DSpace Repository :: Browsing by Author "Arias, Cesar A."

Browsing by Author "Arias, Cesar A."

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Clinical outcomes and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort study
(2021) Wang, Minggui; Earley, Michelle; Chen, Liang; Hanson, Blake M.; Yu, Yunsong; Liu, Zhengyin; Salcedo, Soraya; Cober, Eric; Li, Lanjuan; Kanj, Souha S.; Gao, Hainv; Munita, José; Ordoñez, Karen; Weston, Greg; Satlin, Michael J.; Valderrama-Beltrán, Sandra L.; Marimuthu, Kalisvar; Stryjewski, Martin E.; Komarow, Lauren; Luterbach, Courtney; Marshall, Steve H.; Rudin, Susan D.; Manca, Claudia; Paterson, David L.; Doi, Yohei; Patel, Robin; Kreiswirth, Barry N.; Bonomo, Robert A.; Chambers, Henry F.; Fowler, Jr. Vance G.; Arias, Cesar A.; Duin, David van; Multi-Drug Resistant Organism Network Investigators
Background: Carbapenem-resistant Enterobacterales (CRE) are a global threat. We aimed to describe the clinical and molecular characteristics of Centers for Disease Control and Prevention (CDC)-defined CRE in the USA. Methods: CRACKLE-2 is a prospective, multicentre, cohort study. Patients hospitalised in 49 US hospitals, with clinical cultures positive for CDC-defined CRE between April 30, 2016, and Aug 31, 2017, were included. There was no age exclusion. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after index culture. Clinical data and bacteria were collected, and whole genome sequencing was done. This trial is registered with ClinicalTrials.gov, number NCT03646227. Findings: 1040 patients with unique isolates were included, 449 (43%) with infection and 591 (57%) with colonisation. The CDC-defined CRE admission rate was 57 per 100 000 admissions (95% CI 45-71). Three subsets of CDC-defined CRE were identified: carbapenemase-producing Enterobacterales (618 [59%] of 1040), non-carbapenemase-producing Enterobacterales (194 [19%]), and unconfirmed CRE (228 [22%]; initially reported as CRE, but susceptible to carbapenems in two central laboratories). Klebsiella pneumoniae carbapenemase-producing clonal group 258 K pneumoniae was the most common carbapenemase-producing Enterobacterales. In 449 patients with CDC-defined CRE infections, DOOR outcomes were not significantly different in patients with carbapenemase-producing Enterobacterales, non-carbapenemase-producing Enterobacterales, and unconfirmed CRE. At 30 days 107 (24%, 95% CI 20-28) of these patients had died. Interpretation: Among patients with CDC-defined CRE, similar outcomes were observed among three subgroups, including the novel unconfirmed CRE group. CDC-defined CRE represent diverse bacteria, whose spread might not respond to interventions directed to carbapenemase-producing Enterobacterales. Funding: National Institutes of Health.
Detection of heterogeneous vancomycin intermediate resistance in MRSA isolates from Latin America
(2020-06) Castro, Betsy E.; Berrio, Maritza; Vargas, Mónica L.; Carvajal, Lina P.; Millan, Lina V.; Rios, Rafael; Hernández, Angie K.; Rincon, Sandra; Cubides, Paola; Forero, Erika; Dinh, An; Seas, Carlos; Munita, José; Arias, Cesar A.; Reyes, Jinnethe; Díaz, Lorena
Background: Vancomycin is a common ﬁrst-line option for MRSA infections. The heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) phenotype is associated with therapeutic failure. However, hVISAisolates are usually reported as vancomycin susceptible by routine susceptibility testing procedures. Objectives: To detect and characterize the hVISA phenotype in MRSA isolates causing infections in nine LatinAmerican countries. Methods: We evaluated a total of 1189 vancomycin-susceptible MRSA isolates recovered during 2006–08 and2011–14. After an initial screening of hVISA using glycopeptide-supplemented agar strategies, the detection ofhVISA was performed by Etest (GRD) and Macro-method (MET). Isolates deemed to be hVISA were subjectedto population analysis proﬁle/AUC (PAP/AUC) and WGS for further characterization. Finally, we interrogatedalterations in predicted proteins associated with the development of the VISA phenotype in both hVISA andvancomycin-susceptible S. aureus (VSSA) genomes. Results: A total of 39 MRSA isolates (3.3%) were classiﬁed as hVISA (1.4% and 5.6% in MRSA recovered from2006–08 and 2011–14, respectively). Most of the hVISA strains (95%) belonged to clonal complex (CC) 5. Only6/39 hVISA isolates were categorized as hVISA by PAP/AUC, with 6 other isolates close (0.87–0.89) to the cut-off(0.9). The majority of the 39 hVISA isolates exhibited the Leu-14!Ile (90%) and VraT Glu-156!Gly (90%) aminoacid substitutions in WalK. Additionally, we identiﬁed 10 substitutions present only in hVISA isolates, involvingWalK, VraS, RpoB and RpoC proteins. Conclusions: The hVISA phenotype exhibits low frequency in Latin America. Aminoacid substitutions in proteinsinvolved in cell envelope homeostasis and RNA synthesis were commonly identiﬁed. Our results suggest thatEtest-based methods are an important alternative for the detection of hVISA clinical isolates
Enterococcus faecalis Infective Endocarditis: Is It Time to Abandon Aminoglycosides?
