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Article ; Online: Emergence of cefiderocol resistance during ceftazidime/avibactam treatment caused by a large genomic deletion, including

Gomis-Font, María A / Clari, María A / López-Causapé, Carla / Navarro, David / Oliver, Antonio

2023 Volume 68, Issue 1, Page(s) e0119223

Abstract: We report the emergence of cefiderocol resistance during the treatment of a ... ...

Abstract	We report the emergence of cefiderocol resistance during the treatment of a ST312
MeSH term(s)	Humans ; Ceftazidime/pharmacology ; Ceftazidime/therapeutic use ; Cefiderocol ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Pseudomonas aeruginosa/genetics ; Bacterial Proteins/genetics ; Pseudomonas Infections/drug therapy ; Azabicyclo Compounds/pharmacology ; Azabicyclo Compounds/therapeutic use ; Drug Combinations ; Genomics ; Microbial Sensitivity Tests ; beta-Lactamases/genetics
Chemical Substances	Ceftazidime (9M416Z9QNR) ; Cefiderocol (SZ34OMG6E8) ; Anti-Bacterial Agents ; avibactam (7352665165) ; Bacterial Proteins ; Azabicyclo Compounds ; Drug Combinations ; beta-Lactamases (EC 3.5.2.6)
Language	English
Publishing date	2023-12-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/aac.01192-23
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Article ; Online: In vitro activity of cefiderocol in Pseudomonas aeruginosa isolates from people with cystic fibrosis recovered during three multicentre studies in Spain.

Maruri-Aransolo, Ainhize / López-Causapé, Carla / Hernández-García, Marta / García-Castillo, María / Caballero-Pérez, Juan de Dios / Oliver, Antonio / Cantón, Rafael

The Journal of antimicrobial chemotherapy

2024

Abstract: Objectives: Despite the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, Pseudomonas aeruginosa is still a major pathogen in people with cystic fibrosis (pwCF). We determine the activity of cefiderocol and ... ...

Abstract	Objectives: Despite the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, Pseudomonas aeruginosa is still a major pathogen in people with cystic fibrosis (pwCF). We determine the activity of cefiderocol and comparators in a collection of 154 P. aeruginosa isolates recovered from pwCF during three multicentre studies performed in 17 Spanish hospitals in 2013, 2017 and 2021. Methods: ISO broth microdilution was performed and MICs were interpreted with CLSI and EUCAST criteria. Mutation frequency and WGS were also performed. Results: Overall, 21.4% were MDR, 20.8% XDR and 1.3% pandrug-resistant (PDR). Up to 17% of the isolates showed a hypermutator phenotype. Cefiderocol demonstrated excellent activity; only 13 isolates (8.4%) were cefiderocol resistant by EUCAST (none using CLSI). A high proportion of the isolates resistant to ceftolozane/tazobactam (71.4%), meropenem/vaborbactam (70.0%), imipenem/relebactam (68.0%) and ceftazidime/avibactam (55.6%) were susceptible to cefiderocol. Nine out of 13 cefiderocol-resistant isolates were hypermutators (P < 0.001). Eighty-three STs were detected, with ST98 being the most frequent. Only one isolate belonging to the ST175 high-risk clone carried blaVIM-2. Exclusive mutations affecting genes involved in membrane permeability, AmpC overexpression (L320P-AmpC) and efflux pump up-regulation were found in cefiderocol-resistant isolates (MIC = 4-8 mg/L). Cefiderocol resistance could also be associated with mutations in genes related to iron uptake (tonB-dependent receptors and pyochelin/pyoverdine biosynthesis). Conclusions: Our results position cefiderocol as a therapeutic option in pwCF infected with P. aeruginosa resistant to most recent β-lactam/β-lactamase inhibitor combinations.
Language	English
Publishing date	2024-05-06
Publishing country	England
Document type	Journal Article
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkae126
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Zs.A 1197: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Low Ciprofloxacin Concentrations Select Multidrug-Resistant Mutants Overproducing Efflux Pumps in Clinical Isolates of Pseudomonas aeruginosa.

Sanz-García, Fernando / Hernando-Amado, Sara / López-Causapé, Carla / Oliver, Antonio / Martínez, José Luis

Microbiology spectrum

2022 Volume 10, Issue 5, Page(s) e0072322

Abstract: Low antibiotic concentrations present in natural environments are a severe and often neglected threat to public health. Even if they are present below their MICs, they may select for antibiotic-resistant pathogens. Notably, the minimal subinhibitory ... ...

