência Bacteriana , Klebsiella pneumoniae/isolamento & purificação , Carbapenêmicos/farmacologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Cefalosporinas/farmacologia , Bacteriemia/microbiologia , Fungos
9.
Antimicrob Agents Chemother ; 68(5): e0017424, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38557171

RESUMO

Mycobacterium abscessus (MAB) infections pose a growing public health threat. Here, we assessed the in vitro activity of the boronic acid-based ß-lactamase inhibitor, vaborbactam, with different ß-lactams against 100 clinical MAB isolates. Enhanced activity was observed with meropenem and ceftaroline with vaborbactam (1- and >4-fold MIC50/90 reduction). CRISPRi-mediated blaMAB gene knockdown showed a fourfold MIC reduction to ceftaroline but not the other ß-lactams. Our findings demonstrate vaborbactam's potential in combination therapy against MAB infections.


Assuntos
Antibacterianos , Ácidos Borônicos , Cefoxitina , Ceftarolina , Cefalosporinas , Imipenem , Meropeném , Testes de Sensibilidade Microbiana , Mycobacterium abscessus , Mycobacterium abscessus/efeitos dos fármacos , Meropeném/farmacologia , Ácidos Borônicos/farmacologia , Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Imipenem/farmacologia , Cefoxitina/farmacologia , Humanos , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Inibidores de beta-Lactamases/farmacologia
10.
Microbiol Spectr ; 12(4): e0383623, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38483164

RESUMO

Carbapenem-resistant Pseudomonas aeruginosa and Acinetobacter spp. represent major threats and have few approved therapeutic options. Non-|fermenting Gram-negative isolates were collected from hospitalized inpatients from 49 sites in 6 European countries between 01 January 2020 and 31 December 2020 and underwent susceptibility testing against cefiderocol and ß-lactam/ß-lactamase inhibitor combinations. Meropenem-resistant (MIC >8 mg/L), cefiderocol-susceptible isolates were analyzed by PCR, and cefiderocol-resistant isolates were analyzed by whole-genome sequencing to identify resistance mechanisms. Overall, 1,451 (950 P. aeruginosa; 501 Acinetobacter spp.) isolates were collected, commonly from the respiratory tract (42.0% and 39.3%, respectively). Cefiderocol susceptibility was higher than |ß|-|l|a|c|t|a|m|/|ß|-|l|a|c|t|a|mase| inhibitor combinations against P. aeruginosa (98.9% vs 83.3%-91.4%), and P. |aeruginosa resistant to meropenem (n = 139; 97.8% vs 12.2%-59.7%), ß-lactam/ß-lactamase inhibitor combinations (93.6%-98.1% vs 10.7%-71.8%), and both meropenem and ceftazidime-avibactam (96.7% vs 5.0%-||45.0%) or |ceftolozane-tazobactam (98.4% vs 8.1%-54.8%), respectively. Cefiderocol and sulbactam-durlobactam susceptibilities were high against Acinetobacter spp. (92.4% and 97.0%) and meropenem-resistant Acineto|bacter |spp. (n = 227; 85.0% and 93.8%) but lower against sulbactam-durlobactam- (n |= 15; 13.3%) and cefiderocol- (n = 38; 65.8%) resistant isolates, respectively. Among meropenem-resistant P. aeruginosa and Acinetobacter spp., the most common ß-||lactamase genes were metallo-ß-lactamases [30/139; blaVIM-2 (15/139)] and oxacillinases [215/227; blaOXA-23 (194/227)], respectively. Acquired ß-lactamase genes were identified in 1/10 and 32/38 of cefiderocol-resistant P. aeruginosa and Acinetobacter spp., and pirA-like or piuA mutations in 10/10 and 37/38, respectively. Conclusion: cefiderocol susceptibility was high against P. aeruginosa and Acinetobacter spp., including meropenem-resistant isolates and those resistant to recent ß-lactam/ß-lactamase inhibitor combinations common in first-line treatment of European non-fermenters. IMPORTANCE: This was the first study in which the in vitro activity of cefiderocol and non-licensed ß-lactam/ß-lactamase inhibitor combinations were directly compared against Pseudomonas aeruginosa and Acinetobacter spp., including meropenem- and ß-lactam/ß-lactamase inhibitor combination-resistant isolates. A notably large number of European isolates were collected. Meropenem resistance was defined according to the MIC breakpoint for high-dose meropenem, ensuring that data reflect antibiotic activity against isolates that would remain meropenem resistant in the clinic. Cefiderocol susceptibility was high against non-fermenters, and there was no apparent cross resistance between cefiderocol and ß-lactam/ß-lactamase inhibitor combinations, with the exception of sulbactam-durlobactam. These results provide insights into therapeutic options for infections due to resistant P. aeruginosa and Acinetobacter spp. and indicate how early susceptibility testing of cefiderocol in parallel with ß-lactam/ß-lactamase inhibitor combinations will allow clinicians to choose the effective treatment(s) from all available options. This is particularly important as current treatment options against non-fermenters are limited.


