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Article ; Online: Epidemiology, resistance genomics and susceptibility of

Lasarte-Monterrubio, Cristina / Guijarro-Sánchez, Paula / Alonso-Garcia, Isaac / Outeda, Michelle / Maceiras, Romina / González-Pinto, Lucia / Martínez-Guitián, Marta / Fernández-Lozano, Carlos / Vázquez-Ucha, Juan Carlos / Bou, German / Arca-Suárez, Jorge / Beceiro, Alejandro

Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin

2024 Volume 29, Issue 15

Abstract: BackgroundAs increasing antibiotic resistance ... ...

Abstract	BackgroundAs increasing antibiotic resistance in
MeSH term(s)	Humans ; Colistin/pharmacology ; beta-Lactamases/genetics ; Interleukin-1 Receptor-Like 1 Protein ; Acinetobacter Infections/drug therapy ; Acinetobacter Infections/epidemiology ; Anti-Bacterial Agents/pharmacology ; Acinetobacter baumannii/genetics ; Genomics ; Microbial Sensitivity Tests ; Bacterial Proteins/genetics
Chemical Substances	Colistin (Z67X93HJG1) ; beta-Lactamases (EC 3.5.2.6) ; Interleukin-1 Receptor-Like 1 Protein ; Anti-Bacterial Agents ; Bacterial Proteins
Language	English
Publishing date	2024-04-12
Publishing country	Sweden
Document type	Journal Article
ZDB-ID	1338803-4
ISSN	1560-7917 ; 1025-496X
ISSN (online)	1560-7917
ISSN	1025-496X
DOI	10.2807/1560-7917.ES.2024.29.15.2300352
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Article ; Online: Activity of cefiderocol and innovative β-lactam/β-lactamase inhibitor combinations against isogenic strains of Escherichia coli expressing single and double β-lactamases under high and low permeability conditions.

Blanco-Martín, Tania / Alonso-García, Isaac / González-Pinto, Lucía / Outeda-García, Michelle / Guijarro-Sánchez, Paula / López-Hernández, Inmaculada / Pérez-Vázquez, María / Aracil, Belén / López-Cerero, Lorena / Fraile-Ribot, Pablo / Oliver, Antonio / Vázquez-Ucha, Juan Carlos / Beceiro, Alejandro / Bou, Germán / Arca-Suárez, Jorge

International journal of antimicrobial agents

2024 Volume 63, Issue 5, Page(s) 107150

Abstract: Objectives: To analyse the impact of the most clinically relevant β-lactamases and their interplay with low outer membrane permeability on the activity of cefiderocol, ceftazidime/avibactam, aztreonam/avibactam, cefepime/enmetazobactam, cefepime/ ... ...

Abstract	Objectives: To analyse the impact of the most clinically relevant β-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 β-lactamases circulating in Enterobacterales (70 expressing single β-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 β-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 β-lactam/β-lactamase inhibitors have against recombinant E. coli strains expressing widespread β-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.
MeSH term(s)	Escherichia coli/drug effects ; Escherichia coli/genetics ; beta-Lactamases/genetics ; beta-Lactamases/metabolism ; Cephalosporins/pharmacology ; Microbial Sensitivity Tests ; beta-Lactamase Inhibitors/pharmacology ; Azabicyclo Compounds/pharmacology ; Anti-Bacterial Agents/pharmacology ; Drug Combinations ; Cyclooctanes/pharmacology ; Cefiderocol ; Ceftazidime/pharmacology ; Cefepime/pharmacology ; Boronic Acids/pharmacology ; Meropenem/pharmacology ; Aztreonam/pharmacology ; Imipenem/pharmacology ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Heterocyclic Compounds, 1-Ring/pharmacology ; Cell Membrane Permeability/drug effects ; Borinic Acids ; Carboxylic Acids ; Lactams ; Triazoles
Chemical Substances	beta-Lactamases (EC 3.5.2.6) ; Cephalosporins ; beta-Lactamase Inhibitors ; Azabicyclo Compounds ; Anti-Bacterial Agents ; Drug Combinations ; Cyclooctanes ; Cefiderocol (SZ34OMG6E8) ; Ceftazidime (9M416Z9QNR) ; Cefepime (807PW4VQE3) ; Boronic Acids ; Meropenem (FV9J3JU8B1) ; Aztreonam (G2B4VE5GH8) ; avibactam, ceftazidime drug combination ; Imipenem (71OTZ9ZE0A) ; nacubactam (832O37V7MZ) ; taniborbactam (8IGQ156Z07) ; enmetazobactam (80VUN7L00C) ; meropenem and vaborbactam ; relebactam (Y1MYA2UHFL) ; carbapenemase (EC 3.5.2.6) ; Bacterial Proteins ; Heterocyclic Compounds, 1-Ring ; Borinic Acids ; Carboxylic Acids ; Lactams ; Triazoles
Language	English
Publishing date	2024-03-19
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.2024.107150
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Article ; Online: Antimicrobial Activity of Cefiderocol against the Carbapenemase-Producing Enterobacter cloacae Complex and Characterization of Reduced Susceptibility Associated with Metallo-β-Lactamase VIM-1.

