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Author: search.filters.author.Cesar A. Arias

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    Resistance to novel β-lactam/β-lactamase inhibitors among carbapenem-resistant
    <i>Pseudomonas aeruginosa</i>
    and clinical implications in the prospective observational
    <i>Pseudomonas</i>
    study
    (American Society for Microbiology, 2026-06-03)
    Lee S. Gottesdiener
    ;
    Yixuan Li
    ;
    Kerryl E. Greenwood-Quaintance
    ;
    Lauren Komarow
    ;
    Cesar A. Arias
      6
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    Carbapenem-resistant Enterobacterales in solid organ transplant recipients
    (2024)
    Angelique E. Boutzoukas
    ;
    Weixiao Dai
    ;
    Eric Cober
    ;
    Lilian M. Abbo
    ;
    Lauren Komarow
      1
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    Mechanisms of Antibiotic Resistance
    (2016)
    MUNITA SEPULVEDA, JOSE MANUEL  
    ;
    Cesar A. Arias
    ;
    Indira T. Kudva
    ;
    Qijing Zhang
    <jats:title>ABSTRACT</jats:title> <jats:p>Emergence of resistance among the most important bacterial pathogens is recognized as a major public health threat affecting humans worldwide. Multidrug-resistant organisms have not only emerged in the hospital environment but are now often identified in community settings, suggesting that reservoirs of antibiotic-resistant bacteria are present outside the hospital. The bacterial response to the antibiotic “attack” is the prime example of bacterial adaptation and the pinnacle of evolution. “Survival of the fittest” is a consequence of an immense genetic plasticity of bacterial pathogens that trigger specific responses that result in mutational adaptations, acquisition of genetic material, or alteration of gene expression producing resistance to virtually all antibiotics currently available in clinical practice. Therefore, understanding the biochemical and genetic basis of resistance is of paramount importance to design strategies to curtail the emergence and spread of resistance and to devise innovative therapeutic approaches against multidrug-resistant organisms. In this chapter, we will describe in detail the major mechanisms of antibiotic resistance encountered in clinical practice, providing specific examples in relevant bacterial pathogens.</jats:p>
    Scopus© Citations 1767  1
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    Cefiderocol heteroresistance associated with mutations in TonB-dependent receptor genes in
    <i>Pseudomonas aeruginosa</i>
    of clinical origin
    (2024)
    Stephanie L. Egge
    ;
    Samie A. Rizvi
    ;
    Shelby R. Simar
    ;
    ALCALDE RICO, MANUEL  
    ;
    JOSE RODRIGO WALDEMAR MARTINEZ SOLIS
    <jats:title>ABSTRACT</jats:title> <jats:sec> <jats:title/> <jats:p> The siderophore-cephalosporin cefiderocol (FDC) presents a promising treatment option for carbapenem-resistant (CR) <jats:italic>P. aeruginosa</jats:italic> (PA). FDC circumvents traditional porin and efflux-mediated resistance by utilizing TonB-dependent receptors (TBDRs) to access the periplasmic space. Emerging FDC resistance has been associated with loss of function mutations within TBDR genes or the regulatory genes controlling TBDR expression. Further, difficulties with antimicrobial susceptibility testing (AST) and unexpected negative clinical treatment outcomes have prompted concerns for heteroresistance, where a single lineage isolate contains resistant subpopulations not detectable by standard AST. This study aimed to evaluate the prevalence of TBDR mutations among clinical isolates of <jats:italic>P. aeruginosa</jats:italic> and the phenotypic effect on FDC susceptibility and heteroresistance. We evaluated the sequence of <jats:italic>pirR</jats:italic> , <jats:italic>pirS</jats:italic> , <jats:italic>pirA</jats:italic> , <jats:italic>piuA</jats:italic> , or <jats:italic>piuD</jats:italic> from 498 unique isolates collected before the introduction of FDC from four clinical sites in Portland, OR (1), Houston, TX (2), and Santiago, Chile (1). At some clinical sites, TBDR mutations were seen in up to 25% of isolates, and insertion, deletion, or frameshift mutations were predicted to impair protein function were seen in 3% of all isolates ( <jats:italic>n</jats:italic> = 15). Using population analysis profile testing, we found that <jats:italic>P. aeruginosa</jats:italic> with major TBDR mutations were enriched for a heteroresistant phenotype and undergo a shift in the susceptibility distribution of the population as compared to susceptible strains with wild-type TBDR genes. Our results indicate that mutations in TBDR genes predate the clinical introduction of FDC, and these mutations may predispose to the emergence of FDC resistance. </jats:p> </jats:sec>
    Scopus© Citations 18  2
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    Scopus© Citations 1  1
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      10Scopus© Citations 44