Assuntos
Acinetobacter , Infecções por Pseudomonas , Humanos , Meropeném/farmacologia , Cefiderocol , Inibidores de beta-Lactamases/farmacologia , Pseudomonas aeruginosa , Lactamas/farmacologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefalosporinas/farmacologia , Infecções por Pseudomonas/tratamento farmacológico , Bactérias Gram-Negativas , Testes de Sensibilidade Microbiana , beta-Lactamases/genética
11.
Microbiol Spectr ; 12(5): e0322323, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38526086

RESUMO

Gram-negative metallo-ß-lactamase-producing bacteria can be extremely problematic, especially when found to be extensively drug-resistant (XDR). Cefiderocol is a novel antimicrobial that has been shown to overcome most carbapenemases, with very rare resistance reported to date. Within our institution, two multidrug-resistant and one XDR strains were isolated from a patient who recently emigrated from India. Each isolate underwent whole-genome sequencing to resolve plasmids and determine phylogenetics, strain typing, and mechanisms of resistance. The XDR E. coli was ST167, harbored NDM-5, cirA and PBP3 mutations, consistent with cefiderocol resistance. Our study suggests that the NDM region is required in conjunction with cirA and PBP3 mutations. It is not clear why; however, our study did determine a potential novel iron-transport region unique to the cefiderocol-resistant isolate. This is the first characterized cefiderocol-resistant E.coli reported from Canada. Health centers should be on alert for this clone.IMPORTANCEThe development of cefiderocol, a novel siderophore cephalosporin, has provided additional options to the treatment of extensively drug-resistant (XDR) Gram-negative bacteria. Resistance to cefiderocol is poorly understood and only recently described. Here, we describe a case of a patient with recent travel to India harboring three Escherichia coli isolates, one resistant and two susceptible to cefiderocol. Two isolates are highly similar genetically, allowing the mechanism of resistance to be described more closely. The importance of this manuscript contributes both globally to the understanding of cefiderocol resistance in E. coli as well as nationally as this is the first resistant case reported in Canada. This is especially concerning as cefiderocol is not currently approved in Canada. The implications of reporting emerging resistance to new antimicrobials for XDR Gram negatives are impactful to infectious disease specialists, clinical microbiologists, physicians, and public health.


Assuntos
Antibacterianos , Cefiderocol , Cefalosporinas , Farmacorresistência Bacteriana Múltipla , Infecções por Escherichia coli , Escherichia coli , Testes de Sensibilidade Microbiana , beta-Lactamases , Humanos , Escherichia coli/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/tratamento farmacológico , Antibacterianos/farmacologia , Cefalosporinas/farmacologia , beta-Lactamases/genética , beta-Lactamases/metabolismo , Canadá , Farmacorresistência Bacteriana Múltipla/genética , Índia , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Sequenciamento Completo do Genoma , Plasmídeos/genética , Filogenia , Mutação , Masculino
13.
Antimicrob Agents Chemother ; 68(5): e0136323, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38526050