Lasarte-Monterrubio, Cristina / Guijarro-Sánchez, Paula / Vázquez-Ucha, Juan Carlos / Alonso-Garcia, Isaac / Alvarez-Fraga, Laura / Outeda, Michelle / Martinez-Guitian, Marta / Peña-Escolano, Andrea / Maceiras, Romina / Lence, Emilio / González-Bello, Concepción / Arca-Suárez, Jorge / Bou, German / Beceiro, Alejandro

Antimicrobial agents and chemotherapy

2023 Volume 67, Issue 5, Page(s) e0150522

Abstract: Emergence of cefiderocol resistance among carbapenemase-producing Enterobacterales, particularly those in the Enterobacter cloacae complex (ECC), is becoming of alarming concern; however, the mechanistic basis of this phenomenon remains poorly understood. ...

Abstract	Emergence of cefiderocol resistance among carbapenemase-producing Enterobacterales, particularly those in the Enterobacter cloacae complex (ECC), is becoming of alarming concern; however, the mechanistic basis of this phenomenon remains poorly understood. We describe the acquisition of VIM-1-mediated reduced cefiderocol susceptibility (MICs 0.5 to 4 mg/L) in a collection of 54 carbapenemase-producing isolates belonging to the ECC. MICs were determined by reference methodologies. Antimicrobial resistance genomic analysis was performed through hybrid WGS. The impact of VIM-1 production on cefiderocol resistance in the ECC background was examined at microbiological, molecular, biochemical, and atomic levels. Antimicrobial susceptibility testing yielded 83.3% susceptible isolates and MIC
MeSH term(s)	Enterobacter cloacae ; Carbapenems/pharmacology ; Siderophores/pharmacology ; Cephalosporins/pharmacology ; beta-Lactamases/metabolism ; Carbapenem-Resistant Enterobacteriaceae ; Microbial Sensitivity Tests ; Anti-Infective Agents/pharmacology ; Anti-Bacterial Agents/pharmacology ; Cefiderocol
Chemical Substances	carbapenemase (EC 3.5.2.6) ; Carbapenems ; Siderophores ; Cephalosporins ; beta-Lactamases (EC 3.5.2.6) ; Anti-Infective Agents ; Anti-Bacterial Agents
Language	English
Publishing date	2023-04-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/aac.01505-22
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Article ; Online: Activity of aztreonam in combination with novel β-lactamase inhibitors against metallo-β-lactamase-producing Enterobacterales from Spain.

Vázquez-Ucha, Juan Carlos / Alonso-Garcia, Isaac / Guijarro-Sánchez, Paula / Lasarte-Monterrubio, Cristina / Álvarez-Fraga, Laura / Cendón-Esteve, Arnau / Outeda, Michelle / Maceiras, Romina / Peña-Escolano, Andrea / Martínez-Guitián, Marta / Arca-Suárez, Jorge / Bou, Germán / Beceiro, Alejandro

International journal of antimicrobial agents

2023 Volume 61, Issue 4, Page(s) 106738

Abstract: Metallo-β-lactamase (MBL)-producing Enterobacterales are of particular concern because they are widely disseminated and difficult to treat, being resistant to almost all β-lactam antibiotics. Aztreonam is not hydrolysed by MBLs but is labile to serine β- ... ...