Abstract	Low antibiotic concentrations present in natural environments are a severe and often neglected threat to public health. Even if they are present below their MICs, they may select for antibiotic-resistant pathogens. Notably, the minimal subinhibitory concentrations that select resistant bacteria, and define the respective sub-MIC selective windows, differ between antibiotics. The establishment of these selective concentrations is needed for risk-assessment studies regarding the presence of antibiotics in different habitats. Using short-term evolution experiments in a set of 12 Pseudomonas aeruginosa clinical isolates (including high-risk clones with ubiquitous distribution), we have determined that ciprofloxacin sub-MIC selective windows are strain specific and resistome dependent. Nonetheless, in all cases, clinically relevant multidrug-resistant (MDR) mutants emerged upon exposure to low ciprofloxacin concentrations, with these concentrations being below the levels reported in ciprofloxacin-polluted natural habitats where P. aeruginosa can be present. This feature expands the conditions and habitats where clinically relevant quinolone-resistant mutants can emerge. In addition, we established the lowest concentration threshold beyond which P. aeruginosa, regardless of the strain, becomes resistant to ciprofloxacin. Three days of exposure under this sub-MIC "risk concentration" led to the selection of MDR mutants that displayed resistance mechanisms usually ascribed to high selective pressures, i.e., the overproduction of the efflux pumps MexCD-OprJ and MexEF-OprN. From a One-Health viewpoint, these data stress the transcendent role of low drug concentrations, which can be encountered in natural ecosystems, in aggravating the antibiotic resistance problem, especially when it comes to pathogens of environmental origin.
MeSH term(s)	Pseudomonas aeruginosa/genetics ; Ciprofloxacin/pharmacology ; Ecosystem ; Membrane Transport Proteins ; Microbial Sensitivity Tests ; Anti-Bacterial Agents/pharmacology
Chemical Substances	Ciprofloxacin (5E8K9I0O4U) ; Membrane Transport Proteins ; Anti-Bacterial Agents
Language	English
Publishing date	2022-08-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2807133-5
ISSN	2165-0497 ; 2165-0497
ISSN (online)	2165-0497
ISSN	2165-0497
DOI	10.1128/spectrum.00723-22
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Article ; Online: Insights into the evolution of the mutational resistome of Pseudomonas aeruginosa in cystic fibrosis.

López-Causapé, Carla / Oliver, Antonio

Future microbiology

2017 Volume 12, Page(s) 1445–1448

MeSH term(s)	Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Chronic Disease ; Cystic Fibrosis/drug therapy ; Cystic Fibrosis/microbiology ; Drug Resistance, Multiple, Bacterial/drug effects ; Drug Resistance, Multiple, Bacterial/genetics ; Evolution, Molecular ; Genome, Viral/genetics ; Humans ; Mutation ; Pseudomonas Infections/drug therapy ; Pseudomonas Infections/microbiology ; Pseudomonas aeruginosa/genetics ; Pseudomonas aeruginosa/physiology
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2017-10-25
Publishing country	England
Document type	Editorial ; Research Support, Non-U.S. Gov't
ISSN	1746-0921
ISSN (online)	1746-0921
DOI	10.2217/fmb-2017-0197
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Article ; Online: Pseudomonas aeruginosa epidemic high-risk clones and their association with horizontally-acquired β-lactamases: 2020 update.

Del Barrio-Tofiño, Ester / López-Causapé, Carla / Oliver, Antonio

International journal of antimicrobial agents

2020 Volume 56, Issue 6, Page(s) 106196

Abstract: Pseudomonas aeruginosa global clones associated with multidrug-resistant (MDR) and extensively drug-resistant (XDR) phenotypes, denominated high-risk clones, are a growing threat in hospitals worldwide. Here we provide a 2020 update on nosocomial MDR/XDR ...

