ALCALDE RICO, MANUEL

Preferred name
ALCALDE RICO, MANUEL
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Email
manalcric@gmail.com
ORCID
0000-0002-1987-4600
Scopus Author ID
57189040751
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    Dataset - Dynamics of the MRSA Population in a Chilean Hospital: a Phylogenomic Analysis (2000-2016)
    (2023)
    MARTINEZ SOLIS, JOSE RODRIGO WALDEMAR
    ;
    SPENCER SANDINO, MARÍA DE LOS ÁNGELES
    ;
    RIVAS JIMENEZ, LINA MARIA  
    ;
    DIAZ ORTIZ, SANDRA
    ;
    QUESILLE VILLALOBOS, ANA MARIA  
      5
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    Dataset - NCBI
    (National Library of Medicine, 2022)
    MUNITA SEPULVEDA, JOSE MANUEL  
    ;
    ALCALDE RICO, MANUEL  
    ;
    JOSE RODRIGO WALDEMAR MARTINEZ SOLIS
      15
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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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    Role of the multi-drug efflux systems on the baseline susceptibility to ceftazidime/avibactam and ceftolozane/tazobactam in clinical isolates of non-carbapenemase-producing carbapenem-resistant Pseudomonas aeruginosa
    (2022)
    María José Contreras-Gómez
    ;
    José R. W. Martinez
    ;
    RIVAS JIMENEZ, LINA MARIA  
    ;
    Juan A. Ugalde
    ;
    Roberto Riquelme-Neira  
    <jats:p>Carbapenem-resistant <jats:italic>Pseudomonas aeruginosa</jats:italic> (CRPA) is one of the pathogens that urgently needs new drugs and new alternatives for its control. The primary strategy to combat this bacterium is combining treatments of beta-lactam with a beta-lactamase inhibitor. The most used combinations against <jats:italic>P. aeruginosa</jats:italic> are ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (C/T). Although mechanisms leading to CZA and C/T resistance have already been described, among which are the resistance-nodulation-division (RND) efflux pumps, the role that these extrusion systems may play in CZA, and C/T baseline susceptibility of clinical isolates remains unknown. For this purpose, 161 isolates of non-carbapenemase-producing (Non-CP) CRPA were selected, and susceptibility tests to CZA and C/T were performed in the presence and absence of the RND efflux pumps inhibitor, Phenylalanine-arginine β-naphthylamide (PAβN). In the absence of PAβN, C/T showed markedly higher activity against Non-CP-CRPA isolates than observed for CZA. These results were even more evident in isolates classified as extremely-drug resistant (XDR) or with difficult-to-treat resistance (DTR), where CZA decreased its activity up to 55.2% and 20.0%, respectively, whereas C/T did it up to 82.8% (XDR), and 73.3% (DTR). The presence of PAβN showed an increase in both CZA (37.6%) and C/T (44.6%) activity, and 25.5% of Non-CP-CRPA isolates increased their susceptibility to these two combined antibiotics. However, statistical analysis showed that only the C/T susceptibility of Non-CP-CRPA isolates was significantly increased. Although the contribution of RND activity to CZA and C/T baseline susceptibility was generally low (two-fold decrease of minimal inhibitory concentrations [MIC]), a more evident contribution was observed in a non-minor proportion of the Non-CP-CRPA isolates affected by PAβN [CZA: 25.4% (15/59); C/T: 30% (21/70)]. These isolates presented significantly higher MIC values for C/T. Therefore, we conclude that RND efflux pumps are participating in the phenomenon of baseline susceptibility to CZA and, even more, to C/T. However, the genomic diversity of clinical isolates is so great that deeper analyzes are necessary to determine which elements are directly involved in this phenomenon.</jats:p>
    Scopus© Citations 2  1
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    Ceftazidime/avibactam resistance is associated with PER-3-producing ST309 lineage in Chilean clinical isolates of non-carbapenemase producing Pseudomonas aeruginosa
    (2024)
    Katherine D. Soto
    ;
    ALCALDE RICO, MANUEL  
    ;
    UGALDE, JUAN ANTONIO