Abstract	Metallo-β-lactamase (MBL)-producing Enterobacterales are of particular concern because they are widely disseminated and difficult to treat, being resistant to almost all β-lactam antibiotics. Aztreonam is not hydrolysed by MBLs but is labile to serine β-lactamases (SBLs), which are usually co-produced by MBL-producing Enterobacterales. This study investigated the activity of aztreonam in combination with novel β-lactamase inhibitors (BLIs) against a national multi-centre study collection of strains co-producing MBLs and SBLs. Fifty-five clinical isolates co-producing MBLs (41 VIM producers, 10 NDM producers and 4 IMP producers) and SBLs were selected, and whole-genome sequencing (WGS) was performed. The minimum inhibitory concentration (MIC) values of aztreonam, aztreonam/avibactam, aztreonam/relebactam, aztreonam/zidebactam, aztreonam/taniborbactam, aztreonam/vaborbactam and aztreonam/enmetazobactam were determined. β-lactam/BLI resistance mechanisms were analysed by WGS. All BLIs decreased the MIC values of aztreonam for strains that were not susceptible to aztreonam. Aztreonam/zidebactam (MIC ≤1 mg/L for 96.4% of isolates), aztreonam/avibactam (MIC ≤1 mg/L for 92.7% of isolates) and aztreonam/taniborbactam (MIC ≤1 mg/L for 87.3 % of isolates) were the most active combinations. For other aztreonam/BLI combinations, 50-70% of the isolates yielded MIC values ≤1 mg/L. WGS data revealed that mutations in PBP3, defective OmpE35/OmpK35 porins, and the presence of extended-spectrum β-lactamases and class C β-lactamases were some of the resistance mechanisms involved in reduced susceptibility to aztreonam/BLIs. Combinations of aztreonam with new BLIs show promising activity against Enterobacterales co-producing MBLs and SBLs, particularly aztreonam/zidebactam, aztreonam/avibactam and aztreonam/taniborbactam. The present results show that these novel drugs may represent innovative therapeutic strategies by their use in yet-unexplored combinations as solutions for difficult-to-treat infections.
MeSH term(s)	Aztreonam/pharmacology ; beta-Lactamase Inhibitors/pharmacology ; beta-Lactamase Inhibitors/therapeutic use ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; beta-Lactamases/genetics ; Spain ; Azabicyclo Compounds/pharmacology ; Microbial Sensitivity Tests ; Drug Combinations
Chemical Substances	zidebactam ; Aztreonam (G2B4VE5GH8) ; beta-Lactamase Inhibitors ; Anti-Bacterial Agents ; avibactam (7352665165) ; taniborbactam (8IGQ156Z07) ; beta-Lactamases (EC 3.5.2.6) ; Azabicyclo Compounds ; Drug Combinations
Language	English
Publishing date	2023-02-03
Publishing country	Netherlands
Document type	Multicenter Study ; Journal Article
ZDB-ID	1093977-5
ISSN	1872-7913 ; 0924-8579
ISSN (online)	1872-7913
ISSN	0924-8579
DOI	10.1016/j.ijantimicag.2023.106738
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Article ; Online: Reply to Shapiro, "Cefepime/Enmetazobactam Is a Clinically Effective Combination Targeting Extended-Spectrum β-Lactamase-Producing

Vázquez-Ucha, Juan Carlos / Lasarte-Monterrubio, Cristina / Guijarro-Sánchez, Paula / Oviaño, Marina / Álvarez-Fraga, Laura / Alonso-García, Isaac / Arca-Suárez, Jorge / Bou, German / Beceiro, Alejandro

Antimicrobial agents and chemotherapy

2022 Volume 66, Issue 5, Page(s) e0035322

MeSH term(s)	Azabicyclo Compounds ; Cefepime ; Triazoles ; beta-Lactamases/genetics
Chemical Substances	Azabicyclo Compounds ; Triazoles ; Cefepime (807PW4VQE3) ; enmetazobactam (80VUN7L00C) ; beta-Lactamases (EC 3.5.2.6)
Language	English
Publishing date	2022-04-26
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/aac.00353-22
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Article: Interplay between OXA-10 β-Lactamase Production and Low Outer-Membrane Permeability in Carbapenem Resistance in Enterobacterales.