(2013) Munita, José; Arias, Cesar A.; Murray, Barbara E.
Since the first description of enterococcal infective endocarditis (IE) in 1899 and the subsequent availability of antibiotics for the treatment of this life-threatening infection, clinicians have faced important challenges in the management of this disease Enterococci exhibit intrinsic antibiotic resistance (eg, to cephalosporins , clindamycin), are less susceptible to various antibiotics (eg, β-lactams) that are active against streptococci and staphylococci, and are often tolerant to compounds (penicillin) that normally have a bactericidal effect against other susceptible bacteria.The lack of efficacy of penicillin for many cases of enterococcal IE sparked interest in possible alternative therapies.
Genomic Epidemiology of Vancomycin-Resistant Enterococcus faecium (VREfm) in Latin America: Revisiting The Global VRE Population Structure
(2020) Rios, Rafael; Reyes, Jinnethe; Carvajal, Lina P.; Rincon, Sandra; Panesso, Diana; Echeverri, Aura M.; Dinh, An; Kolokotronis, Sergios-Orestis; Narechania, Apurva; Tran, Truc T.; Munita, José; Murray, Bárbara E.; Planet, Paul J.; Arias, Cesar A.; Díaz, Lorena
Little is known about the population structure of vancomycin-resistant Enterococcus faecium (VREfm) in Latin America (LATAM). Here, we provide a complete genomic characterization of 55 representative Latin American VREfm recovered from 1998–2015 in 5 countries. The LATAM VREfm population is structured into two main clinical clades without geographical clustering. Using the LATAM genomes, we reconstructed the global population of VREfm by including 285 genomes from 36 countries spanning from 1946 to 2017. In contrast to previous studies, our results show an early branching of animal related isolates and a further split of clinical isolates into two sub-clades within clade A. The overall phylogenomic structure of clade A was highly dependent on recombination (54% of the genome) and the split between clades A and B was estimated to have occurred more than 2,765 years ago. Furthermore, our molecular clock calculations suggest the branching of animal isolates and clinical clades occurred ~502 years ago whereas the split within the clinical clade occurred ~302 years ago (previous studies showed a more recent split between clinical an animal branches around ~74 years ago). By including isolates from Latin America, we present novel insights into the population structure of VREfm and revisit the evolution of these pathogens.
Influence of Inoculum Effect on the Efficacy of Daptomycin Monotherapy and in Combination with -Lactams against Daptomycin-Susceptible Enterococcus faecium Harboring LiaSR Substitutions
(2018) Kebriaei, Razieh; Rice, Seth A.; Singh, Kavindra V.; Stamper, Kyle C.; Dinh, An Q.; Rios, Rafael; Díaz, Lorena; Murray, Bárbara E.; Munita, José; Tran, Truc T.; Arias, Cesar A.; Rybak, Michael J.