Abstract	Pseudomonas aeruginosa global clones associated with multidrug-resistant (MDR) and extensively drug-resistant (XDR) phenotypes, denominated high-risk clones, are a growing threat in hospitals worldwide. Here we provide a 2020 update on nosocomial MDR/XDR high-risk P. aeruginosa clones. According to their prevalence, global spread and association with MDR/XDR profiles and regarding extended-spectrum β-lactamases (ESBLs) and carbapenemases, the worldwide top 10 P. aeruginosa high-risk clones includes ST235, ST111, ST233, ST244, ST357, ST308, ST175, ST277, ST654 and ST298. ST235 is certainly the most relevant high-risk clone, showing a worldwide dissemination associated with over 60 different β-lactamase variants, including multiple carbapenemases from classes A and B. Moreover, ST235 shows a highly virulent phenotype associated with a high mortality rate, likely due to the production of the ExoU cytotoxin. ST111 and ST233 are also worldwide disseminated MDR/XDR clones, particularly linked to VIM-2 metallo-β-lactamase (MBL), whereas ST244 is a very prevalent clone not always associated with MDR/XDR profiles. ST357, ST308 and ST298 are also exoU+ and are therefore potentially associated with higher virulence. In contrast, ST175, prevalent in some European countries, shows a MDR/XDR phenotype frequently caused by specific chromosomal mutations and is associated with lower virulence. Finally, ST277 is highly prevalent in Brazil and is specifically associated with the SPM MBL. A deeper understanding of the underlying factors driving the success of high-risk clones, including the reported increased capacity for acquiring exogenous determinants, increased spontaneous mutation rates or greater ability to develop biofilms, is required to develop global strategies to combat them.
MeSH term(s)	Anti-Bacterial Agents/pharmacology ; Bacterial Proteins/genetics ; Brazil/epidemiology ; Drug Resistance, Multiple, Bacterial/genetics ; Gene Transfer, Horizontal/genetics ; Humans ; Microbial Sensitivity Tests ; Molecular Epidemiology ; Pseudomonas Infections/drug therapy ; Pseudomonas Infections/epidemiology ; Pseudomonas Infections/microbiology ; Pseudomonas aeruginosa/drug effects ; Pseudomonas aeruginosa/genetics ; Pseudomonas aeruginosa/isolation & purification ; beta-Lactamases/genetics
Chemical Substances	Anti-Bacterial Agents ; Bacterial Proteins ; beta-Lactamases (EC 3.5.2.6) ; carbapenemase (EC 3.5.2.6)
Language	English
Publishing date	2020-10-09
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1093977-5
ISSN	1872-7913 ; 0924-8579
ISSN (online)	1872-7913
ISSN	0924-8579
DOI	10.1016/j.ijantimicag.2020.106196
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Article ; Online: Predicting Pseudomonas aeruginosa susceptibility phenotypes from whole genome sequence resistome analysis.

Cortes-Lara, Sara / Barrio-Tofiño, Ester Del / López-Causapé, Carla / Oliver, Antonio

Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases

2021 Volume 27, Issue 11, Page(s) 1631–1637

Abstract: Objectives: The aim was to develop and validate a Pseudomonas aeruginosa genotypic resistance score, based on analysis of the whole genome sequence resistome, to predict antimicrobial susceptibility phenotypes.: Methods: A scoring system based on the ...

Abstract	Objectives: The aim was to develop and validate a Pseudomonas aeruginosa genotypic resistance score, based on analysis of the whole genome sequence resistome, to predict antimicrobial susceptibility phenotypes. Methods: A scoring system based on the analysis of mutation-driven resistance in 40 chromosomal genes and horizontally acquired resistance (Resfinder) was developed for ceftazidime, ceftolozane/tazobactam, meropenem, ciprofloxacin and tobramycin. Resistance genes/mutations were scored from 0 (no effect) to 1 (EUCAST clinical resistance). One hundred wild-type strains obtained from 51 different hospitals during a 2017 multicentre study were fully sequenced and analysed in order to define a catalogue of natural polymorphisms in the 40 chromosomal resistance genes. The capacity of genotypic score to predict the susceptibility phenotype was tested in 204 isolates randomly selected from the 51 hospitals (four from each hospital). Results: The analysis of the 100 wild-type isolates yielded a catalogue of 455 natural polymorphisms in the 40 genes involved in mutational resistance. However, resistance mutations and high-risk clones (such as ST235) were also documented among a few wild-type isolates. Overall, the capacity of the genotypic score (<0.5) for predicting phenotypic susceptibility (S + I in the case of meropenem) was very high (95-100%). In contrast, the capacity of the genotypic score to predict resistance (≥1) was far more variable depending on the agent. Prediction of meropenem clinical resistance was particularly low (18/39, 46.1%), whereas it classified clinical ceftolozane/tazobactam resistance in 100% (7/7) of cases. Discussion: Although a margin for improvement was evidenced in this proof of concept study, an overall good correlation between the genotypic resistance score and the susceptibility profile was documented. Further refining of the scoring system, automatization and testing of large international cohorts should follow.
MeSH term(s)	Anti-Bacterial Agents/pharmacology ; Cephalosporins ; Drug Resistance, Multiple, Bacterial/genetics ; Genome, Bacterial ; Humans ; Meropenem ; Microbial Sensitivity Tests ; Phenotype ; Pseudomonas Infections/drug therapy ; Pseudomonas aeruginosa/drug effects ; Pseudomonas aeruginosa/genetics ; Tazobactam
Chemical Substances	Anti-Bacterial Agents ; Cephalosporins ; Meropenem (FV9J3JU8B1) ; Tazobactam (SE10G96M8W)
Language	English
Publishing date	2021-05-18
Publishing country	England
Document type	Journal Article ; Multicenter Study
ZDB-ID	1328418-6
ISSN	1469-0691 ; 1470-9465 ; 1198-743X
ISSN (online)	1469-0691
ISSN	1470-9465 ; 1198-743X
DOI	10.1016/j.cmi.2021.05.011
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Article: Pseudomonas aeruginosa epidemic high-risk clones and their association with horizontally-acquired β-lactamases: 2020 update