Alonso-García, Isaac / Vázquez-Ucha, Juan Carlos / Martínez-Guitián, Marta / Lasarte-Monterrubio, Cristina / Rodríguez-Pallares, Salud / Camacho-Zamora, Pablo / Rumbo-Feal, Soraya / Aja-Macaya, Pablo / González-Pinto, Lucía / Outeda-García, Michelle / Maceiras, Romina / Guijarro-Sánchez, Paula / Muíño-Andrade, María José / Fernández-González, Ana / Oviaño, Marina / González-Bello, Concepción / Arca-Suárez, Jorge / Beceiro, Alejandro / Bou, Germán

Antibiotics (Basel, Switzerland)

2023 Volume 12, Issue 6

Abstract: The OXA-10 class D β-lactamase has been reported to contribute to carbapenem resistance in non-fermenting Gram-negative bacilli; however, its contribution to carbapenem resistance in Enterobacterales is unknown. In this work, minimum inhibitory ... ...

Abstract	The OXA-10 class D β-lactamase has been reported to contribute to carbapenem resistance in non-fermenting Gram-negative bacilli; however, its contribution to carbapenem resistance in Enterobacterales is unknown. In this work, minimum inhibitory concentrations (MICs), whole genome sequencing (WGS), cloning experiments, kinetic assays, molecular modelling studies, and biochemical assays for carbapenemase detection were performed to determine the impact of OXA-10 production on carbapenem resistance in two XDR clinical isolates of
Language	English
Publishing date	2023-06-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2681345-2
ISSN	2079-6382
ISSN	2079-6382
DOI	10.3390/antibiotics12060999
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Article ; Online: Assessment of Activity and Resistance Mechanisms to Cefepime in Combination with the Novel β-Lactamase Inhibitors Zidebactam, Taniborbactam, and Enmetazobactam against a Multicenter Collection of Carbapenemase-Producing

Antimicrobial agents and chemotherapy

2021 Volume 66, Issue 2, Page(s) e0167621

Abstract: The global distribution of carbapenemases such as KPC, OXA-48, and metallo-β-lactamases (MBLs) gives cause for concern, as these enzymes are not inhibited by classical β-lactamase inhibitors (BLIs). The current development of new inhibitors is one of the ...

Abstract	The global distribution of carbapenemases such as KPC, OXA-48, and metallo-β-lactamases (MBLs) gives cause for concern, as these enzymes are not inhibited by classical β-lactamase inhibitors (BLIs). The current development of new inhibitors is one of the most promising highlights for the treatment of multidrug-resistant bacteria. The activity of cefepime in combination with the novel BLIs zidebactam, taniborbactam, and enmetazobactam was studied in a collection of 400 carbapenemase-producing
MeSH term(s)	Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Azabicyclo Compounds/pharmacology ; Bacterial Proteins ; Borinic Acids ; Carboxylic Acids ; Cefepime/pharmacology ; Cyclooctanes ; Microbial Sensitivity Tests ; Penicillins ; Piperidines ; Triazoles ; beta-Lactamase Inhibitors/pharmacology ; beta-Lactamase Inhibitors/therapeutic use ; beta-Lactamases/genetics ; beta-Lactamases/metabolism
Chemical Substances	Anti-Bacterial Agents ; Azabicyclo Compounds ; Bacterial Proteins ; Borinic Acids ; Carboxylic Acids ; Cyclooctanes ; Penicillins ; Piperidines ; Triazoles ; beta-Lactamase Inhibitors ; zidebactam ; Cefepime (807PW4VQE3) ; enmetazobactam (80VUN7L00C) ; taniborbactam (8IGQ156Z07) ; beta-Lactamases (EC 3.5.2.6) ; carbapenemase (EC 3.5.2.6)
Language	English
Publishing date	2021-11-22
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.01676-21
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Article ; Online: Simultaneous and divergent evolution of resistance to cephalosporin/β-lactamase inhibitor combinations and imipenem/relebactam following ceftazidime/avibactam treatment of MDR Pseudomonas aeruginosa infections.

