Examinando por Autor "Pasteran, Fernando"

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    Acinetobacter baumannii response to cefiderocol challenge in human urine
    (Springer Nature, 2022-05-24) Nishimura, Brent; Escalante, Jenny; Tuttobene, Marisel Romina; Subils, Tomás; Mezcord, Vyanka; Pimentel, Camila; Georgeos, Nardin; Pasteran, Fernando; Rodríguez, Cecilia; Sieira, Rodrigo; Actis, Luis A.; Tolmasky,, Marcelo E.; Bonomo, Robert A.; Ramírez, María Soledad
    Cefiderocol (CFDC) is a novel chlorocatechol-substituted siderophore antibiotic approved to treat complicated urinary tract infections (cUTI) and hospital-acquired and ventilator-acquired pneumonia (HAP/VAP). Previous work determined that albumin-rich human fluids increase the minimum inhibitory concentration (MICs) of Acinetobacter baumannii against CFDC and reduce the expression of genes related to iron uptake systems. This latter effect may contribute to the need for higher concentrations of CFDC to inhibit growth. The presence of human urine (HU), which contains low albumin concentrations, did not modify MIC values of two carbapenem-resistant A. baumannii. Levels of resistance to CFDC were not modified by HU in strain AMA40 but were reduced in strain AB5075. Expanding the studies to other carbapenem-resistant A. baumannii isolates showed that the presence of HU resulted in unmodified or reduced MIC of CDFC values. The expression of piuA, pirA, bauA, and bfnH determined by qRT-PCR was enhanced in A. baumannii AMA40 and AB5075 by the presence of HU in the culture medium. All four tested genes code for functions related to recognition and transport of ferric-siderophore complexes. The effect of HU on expression of pbp1, pbp3, blaOXA-51-like, blaADC, and blaNDM-1, genes associated with resistance to β-lactams, as well as genes coding for efflux pumps and porins was variable, showing dependence with the strain analyzed. We conclude that the lack of significant concentrations of albumin and free iron in HU makes this fluid behave differently from others we tested. Unlike other albumin rich fluids, the presence of HU does not impact the antibacterial activity of CFDC when tested against A. baumannii.
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    Characterisation of ST25 NDM-1-producing Acinetobacter spp. strains leading the increase in NDM-1 emergence in Argentina
    (Elsevier, 2020-09-02) Rodgers, Deja; Pasteran, Fernando; Calderon, Manuel; Jaber, Sara; Traglia, German M.; Albornoz, Ezequiel; Corso, Alejandra; Vila, Alejandro J.; Bonomo, Robert A.; Adams, Mark D.; Ramírez, María Soledad
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    ÍtemAcceso Abierto
    Human Serum Proteins and Susceptibility of Acinetobacter baumannii to Cefiderocol: Role of Iron Transport
    (MDPI, 2022-03-03) Le, Casin; Pimentel, Camila; Pasteran, Fernando; Tuttobene, Marisel Romina; Subils, Tomás; Escalante, Jenny; Nishimura, Brent; Arriaga, Susana; Carranza, Aimee; Mezcord, Vyanka; Vila, Alejandro J.; Corso, Alejandra; Actis, Luis A.; Tolmasky, Marcelo E.; Bonomo, Robert A.; Ramírez, María Soledad
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    Induced Heteroresistance in Carbapenem-Resistant Acinetobacter baumannii (CRAB) via Exposure to Human Pleural Fluid (HPF) and Its Impact on Cefiderocol Susceptibility
    (MDPI, 2023-07-21) Mezcord, Vyanka; Escalante, Jenny; Nishimura, Brent; Traglia, German M.; Sharma, Rajnikant; Vallé, Quentin; Tuttobene, Marisel Romina; Subils, Tomás; Marin, Ingrid; Pasteran, Fernando; Actis, Luis A.; Tolmasky, Marcelo E.; Bonomo, Robert A.; Rao, Gauri; Ramírez, María Soledad; https://orcid.org/0000-0003-1896-8450; https://orcid.org/0000-0002-4780-5311; https://orcid.org/0000-0001-5840-5869; https://orcid.org/0000-0001-9644-9088; https://orcid.org/0000-0002-6298-7811; https://orcid.org/0000-0002-9904-7890
    Infections caused by Carbapenem-resistant Acinetobacter baumannii (CRAB) isolates, such as hospital-acquired pneumonia (HAP), bacteremia, and skin and soft tissue infections, among others, are particularly challenging to treat. Cefiderocol, a chlorocatechol-substituted siderophore antibiotic, was approved by the U.S. Food and Drug Administration (FDA) in 2019 and prescribed for the treatment of CRAB infections. Despite the initial positive treatment outcomes with this antimicrobial, recent studies reported a higher-than-average all-cause mortality rate in patients treated with cefiderocol compared to the best available therapy. The cause(s) behind these outcomes remains unconfirmed. A plausible hypothesis is heteroresistance, a phenotype characterized by the survival of a small proportion of cells in a population that is seemingly isogenic. Recent results have demonstrated that the addition of human fluids to CRAB cultures leads to cefiderocol heteroresistance. Here, we describe the molecular and phenotypic analyses of CRAB heteroresistant bacterial subpopulations to better understand the nature of the less-than-expected successful outcomes after cefiderocol treatment. Isolation of heteroresistant variants of the CRAB strain AMA40 was carried out in cultures supplemented with cefiderocol and human pleural fluid (HPF). Two AMA40 variants, AMA40 IHC1 and IHC2, were resistant to cefiderocol. To identify mutations and gene expression changes associated with cefiderocol heteroresistance, we subjected these variants to whole genome sequencing and global transcriptional analysis. We then assessed the impact of these mutations on the pharmacodynamic activity of cefiderocol via susceptibility testing, EDTA and boronic acid inhibition analysis, biofilm formation, and static time-kill assays. Heteroresistant variants AMA40 IHC1 and AMA40 IHC2 have 53 chromosomal mutations, of which 40 are common to both strains. None of the mutations occurred in genes associated with high affinity iron-uptake systems or β-lactam resistance. However, transcriptional analyses demonstrated significant modifications in levels of expression of genes associated with iron-uptake systems or β-lactam resistance. The blaNDM-1 and blaADC-2, as well as various iron-uptake system genes, were expressed at higher levels than the parental strain. On the other hand, the carO and ompA genes’ expression was reduced. One of the mutations common to both heteroresistant strains was mapped within ppiA, a gene associated with iron homeostasis in other species. Static time-kill assays demonstrated that supplementing cation-adjusted Mueller–Hinton broth with human serum albumin (HAS), the main protein component of HPF, considerably reduced cefiderocol killing activity for all three strains tested. Notably, collateral resistance to amikacin was observed in both variants. We conclude that exposing CRAB to fluids with high HSA concentrations facilitates the rise of heteroresistance associated with point mutations and transcriptional upregulation of genes coding for β-lactamases and biofilm formation. The findings from this study hold significant implications for understanding the emergence of CRAB resistance mechanisms against cefiderocol treatment. This understanding is vital for the development of treatment guidelines that can effectively address the challenges posed by CRAB infections.
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    Pseudomonas putida group species as reservoirs of mobilizable Tn402-like class 1 integrons carrying blaVIM-2 metallo-β-lactamase genes
    (Elsevier B.V., 2021-11-06) Brovedan, Marco Alcides; Marchiaro, Patricia M.; Díaz, María S.; Faccone, Diego; Corso, Alejandra; Pasteran, Fernando; Viale, Alejandro M.; Limansky, Adriana S.