del Barrio-Tofiño, Ester / López-Causapé, Carla / Oliver, Antonio

International journal of antimicrobial agents. 2020 Dec., v. 56, no. 6

2020

Abstract	Pseudomonas aeruginosa global clones associated with multidrug-resistant (MDR) and extensively drug-resistant (XDR) phenotypes, denominated high-risk clones, are a growing threat in hospitals worldwide. Here we provide a 2020 update on nosocomial MDR/XDR high-risk P. aeruginosa clones. According to their prevalence, global spread and association with MDR/XDR profiles and regarding extended-spectrum β-lactamases (ESBLs) and carbapenemases, the worldwide top 10 P. aeruginosa high-risk clones includes ST235, ST111, ST233, ST244, ST357, ST308, ST175, ST277, ST654 and ST298. ST235 is certainly the most relevant high-risk clone, showing a worldwide dissemination associated with over 60 different β-lactamase variants, including multiple carbapenemases from classes A and B. Moreover, ST235 shows a highly virulent phenotype associated with a high mortality rate, likely due to the production of the ExoU cytotoxin. ST111 and ST233 are also worldwide disseminated MDR/XDR clones, particularly linked to VIM-2 metallo-β-lactamase (MBL), whereas ST244 is a very prevalent clone not always associated with MDR/XDR profiles. ST357, ST308 and ST298 are also exoU+ and are therefore potentially associated with higher virulence. In contrast, ST175, prevalent in some European countries, shows a MDR/XDR phenotype frequently caused by specific chromosomal mutations and is associated with lower virulence. Finally, ST277 is highly prevalent in Brazil and is specifically associated with the SPM MBL. A deeper understanding of the underlying factors driving the success of high-risk clones, including the reported increased capacity for acquiring exogenous determinants, increased spontaneous mutation rates or greater ability to develop biofilms, is required to develop global strategies to combat them.
Keywords	Pseudomonas aeruginosa ; anti-infective agents ; beta-lactamase ; biofilm ; clones ; cross infection ; cytotoxins ; exhibitions ; hospitals ; mortality ; multiple drug resistance ; mutation rate ; phenotype ; prevalence ; spontaneous mutation ; virulence ; Brazil ; Europe
Language	English
Dates of publication	2020-12
Publishing place	Elsevier Ltd
Document type	Article
Note	NAL-light
ZDB-ID	1093977-5
ISSN	1872-7913 ; 0924-8579
ISSN (online)	1872-7913
ISSN	0924-8579
DOI	10.1016/j.ijantimicag.2020.106196
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Article ; Online: Rapid Phenotypic Convergence towards Collateral Sensitivity in Clinical Isolates of Pseudomonas aeruginosa Presenting Different Genomic Backgrounds.

Hernando-Amado, Sara / López-Causapé, Carla / Laborda, Pablo / Sanz-García, Fernando / Oliver, Antonio / Martínez, José Luis

Microbiology spectrum

2022 Volume 11, Issue 1, Page(s) e0227622

Abstract: Collateral sensitivity (CS) is an evolutionary trade-off by which acquisition of resistance to an antibiotic leads to increased susceptibility to another. This Achilles' heel of antibiotic resistance could be exploited to design evolution-based ... ...