Alonso-García, Isaac / Vázquez-Ucha, Juan Carlos / Lasarte-Monterrubio, Cristina / González-Mayo, Elena / Lada-Salvador, Paula / Vela-Fernández, Ramón / Aja-Macaya, Pablo / Guijarro-Sánchez, Paula / Rumbo-Feal, Soraya / Muíño-Andrade, María / Fernández-González, Ana / Martínez-Guitián, Marta / Beceiro, Alejandro / Rodríguez-Iglesias, Manuel / Oliver, Antonio / Arca-Suárez, Jorge / Galán-Sánchez, Fátima / Bou, Germán

The Journal of antimicrobial chemotherapy

2023 Volume 78, Issue 5, Page(s) 1195–1200

Abstract: Objectives: To describe and characterize the emergence of resistance to ceftolozane/tazobactam, ceftazidime/avibactam and imipenem/relebactam in a patient receiving ceftazidime/avibactam treatment for an MDR Pseudomonas aeruginosa CNS infection.: ... ...

Abstract	Objectives: To describe and characterize the emergence of resistance to ceftolozane/tazobactam, ceftazidime/avibactam and imipenem/relebactam in a patient receiving ceftazidime/avibactam treatment for an MDR Pseudomonas aeruginosa CNS infection. Methods: One baseline (PA1) and two post-exposure (PA2 and PA3) isolates obtained before and during treatment of a nosocomial P. aeruginosa meningoventriculitis were evaluated. MICs were determined by broth microdilution. Mutational changes were investigated through WGS. The impact on β-lactam resistance of mutations in blaPDC and mexR was determined through cloning experiments and complementation assays. Results: Isolate PA1 showed baseline resistance mutations in DacB (I354A) and OprD (N142fs) conferring resistance to conventional antipseudomonals but susceptibility to ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. Post-exposure isolates showed two divergent ceftazidime/avibactam-resistant phenotypes associated with distinctive mutations affecting the intrinsic P PDC β-lactamase (S254Ins) (PA2: ceftolozane/tazobactam and ceftazidime/avibactam-resistant) or MexAB-OprM negative regulator MexR in combination with modification of PBP3 (PA3: ceftazidime/avibactam and imipenem/relebactam-relebactam-resistant). Cloning experiments demonstrated the role of PDC modification in resistance to ceftolozane/tazobactam and ceftazidime/avibactam. Complementation with a functional copy of the mexR gene in isolate PA3 restored imipenem/relebactam susceptibility. Conclusions: We demonstrated how P. aeruginosa may simultaneously develop resistance and compromise the activity of new β-lactam/β-lactamase inhibitor combinations when exposed to ceftazidime/avibactam through selection of mutations leading to PDC modification and up-regulation of MexAB-OprM-mediated efflux.
MeSH term(s)	Humans ; Ceftazidime/pharmacology ; Ceftazidime/therapeutic use ; beta-Lactamase Inhibitors/pharmacology ; beta-Lactamase Inhibitors/therapeutic use ; Pseudomonas Infections/drug therapy ; Cephalosporinase ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Cephalosporins/pharmacology ; Cephalosporins/therapeutic use ; Azabicyclo Compounds/pharmacology ; Azabicyclo Compounds/therapeutic use ; Tazobactam/pharmacology ; Drug Combinations ; Imipenem/pharmacology ; Imipenem/therapeutic use ; Pseudomonas aeruginosa/genetics ; Microbial Sensitivity Tests
Chemical Substances	ceftolozane (37A4IES95Q) ; Ceftazidime (9M416Z9QNR) ; avibactam (7352665165) ; beta-Lactamase Inhibitors ; relebactam (Y1MYA2UHFL) ; Cephalosporinase (EC 3.5.2.-) ; Anti-Bacterial Agents ; Cephalosporins ; Azabicyclo Compounds ; ceftolozane, tazobactam drug combination ; Tazobactam (SE10G96M8W) ; Drug Combinations ; Imipenem (71OTZ9ZE0A)
Language	English
Publishing date	2023-03-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkad062
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Article ; Online: Activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam against ceftolozane/tazobactam- and ceftazidime/avibactam-resistant Pseudomonas aeruginosa.

