MUNITA SEPULVEDA, JOSE MANUEL
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MUNITA SEPULVEDA, JOSE MANUEL
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josemunita@udd.cl
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24825037700

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Cefiderocol heteroresistance associated with mutations in TonB-dependent receptor genes in Pseudomonas aeruginosa of clinical origin

2024 , Stephanie L. Egge , Samie A. Rizvi , Shelby R. Simar , ALCALDE RICO, MANUEL , JOSE RODRIGO WALDEMAR MARTINEZ SOLIS , Blake M. Hanson , An Q. Dinh , Rodrigo P. Baptista , Truc T. Tran , Samuel A. Shelburne , MUNITA SEPULVEDA, JOSE MANUEL , Cesar A. Arias , Morgan Hakki , William R. Miller , Ryan K. Shields

ABSTRACT The siderophore-cephalosporin cefiderocol (FDC) presents a promising treatment option for carbapenem-resistant (CR) P. aeruginosa (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 P. aeruginosa and the phenotypic effect on FDC susceptibility and heteroresistance. We evaluated the sequence of pirR , pirS , pirA , piuA , or piuD 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 ( n = 15). Using population analysis profile testing, we found that P. aeruginosa 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.

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Influence of Inoculum Effect on the Efficacy of Daptomycin Monotherapy and in Combination with beta-Lactams against Daptomycin-Susceptible Enterococcus faecium Harboring LiaSR Substitutions

2018 , Razieh Kebriaei , Seth A. Rice , Kavindra V. Singh , Kyle C. Stamper , An Q. Dinh , Rafael Rios , Lorena Diaz , Barbara E. Murray , MUNITA SEPULVEDA, JOSE MANUEL , Truc T. Tran , Cesar A. Arias , Michael J. Rybak

Enterococcus faecium isolates that harbor LiaFSR substitutions but are phenotypically susceptible to daptomycin (DAP) by current breakpoints are problematic, since predisposition to resistance may lead to therapeutic failure. Using a simulated endocardial vegetation (SEV) pharmacokinetic/pharmacodynamic (PK/PD) model, we investigated DAP regimens (6, 8, and 10 mg/kg of body weight/day) as monotherapy and in combination with ampicillin (AMP), ceftaroline (CPT), or ertapenem (ERT) against E. faecium HOU503, a DAP-susceptible strain that harbors common LiaS and LiaR substitutions found in clinical isolates (T120S and W73C, respectively).

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In Vivo Resistance to Ceftolozane/Tazobactam in Pseudomonas aeruginosa Arising by AmpC- and Non-AmpC-Mediated Pathways

2018 , Erik Skoglund , Henrietta Abodakpi , Rafael Rios , Lorena Diaz , Elsa De La Cadena , An Q. Dinh , Javier Ardila , William R. Miller , MUNITA SEPULVEDA, JOSE MANUEL , Cesar A. Arias , Vincent H. Tam , Truc T. Tran

Two pairs of ceftolozane/tazobactam susceptible/resistant P. aeruginosa were isolated from 2 patients after exposure to β-lactams. The genetic basis of ceftolozane/tazobactam resistance was evaluated, and β-lactam-resistant mechanisms were assessed by phenotypic assays. Whole genome sequencing identified mutations in AmpC including the mutation (V213A) and a deletion of 7 amino acids (P210–G216) in the Ω-loop. Phenotypic assays showed that ceftolozane/tazobactam resistance in the strain with AmpCV213A variant was associated with increased β-lactamase hydrolysis activity. On the other hand, the deletion of 7 amino acids in the Ω-loop of AmpC did not display enhanced β-lactamase activity. Resistance to ceftolozane/tazobactam in P. aeruginosa is associated with changes in AmpC; however, the apparent loss of β-lactamase activity in AmpC∆7 suggests that non-AmpC mechanisms could play an important role in resistance to β-lactam/β-lactamase inhibitor combinations.

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Corrigendum to “In Vivo Resistance to Ceftolozane/Tazobactam in Pseudomonas aeruginosa Arising by AmpC- and Non-AmpC-Mediated Pathways”

2019 , Erik Skoglund , Henrietta Abodakpi , Rafael Rios , Lorena Diaz , Elsa De La Cadena , An Q. Dinh , Javier Ardila , William R. Miller , MUNITA SEPULVEDA, JOSE MANUEL , Cesar A. Arias , Vincent H. Tam , Truc T. Tran

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Multisite Detection of Tn 1549 -Mediated vanB Vancomycin Resistance in Multidrug-Resistant Enterococcus faecalis ST6 in Texas and Florida

2023 , Shelby R. Simar , Truc T. Tran , Kirsten B. Rydell , Diana Panesso , German A. Contreras , MUNITA SEPULVEDA, JOSE MANUEL , Renzo O. Cifuentes , Lilian M. Abbo , Pranoti Sahasrabhojane , An Q. Dinh , Dierdre B. Axell-House , Tor Savidge , Samuel A. Shelburne , Blake M. Hanson , Cesar A. Arias

In the United States, vanB -mediated resistance in enterococci is rare. We characterized three sequence type (ST) 6, vancomycin-resistant Enterococcus faecalis isolates causing bacteremia in unique patients in spatiotemporally distinct settings.

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