    ;
    Jorge Olivares Pacheco
    ;
    Valeria Quiroz
    <jats:sec><jats:title>Introduction</jats:title><jats:p>Ceftazidime/avibactam (CZA) is indicated against multidrug-resistant <jats:italic>Pseudomonas aeruginosa</jats:italic>, particularly those that are carbapenem resistant. CZA resistance in <jats:italic>P. aeruginosa</jats:italic> producing PER, a class A extended-spectrum β-lactamase, has been well documented <jats:italic>in vitro</jats:italic>. However, data regarding clinical isolates are scarce. Our aim was to analyze the contribution of PER to CZA resistance in non-carbapenemase-producing <jats:italic>P. aeruginosa</jats:italic> clinical isolates that were ceftazidime and/or carbapenem non-susceptible.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Antimicrobial susceptibility was determined through agar dilution and broth microdilution, while <jats:italic>bla</jats:italic><jats:sub>PER</jats:sub> gene was screened through PCR. All PER-positive isolates and five PER-negative isolates were analyzed through Whole Genome Sequencing. The mutational resistome associated to CZA resistance was determined through sequence analysis of genes coding for PBPs 1b, 3 and 4, MexAB-OprM regulators MexZ, MexR, NalC and NalD, AmpC regulators AmpD and AmpR, and OprD porin. Loss of <jats:italic>bla</jats:italic><jats:sub>PER-3</jats:sub> gene was induced in a PER-positive isolate by successive passages at 43°C without antibiotics. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Twenty-six of 287 isolates studied (9.1%) were CZA-resistant. Thirteen of 26 CZA-resistant isolates (50%) carried <jats:italic>bla</jats:italic><jats:sub>PER</jats:sub>. One isolate carried <jats:italic>bla</jats:italic><jats:sub>PER</jats:sub> but was CZA-susceptible. PER-producing isolates had significantly higher MICs for CZA, amikacin, gentamicin, ceftazidime, meropenem and ciprofloxacin than non-PER-producing isolates. All PER-producing isolates were ST309 and their <jats:italic>bla</jats:italic><jats:sub>PER-3</jats:sub> gene was associated to ISCR1, an insertion sequence known to mobilize adjacent DNA. PER-negative isolates were classified as ST41, ST235 (two isolates), ST395 and ST253. PER-negative isolates carried genes for narrow-spectrum β-lactamases and the mutational resistome showed that all isolates had one major alteration in at least one of the genes analyzed. Loss of <jats:italic>bla</jats:italic><jats:sub>PER-3</jats:sub> gene restored susceptibility to CZA, ceftolozane/tazobactam and other β-lactamsin the <jats:italic>in vitro</jats:italic> evolved isolate. </jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>PER-3-producing ST309 <jats:italic>P. aeruginosa</jats:italic> is a successful multidrug-resistant clone with <jats:italic>bla<jats:sub>PER-3</jats:sub></jats:italic> gene implicated in resistance to CZA and other β-lactams.</jats:p></jats:sec>
    Scopus© Citations 1  4
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    Dataset - GenBank Overview
    (National Library of Medicine, 2022)
    ALCALDE RICO, MANUEL  
    ;
    MUNITA SEPULVEDA, JOSE MANUEL  
    ;
    JOSE RODRIGO WALDEMAR MARTINEZ SOLIS
      3
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    Dynamics of the MRSA Population in a Chilean Hospital: a Phylogenomic Analysis (2000–2016)
    (2023)
    José R. W. Martínez
    ;
    Paul J. Planet
    ;
    Maria Spencer-Sandino
    ;
    RIVAS JIMENEZ, LINA MARIA  
    ;
    Ahmed M. Moustafa
    <jats:p> Methicillin-resistant <jats:named-content content-type="genus-species">Staphylococcus aureus</jats:named-content> (MRSA) is a major public health pathogen that disseminates through the emergence of successful dominant clones in specific geographic regions. Knowledge of the dissemination and molecular epidemiology of MRSA in Latin America is scarce and is largely based on small studies or more limited typing techniques that lack the resolution to represent an accurate description of the genomic landscape. </jats:p>
    Scopus© Citations 6  4