Lasarte-Monterrubio, Cristina / Fraile-Ribot, Pablo Arturo / Vázquez-Ucha, Juan Carlos / Cabot, Gabriel / Guijarro-Sánchez, Paula / Alonso-García, Isaac / Rumbo-Feal, Soraya / Galán-Sánchez, Fátima / Beceiro, Alejandro / Arca-Suárez, Jorge / Oliver, Antonio / Bou, Germán

The Journal of antimicrobial chemotherapy

2022 Volume 77, Issue 10, Page(s) 2809–2815

Abstract: Objectives: To evaluate the activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam against a clinical and laboratory collection of ceftolozane/tazobactam- and ceftazidime/avibactam-resistant Pseudomonas aeruginosa β- ...

Abstract	Objectives: To evaluate the activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam against a clinical and laboratory collection of ceftolozane/tazobactam- and ceftazidime/avibactam-resistant Pseudomonas aeruginosa β-lactamase mutants. Methods: The activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam, cefepime/zidebactam and comparators was evaluated against a collection of 30 molecularly characterized ceftolozane/tazobactam- and/or ceftazidime/avibactam-resistant P. aeruginosa isolates from patients previously treated with cephalosporins. To evaluate how the different β-lactamases in the clinical isolates affected the resistance to these agents, a copy of each blaPDC, blaOXA-2 and blaOXA-10 ancestral and mutant allele from the clinical isolates was cloned in pUCp24 and expressed in dual blaPDC-oprD (for blaPDC-like genes) or single oprD (for blaOXA-2-like and blaOXA-10-like genes) PAO1 knockout mutants. MICs were determined using reference methodologies. Results: For all isolates, MICs were higher than 4 and/or 8 mg/L for ceftolozane/tazobactam and ceftazidime/avibactam, respectively. Cefiderocol was the most active agent, showing activity against all isolates, except one clinical isolate that carried an R504C substitution in PBP3 (MIC = 16 mg/L). Imipenem/relebactam was highly active against all isolates, except two clinical isolates that carried the VIM-20 carbapenemase. Cefepime/zidebactam and cefepime/taniborbactam displayed activity against most of the isolates, but resistance was observed in some strains with PBP3 amino acid substitutions or that overexpressed mexAB-oprM or mexXY efflux pumps. Evaluation of transformants revealed that OXA-2 and OXA-10 extended-spectrum variants cause a 2-fold increase in the MIC of cefiderocol relative to parental enzymes. Conclusions: Cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam show promising and complementary in vitro activity against ceftolozane/tazobactam- and ceftazidime/avibactam-resistant P. aeruginosa. These agents may represent potential therapeutic options for ceftolozane/tazobactam- and ceftazidime/avibactam-resistant P. aeruginosa infections.
MeSH term(s)	Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Azabicyclo Compounds/pharmacology ; Azabicyclo Compounds/therapeutic use ; Borinic Acids ; Carboxylic Acids ; Cefepime/pharmacology ; Cefepime/therapeutic use ; Ceftazidime/pharmacology ; Ceftazidime/therapeutic use ; Cephalosporins/pharmacology ; Cephalosporins/therapeutic use ; Cyclooctanes ; Humans ; Imipenem/pharmacology ; Imipenem/therapeutic use ; Piperidines ; Pseudomonas Infections/drug therapy ; Pseudomonas aeruginosa/genetics ; Tazobactam/pharmacology ; Tazobactam/therapeutic use ; beta-Lactamases/genetics ; Cefiderocol
Chemical Substances	Anti-Bacterial Agents ; Azabicyclo Compounds ; Borinic Acids ; Carboxylic Acids ; Cephalosporins ; Cyclooctanes ; Piperidines ; WCK 5222 ; ceftolozane, tazobactam drug combination ; zidebactam ; ceftolozane (37A4IES95Q) ; Imipenem (71OTZ9ZE0A) ; avibactam (7352665165) ; Cefepime (807PW4VQE3) ; taniborbactam (8IGQ156Z07) ; Ceftazidime (9M416Z9QNR) ; beta-Lactamases (EC 3.5.2.6) ; Tazobactam (SE10G96M8W) ; relebactam (Y1MYA2UHFL)
Language	English
Publishing date	2022-07-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkac241
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Article ; Online: In vitro development of imipenem/relebactam resistance in KPC-producing Klebsiella pneumoniae involves multiple mutations including OmpK36 disruption and KPC modification.