RESUMO

We subjected seven P. aeruginosa isolates to a 10-day serial passaging against five antipseudomonal agents to evaluate resistance levels post-exposure and putative resistance mechanisms in terminal mutants were analyzed by whole-genome sequencing analysis. Meropenem (mean, 38-fold increase), cefepime (14.4-fold), and piperacillin-tazobactam (52.9-fold) terminal mutants displayed high minimum inhibitory concentration (MIC) values compared to those obtained after exposure to ceftolozane-tazobactam (11.4-fold) and ceftazidime-avibactam (5.7-fold). Fewer isolates developed elevated MIC values for other ß-lactams and agents belonging to other classes when exposed to meropenem in comparison to other agents. Alterations in nalC and nalD, involved in the upregulation of the efflux pump system MexAB-OprM, were common and observed more frequently in isolates exposed to ceftazidime-avibactam and meropenem. These alterations, along with ones in mexR and amrR, provided resistance to most ß-lactams and levofloxacin but not imipenem. The second most common gene altered was mpl, which is involved in the recycling of the cell wall peptidoglycan. These alterations were mainly noted in isolates exposed to ceftolozane-tazobactam and piperacillin-tazobactam but also in one cefepime-exposed isolate. Alterations in other genes known to be involved in ß-lactam resistance (ftsI, oprD, phoP, pepA, and cplA) and multiple genes involved in lipopolysaccharide biosynthesis were also present. The data generated here suggest that there is a difference in the mechanisms selected for high-level resistance between newer ß-lactam/ß-lactamase inhibitor combinations and older agents. Nevertheless, the isolates exposed to all agents displayed elevated MIC values for other ß-lactams (except imipenem) and quinolones tested mainly due to alterations in the MexAB-OprM regulators that extrude these agents.


Assuntos
Antibacterianos , Compostos Azabicíclicos , Ceftazidima , Meropeném , Testes de Sensibilidade Microbiana , Combinação Piperacilina e Tazobactam , Pseudomonas aeruginosa , Tazobactam , Inibidores de beta-Lactamases , beta-Lactamas , Antibacterianos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Inibidores de beta-Lactamases/farmacologia , Compostos Azabicíclicos/farmacologia , Meropeném/farmacologia , Tazobactam/farmacologia , Ceftazidima/farmacologia , beta-Lactamas/farmacologia , Combinação Piperacilina e Tazobactam/farmacologia , Combinação de Medicamentos , Cefalosporinas/farmacologia , Cefepima/farmacologia , Humanos , Piperacilina/farmacologia , Sequenciamento Completo do Genoma , Farmacorresistência Bacteriana Múltipla/genética
14.
J Clin Microbiol ; 62(4): e0078821, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38457194

RESUMO

Traditionally, cephalothin susceptibility results were used to predict the susceptibility of additional cephalosporins; however, in 2013-2014, the Clinical and Laboratory Standards Institute (CLSI) revisited this practice and determined that cefazolin is a more accurate proxy than cephalothin for uncomplicated urinary tract infections (uUTIs). Therefore, a cefazolin surrogacy breakpoint was established to predict the susceptibility of seven oral cephalosporins for Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis in the context of uUTIs. Clinical microbiology laboratories face several operational challenges when implementing the cefazolin surrogacy breakpoint, which may lead to confusion for the best path forward. Here, we review the historical context and data behind the surrogacy breakpoints, review PK/PD profiles for oral cephalosporins, discuss challenges in deploying the breakpoint, and highlight the limited clinical outcome data in this space.


Assuntos
Cefazolina , Infecções Urinárias , Humanos , Cefazolina/farmacologia , Cefazolina/uso terapêutico , Cefalosporinas/farmacologia , Cefalotina , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Testes de Sensibilidade Microbiana , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Escherichia coli , Monobactamas
15.
ACS Infect Dis ; 10(4): 1298-1311, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38446051