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    Whole-Genome Analysis of a Daptomycin-Susceptible Enterococcus faecium Strain and Its Daptomycin-Resistant Variant Arising during Therapy
    (2013)
    Truc T. Tran
    ;
    Diana Panesso
    ;
    Hongyu Gao
    ;
    Jung H. Roh
    ;
    MUNITA SEPULVEDA, JOSE MANUEL  
    Development of daptomycin (DAP) resistance in Enterococcus faecalis has recently been associated with mutations in genes encoding proteins with two main functions: (i) control of the cell envelope stress response to antibiotics and antimicrobial peptides (LiaFSR system) and (ii) cell membrane phospholipid metabolism (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase [cls]). However, the genetic bases for DAP resistance in Enterococcus faecium are unclear. We performed whole-genome comparative analysis of a clinical strain pair, DAP-susceptible E. faecium S447 and its DAP-resistant derivative R446, which was recovered from a single patient during DAP therapy. By comparative whole-genome sequencing, DAP resistance in R446 was associated with changes in 8 genes. Two of these genes encoded proteins involved in phospholipid metabolism: (i) an R218Q substitution in Cls and (ii) an A292G reversion in a putative cyclopropane fatty acid synthase enzyme. The DAP-resistant derivative R446 also exhibited an S333L substitution in the putative histidine kinase YycG, a member of the YycFG system, which, similar to LiaFSR, has been involved in cell envelope homeostasis and DAP resistance in other Gram-positive cocci. Additional changes identified in E. faecium R446 (DAP resistant) included two putative proteins involved in transport (one for carbohydrate and one for sulfate) and three enzymes predicted to play a role in general metabolism. Exchange of the "susceptible" cls allele from S447 for the "resistant" one belonging to R446 did not affect DAP susceptibility. Our results suggest that, apart from the LiaFSR system, the essential YycFG system is likely to be an important mediator of DAP resistance in some E. faecium strains.
      2Scopus© Citations 108
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    Correlation between Mutations in
    <i>liaFSR</i>
    of Enterococcus faecium and MIC of Daptomycin: Revisiting Daptomycin Breakpoints
    (2012)
    MUNITA SEPULVEDA, JOSE MANUEL  
    ;
    Diana Panesso
    ;
    Lorena Diaz
    ;
    Truc T. Tran
    ;
    Jinnethe Reyes
    Mutations in liaFSR, a three-component regulatory system controlling cell-envelope stress response, were recently linked with the emergence of daptomycin (DAP) resistance in enterococci. Our previous work showed that a liaF mutation increased the DAP MIC of a vancomycin-resistant Enterococcus faecalis strain from 1 to 3 μg/ml (the DAP breakpoint is 4 μg/ml), suggesting that mutations in the liaFSR system could be a pivotal initial event in the development of DAP resistance. With the hypothesis that clinical enterococcal isolates with DAP MICs between 3 and 4 μg/ml might harbor mutations in liaFSR, we studied 38 Enterococcus faecium bloodstream isolates, of which 8 had DAP MICs between 3 and 4 μg/ml by Etest in Mueller-Hinton agar. Interestingly, 6 of these 8 isolates had predicted amino acid changes in the LiaFSR system. Moreover, we previously showed that among 6 DAP-resistant E. faecium isolates (MICs of >4 μg/ml), 5 had mutations in liaFSR. In contrast, none of 16 E. faecium isolates with a DAP MIC of ≤2 μg/ml harbored mutations in this system (P<0.0001). All but one isolate with liaFSR changes exhibited DAP MICs of ≥16 μg/ml by Etest using brain heart infusion agar (BHIA), a medium that better supports enterococcal growth. Our findings provide a strong association between DAP MICs within the upper susceptibility range and mutations in the liaFSR system. Concomitant susceptibility testing on BHIA may be useful for identifying these E. faecium first-step mutants. Our results also suggest that the current DAP breakpoint for E. faecium may need to be reevaluated
      14Scopus© Citations 104
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      9Scopus© Citations 17
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    A liaF Codon Deletion Abolishes Daptomycin Bactericidal Activity against Vancomycin-Resistant Enterococcus faecalis
    (2013)
    MUNITA SEPULVEDA, JOSE MANUEL  
    ;
    Truc T. Tran
    ;
    Lorena Diaz
    ;
    Diana Panesso
    ;
    Jinnethe Reyes
    The genetic bases for antibiotic tolerance are obscure. Daptomycin (DAP) is a lipopeptide antibiotic with bactericidal activity against enterococci. Using time-kill assays, we provide evidence for the first time that a deletion of isoleucine in position 177 of LiaF, a member of the three-component regulatory system LiaFSR involved in the cell envelope response to antimicrobials, is directly responsible for a DAP-tolerant phenotype and is likely to negatively affect response to DAP therapy.
      4Scopus© Citations 66