Gato, Eva / Guijarro-Sánchez, Paula / Alonso-García, Isaac / Pedraza-Merino, Rosa / Conde, Adrian / Lence, Emilio / Rumbo-Feal, Soraya / Peña-Escolano, Andrea / Lasarte-Monterrubio, Cristina / Blanco-Martín, Tania / Fernández-González, Ana / Fernández-López, M Del Carmen / Maceiras, Romina / Martínez-Guitián, Marta / Vázquez-Ucha, Juan Carlos / Martínez-Martínez, Luis / González-Bello, Concepción / Arca-Suárez, Jorge / Beceiro, Alejandro /

Bou, Germán

International journal of antimicrobial agents

2023 Volume 62, Issue 4, Page(s) 106935

Abstract: Objectives: In order to inform and anticipate potential strategies aimed at combating KPC-producing Klebsiella pneumoniae infections, we analysed imipenem/relebactam and ceftazidime/avibactam single-step mutant frequencies, resistance development ... ...

Abstract	Objectives: In order to inform and anticipate potential strategies aimed at combating KPC-producing Klebsiella pneumoniae infections, we analysed imipenem/relebactam and ceftazidime/avibactam single-step mutant frequencies, resistance development trajectories, differentially selected resistance mechanisms and their associated fitness cost using four representative high-risk K. pneumoniae clones. Methods: Mutant frequencies and mutant preventive concentrations were determined using agar plates containing incremental concentrations of β-lactam/β-lactamase inhibitor. Resistance dynamics were determined through incubation for 7 days in 10 mL MH tubes containing incremental concentrations of each antibiotic combination up to their 64 × baseline MIC. Two colonies per strain from each experiment were characterized by antimicrobial susceptibility testing, whole genome sequencing and competitive growth assays (to determine in vitro fitness). KPC variants associated with imipenem/relebactam resistance were characterized by cloning and biochemical experiments, atomic models and molecular dynamics simulation studies. Results: Imipenem/relebactam prevented the emergence of single-step resistance mutants at lower concentrations than ceftazidime/avibactam. In three of the four strains evaluated, imipenem/relebactam resistance development emerged more rapidly, and in the ST512/KPC-3 clone reached higher levels compared to baseline MICs than for ceftazidime/avibactam. Lineages evolved in the presence of ceftazidime/avibactam showed KPC substitutions associated with high-level ceftazidime/avibactam resistance, increased imipenem/relebactam susceptibility and low fitness costs. Lineages that evolved in the presence of imipenem/relebactam showed OmpK36 disruption, KPC modifications (S106L, N132S, L167R) and strain-specific substitutions associated with imipenem/relebactam resistance and high fitness costs. Imipenem/relebactam-selected KPC derivatives demonstrated enhanced relebactam resistance through important changes affecting relebactam recognition and positioning. Conclusions: Our findings anticipate potential resistance mechanisms affecting imipenem/relebactam during treatment of KPC-producing K. pneumoniae infections.
Language	English
Publishing date	2023-08-03
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.2023.106935
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