RESUMO

Effective treatment of gonorrhea is threatened by the increasing prevalence of Neisseria gonorrhoeae strains resistant to the extended-spectrum cephalosporins (ESCs). Recently, we demonstrated the promise of the third-generation cephalosporin cefoperazone as an antigonococcal agent due to its rapid second-order rate of acylation against penicillin-binding protein 2 (PBP2) from the ESC-resistant strain H041 and robust antimicrobial activity against H041. Noting the presence of a ureido moiety in cefoperazone, we evaluated a subset of structurally similar ureido ß-lactams, including piperacillin, azlocillin, and mezlocillin, for activity against PBP2 from H041 using biochemical and structural analyses. We found that the ureidopenicillin piperacillin has a second-order rate of acylation against PBP2 that is 12-fold higher than cefoperazone and 85-fold higher than ceftriaxone and a lower MIC against H041 than ceftriaxone. Surprisingly, the affinity of ureidopenicillins for PBP2 is minimal, indicating that their inhibitory potency is due to a higher rate of the acylation step of the reaction compared to cephalosporins. Enhanced acylation results from the combination of a penam scaffold with a 2,3-dioxopiperazine-containing R1 group. Crystal structures show that the ureido ß-lactams overcome the effects of resistance mutations present in PBP2 from H041 by eliciting conformational changes that are hindered when PBP2 interacts with the weaker inhibitor ceftriaxone. Overall, our results support the potential of piperacillin as a treatment for gonorrhea and provide a framework for the future design of ß-lactams with improved activity against ESC-resistant N. gonorrhoeae.


Assuntos
Ceftriaxona , Gonorreia , Humanos , Ceftriaxona/metabolismo , Ceftriaxona/farmacologia , Neisseria gonorrhoeae/genética , Gonorreia/tratamento farmacológico , Proteínas de Ligação às Penicilinas/genética , Proteínas de Ligação às Penicilinas/metabolismo , Cefoperazona/farmacologia , Cefalosporinas/farmacologia , Cefalosporinas/metabolismo , Piperacilina/metabolismo , Piperacilina/farmacologia , beta-Lactamas/farmacologia
16.
Eur J Med Chem ; 268: 116293, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38447461

RESUMO

Global public health is facing a serious problem as a result of the rise in antibiotic resistance and the decline in the discovery of new antibiotics. In this study, two series of amphiphilic-cephalosporins were designed and synthesized, several of which showed good antibacterial activity against both Gram-positive and Gram-negative bacteria. Structure-activity relationships indicated that the length of the hydrophobic alkyl chain significantly affects the antibacterial activity against Gram-negative bacteria. The best compound 2d showed high activity against drug-susceptible Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) with MICs of 0.5 and 2-4 µg/mL, respectively. Furthermore, 2d remained active in complex mammalian body fluids and had a longer post-antibiotic effect (PAE) than vancomycin. Mechanism studies indicated that compound 2d lacks membrane-damaging properties and can target penicillin-binding proteins to disrupt bacterial cell wall structure, inhibit the metabolic activity and induce the accumulation of reactive oxygen species (ROS) in bacteria. Compound 2d showed minimal drug resistance and was nontoxic to HUVEC and HBZY-1 cells with CC50 > 128 µg/mL. These findings suggest that 2d is a promising drug candidate for treating bacterial infections.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Animais , Antibacterianos/química , Cefalosporinas/farmacologia , Bactérias Gram-Positivas , Bactérias Gram-Negativas , Monobactamas/farmacologia , Testes de Sensibilidade Microbiana , Mamíferos
17.
PLoS Genet ; 20(3): e1011215, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38512984