Abstract	Collateral sensitivity (CS) is an evolutionary trade-off by which acquisition of resistance to an antibiotic leads to increased susceptibility to another. This Achilles' heel of antibiotic resistance could be exploited to design evolution-based strategies for treating bacterial infections. To date, most studies in the field have focused on the identification of CS patterns in model strains. However, one of the main requirements for the clinical application of this trade-off is that it must be robust and has to emerge in different genomic backgrounds, including preexisting drug-resistant isolates, since infections are frequently caused by pathogens already resistant to antibiotics. Here, we report the first analysis of CS robustness in clinical strains of Pseudomonas aeruginosa presenting different
MeSH term(s)	Humans ; Pseudomonas aeruginosa/genetics ; Aztreonam/therapeutic use ; Pseudomonas Infections/microbiology ; Drug Collateral Sensitivity ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Tobramycin/therapeutic use ; Ciprofloxacin/pharmacology ; Genomics ; Microbial Sensitivity Tests
Chemical Substances	Aztreonam (G2B4VE5GH8) ; Anti-Bacterial Agents ; Tobramycin (VZ8RRZ51VK) ; Ciprofloxacin (5E8K9I0O4U)
Language	English
Publishing date	2022-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2807133-5
ISSN	2165-0497 ; 2165-0497
ISSN (online)	2165-0497
ISSN	2165-0497
DOI	10.1128/spectrum.02276-22
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Article ; Online: Synergistic effects of inhaled aztreonam plus tobramycin on hypermutable cystic fibrosis Pseudomonas aeruginosa isolates in a dynamic biofilm model evaluated by mechanism-based modelling and whole genome sequencing.

Breen, Siobhonne K J / Harper, Marina / López-Causapé, Carla / Rogers, Kate E / Tait, Jessica R / Smallman, Thomas R / Lang, Yinzhi / Lee, Wee L / Zhou, Jieqiang / Zhang, Yongzhen / Bulitta, Jurgen B / Nation, Roger L / Oliver, Antonio / Boyce, John D / Landersdorfer, Cornelia B

International journal of antimicrobial agents

2024 Volume 63, Issue 6, Page(s) 107161

Abstract: Objective: Hypermutable Pseudomonas aeruginosa strains are highly prevalent in chronic lung infections of patients with cystic fibrosis (CF). Acute exacerbations of these infections have limited treatment options. This study aimed to investigate inhaled ...

Abstract	Objective: Hypermutable Pseudomonas aeruginosa strains are highly prevalent in chronic lung infections of patients with cystic fibrosis (CF). Acute exacerbations of these infections have limited treatment options. This study aimed to investigate inhaled aztreonam and tobramycin against clinical hypermutable P. aeruginosa strains using the CDC dynamic in vitro biofilm reactor (CBR), mechanism-based mathematical modelling (MBM) and genomic studies. Methods: Two CF multidrug-resistant strains were investigated in a 168 h CBR (n = 2 biological replicates). Regimens were inhaled aztreonam (75 mg 8-hourly) and tobramycin (300 mg 12-hourly) in monotherapies and combination. The simulated pharmacokinetic profiles of aztreonam and tobramycin (t Results: Both isolates showed reproducible bacterial regrowth and resistance amplification for the monotherapies by 168 h. The combination performed synergistically, with minimal resistant subpopulations compared to the respective monotherapies at 168 h. Mechanistic synergy appropriately described the antibacterial effects of the combination regimen in the MBM. Genomic analysis of colonies recovered from monotherapy regimens indicated noncanonical resistance mechanisms were likely responsible for treatment failure. Conclusion: The combination of aztreonam and tobramycin was required to suppress the regrowth and resistance of planktonic and biofilm bacteria in all biological replicates of both hypermutable multidrug-resistant P. aeruginosa CF isolates. The developed MBM could be utilised for future investigations of this promising inhaled combination.
Language	English
Publishing date	2024-03-30
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1093977-5
ISSN	1872-7913 ; 0924-8579
ISSN (online)	1872-7913
ISSN	0924-8579
DOI	10.1016/j.ijantimicag.2024.107161
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Article ; Online: Corrigendum to ``Emergence of high level and stable metronidazole resistance in Clostridioides difficile'' [International Journal of Antimicrobial Agents Vol. 55 (2020) 5830].

Arcay, Ricardo M / Suárez-Bode, Loreto / López-Causapé, Carla / Oliver, Antonio / Mena, Ana

International journal of antimicrobial agents

2020 Volume 55, Issue 6, Page(s) 105991

Language	English
Publishing date	2020-05-04
Publishing country	Netherlands
Document type	Journal Article ; Published Erratum
ZDB-ID	1093977-5
ISSN	1872-7913 ; 0924-8579
ISSN (online)	1872-7913
ISSN	0924-8579
DOI	10.1016/j.ijantimicag.2020.105991
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