RESUMO

Enterococci are commensal members of the gastrointestinal tract and also major nosocomial pathogens. They possess both intrinsic and acquired resistance to many antibiotics, including intrinsic resistance to cephalosporins that target bacterial cell wall synthesis. These antimicrobial resistance traits make enterococcal infections challenging to treat. Moreover, prior therapy with antibiotics, including broad-spectrum cephalosporins, promotes enterococcal proliferation in the gut, resulting in dissemination to other sites of the body and subsequent infection. As a result, a better understanding of mechanisms of cephalosporin resistance is needed to enable development of new therapies to treat or prevent enterococcal infections. We previously reported that flow of metabolites through the peptidoglycan biosynthesis pathway is one determinant of enterococcal cephalosporin resistance. One factor that has been implicated in regulating flow of metabolites into cell wall biosynthesis pathways of other Gram-positive bacteria is GlmR. In enterococci, GlmR is encoded as the middle gene of a predicted 3-gene operon along with YvcJ and YvcL, whose functions are poorly understood. Here we use genetics and biochemistry to investigate the function of the enterococcal yvcJ-glmR-yvcL gene cluster. Our results reveal that YvcL is a DNA-binding protein that regulates expression of the yvcJ-glmR-yvcL operon in response to cell wall stress. YvcJ and GlmR bind UDP-GlcNAc and reciprocally regulate cephalosporin resistance in E. faecalis, and binding of UDP-GlcNAc by YvcJ appears essential for its activity. Reciprocal regulation by YvcJ/GlmR is essential for fitness during exposure to cephalosporin stress. Additionally, our results indicate that enterococcal GlmR likely acts by a different mechanism than the previously studied GlmR of Bacillus subtilis, suggesting that the YvcJ/GlmR regulatory module has evolved unique targets in different species of bacteria.


Assuntos
Resistência às Cefalosporinas , Cefalosporinas , Cefalosporinas/farmacologia , Cefalosporinas/metabolismo , Resistência às Cefalosporinas/genética , Antibacterianos/farmacologia , Enterococcus faecalis/genética , Óperon/genética , Difosfato de Uridina/metabolismo
18.
Int J Antimicrob Agents ; 63(5): 107148, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38508535

RESUMO

OBJECTIVE: Predictions of antimicrobial effects typically rely on plasma-based pharmacokinetic-pharmacodynamic (PK-PD) targets, ignoring target-site concentrations and potential differences in tissue penetration between antibiotics. In this study, we applied PK-PD modelling to compare target site-specific effects of antibiotics by integrating clinical microdialysis data, in vitro time-kill curves, and antimicrobial susceptibility distributions. As a case study, we compared the effect of lefamulin and ceftaroline against methicillin-resistant Staphylococcus aureus (MRSA) at soft-tissue concentrations. METHODS: A population PK model describing lefamulin concentrations in plasma, subcutaneous adipose and muscle tissue was developed. For ceftaroline, a similar previously reported PK model was adopted. In vitro time-kill experiments were performed with six MRSA isolates and a PD model was developed to describe bacterial growth and antimicrobial effects. The clinical PK and in vitro PD models were linked to compare antimicrobial effects of ceftaroline and lefamulin at the different target sites. RESULTS: Considering minimum inhibitory concentration (MIC) distributions and standard dosages, ceftaroline showed superior anti-MRSA effects compared to lefamulin both at plasma and soft-tissue concentrations. Looking at the individual antibiotics, lefamulin effects were highest at soft-tissue concentrations, while ceftaroline effects were highest at plasma concentrations, emphasising the importance of considering target-site PK-PD in antibiotic treatment optimisation. CONCLUSION: Given standard dosing regimens, ceftaroline appeared more effective than lefamulin against MRSA at soft-tissue concentrations. The PK-PD model-based approach applied in this study could be used to compare or explore the potential of antibiotics for specific indications or in populations with unique target-site PK.


Assuntos
Antibacterianos , Ceftarolina , Cefalosporinas , Diterpenos , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Compostos Policíclicos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Cefalosporinas/farmacologia , Cefalosporinas/farmacocinética , Humanos , Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Tioglicolatos/farmacologia , Tioglicolatos/farmacocinética , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia
19.
Int J Antimicrob Agents ; 63(5): 107150, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38513748

RESUMO

OBJECTIVES: To analyse the impact of the most clinically relevant ß-lactamases and their interplay with low outer membrane permeability on the activity of cefiderocol, ceftazidime/avibactam, aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/xeruborbactam and meropenem/nacubactam against recombinant Escherichia coli strains. METHODS: We constructed 82 E. coli laboratory transformants expressing the main ß-lactamases circulating in Enterobacterales (70 expressing single ß-lactamase and 12 producing double carbapenemase) under high (E. coli TG1) and low (E. coli HB4) permeability conditions. Antimicrobial susceptibility testing was determined by reference broth microdilution. RESULTS: Aztreonam/avibactam, cefepime/zidebactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam were active against all E. coli TG1 transformants. Imipenem/relebactam, meropenem/vaborbactam, cefepime/taniborbactam and cefepime/enmetazobactam were also highly active, but unstable against most of MBL-producing transformants. Combination of ß-lactamases with porin deficiency (E. coli HB4) did not significantly affect the activity of aztreonam/avibactam, cefepime/zidebactam, cefiderocol or meropenem/nacubactam, but limited the effectiveness of the rest of carbapenem- and cefepime-based combinations. Double-carbapenemase production resulted in the loss of activity of most of the compounds tested, an effect particularly evident for those E. coli HB4 transformants in which MBLs were present. CONCLUSIONS: Our findings highlight the promising activity that cefiderocol and new ß-lactam/ß-lactamase inhibitors have against recombinant E. coli strains expressing widespread ß-lactamases, including when these are combined with low permeability or other enzymes. Aztreonam/avibactam, cefiderocol, cefepime/zidebactam and meropenem/nacubactam will help to mitigate to some extent the urgency of new compounds able to resist MBL action, although NDM enzymes represent a growing challenge against which drug development efforts are still needed.


Assuntos
Antibacterianos , Compostos Azabicíclicos , Ácidos Borínicos , Ácidos Carboxílicos , Cefepima , Cefiderocol , Ceftazidima , Cefalosporinas , Ciclo-Octanos , Combinação de Medicamentos , Escherichia coli , Lactamas , Testes de Sensibilidade Microbiana , Triazóis , Inibidores de beta-Lactamases , beta-Lactamases , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , beta-Lactamases/genética , beta-Lactamases/metabolismo , Cefalosporinas/farmacologia , Inibidores de beta-Lactamases/farmacologia , Compostos Azabicíclicos/farmacologia , Antibacterianos/farmacologia , Ciclo-Octanos/farmacologia , Ceftazidima/farmacologia , Cefepima/farmacologia , Ácidos Borônicos/farmacologia , Meropeném/farmacologia , Aztreonam/farmacologia , Imipenem/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Compostos Heterocíclicos com 1 Anel/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos
20.
J Appl Microbiol ; 135(4)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38444193

RESUMO

AIM: This study aimed to compare and characterize the resistance profile and the presence of extended-spectrum beta-lactamase (ESBL) related genes in Escherichia coli isolated from healthy finishing pigs fed with or without antibiotics in their diets. METHODS AND RESULTS: A total of 27 ceftiofur-resistant E. coli isolates were obtained from 96 healthy pigs. The antibiotic resistance profile was tested, and all 27 isolates were classified as multidrug-resistant (MDR). A high proportion of isolates were resistant to cephalosporins, ampicillin, ciprofloxacin, and tetracyclines. The ESBL production was observed in 85% of isolates by double-disc synergy test. The MDR-E. coli isolates harbored ESBL genes, such as blaTEM, blaCTX-M-1, blaCTX-M-2, and blaCTX-M-8,25. In addition, other antibiotics resistance genes (ARGs) were also detected, such as sul2, ant(3″)-I, tetA, and mcr-1. The mobilization of the blaCTX-M gene was confirmed for nine E. coli isolates by conjugation assays. The presence of blaCTX-M on mobile genetic elements in these isolates was demonstrated by Southern blot hybridization, and the resistance to cephalosporins was confirmed in the transconjugants. Our results indicate the prevalence of CTX-M-producing E. coli strains harboring mobile genetic elements in the normal microbiota of healthy pigs. CONCLUSIONS: These findings highlight the significance of ESBL genes as a global health concern in livestock and the potential spread of antimicrobial resistance to other members of the gastrointestinal tract microbiota.


Assuntos
Infecções por Escherichia coli , Escherichia coli , Animais , Suínos , Gado , Prevalência , beta-Lactamases/genética , beta-Lactamases/metabolismo , Cefalosporinas/farmacologia , Antibacterianos/farmacologia , Infecções por Escherichia coli/epidemiologia , Infecções por Escherichia coli/veterinária , Farmacorresistência Bacteriana Múltipla/genética , Plasmídeos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...