Enterococcus faecium isolates that harbor LiaFSR substitutions but are phenotypically susceptible to daptomycin (DAP) by current breakpoints are problem- atic, since predisposition to resistance may lead to therapeutic failure. Using a simu- lated endocardial vegetation (SEV) pharmacokinetic/pharmacodynamic (PK/PD) model, we investigated DAP regimens (6, 8, and 10 mg/kg of body weight/day) as mono- therapy 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). Of interest, the efficacy of DAP monotherapy, at any dose regimen, was dependent on the size of the inoculum. At an inoculum of 109 CFU/g, DAP doses of 6 to 8 mg/ kg/day were not effective and led to significant regrowth with emergence of resis- tant derivatives. In contrast, at an inoculum of 107 CFU/g, marked reductions in bacterial counts were observed with DAP at 6 mg/kg/day, with no resistance. The in- oculum effect was confirmed in a rat model using humanized DAP exposures. Com- binations of DAP with AMP, CPT, or ERT demonstrated enhanced eradication and re- duced potential for resistance, allowing de-escalation of the DAP dose. Persistence of the LiaRS substitutions was identified in DAP-resistant isolates recovered from the SEV model and in DAP-resistant derivatives of an initially DAP-susceptible clinical isolate of E. faecium (HOU668) harboring LiaSR substitutions that was recovered from a patient with a recurrent bloodstream infection. Our results provide novel data for the use of DAP monotherapy and combinations for recalcitrant E. faecium infections and pave the way for testing these approaches in humans.
Multiomics characterization of methicillin-resistant Staphylococcus aureus (MRSA) isolates with heterogeneous intermediate resistance to vancomycin (hVISA) in Latin America
(2023) Castro, Betsy E.; Ríos, Rafael; Carvajal, Lina P.; Vargas, Mónica L.; Cala, Mónica P.; León, Lizeth; Hanson, Blake; Dinh, An Q.; Ortega-Recalde, Oscar; Seas, Carlos; Munita, José; Arias, Cesar A.; Rincón, Sandra; Reyes, Jinnethe; Díaz, Lorena
Background: Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) compromise the clinical efficacy of vancomycin. The hVISA isolates spontaneously produce vancomycin-intermediate Staphylococcus aureus (VISA) cells generated by diverse and intriguing mechanisms. Objective: To characterize the biomolecular profile of clinical hVISA applying genomic, transcriptomic and metabolomic approaches. Methods: 39 hVISA and 305 VSSA and their genomes were included. Core genome-based Bayesian phylogenetic reconstructions were built and alterations in predicted proteins in VISA/hVISA were interrogated. Linear discriminant analysis and a Genome-Wide Association Study were performed. Differentially expressed genes were identified in hVISA-VSSA by RNA-sequencing. The undirected profiles of metabolites were determined by liquid chromatography and hydrophilic interaction in six CC5-MRSA. Results: Genomic relatedness of MRSA associated to hVISA phenotype was not detected. The change Try38 →His in Atl (autolysin) was identified in 92% of the hVISA. We identified SNPs and k-mers associated to hVISA in 11 coding regions with predicted functions in virulence, transport systems, carbohydrate metabolism and tRNA synthesis. Further, capABCDE, sdrD, esaA, esaD, essA and ssaA genes were overexpressed in hVISA, while lacABCDEFG genes were downregulated. Additionally, valine, threonine, leucine tyrosine, FAD and NADH were more abundant in VSSA, while arginine, glycine and betaine were more abundant in hVISA. Finally, we observed altered metabolic pathways in hVISA, including purine and pyrimidine pathway, CoA biosynthesis, amino acid metabolism and aminoacyl tRNA biosynthesis. Conclusions: Our results show that the mechanism of hVISA involves major changes in regulatory systems, expression of virulence factors and reduction in glycolysis via TCA cycle. This work contributes to the understanding of the development of this complex resistance mechanism in regional strains.
Real-world Performance of Susceptibility Testing for Ceftolozane/Tazobactam Against Non-Carbapenemase-Producing Carbapenem-Resistant Pseudomonas aeruginosa
(2021) Rivas, Lina; Alcalde-Rico, Manuel; Martínez, José R.; Moreno, Victoria; Rojas, Pamela; Wozniak, Aniela; García, Patricia; Olivares, Jorge; Miller, William R.; Arias, Cesar A.; Khan, Ayesha; Munita, José
Ceftolozane/tazbactam (C/T) is a potent anti-pseudomonal agent that has clinical utility against infections caused by non-carbapenemase producing carbapenem-resistant P. aeruginosa (non-CP-CR-PA). Accurate, precise and reliable antimicrobial susceptibility testing (AST) is crucial to guide clinical decisions. However, studies assessing the performance of different AST methods against non-CP-CR-PA- (the main clinical niche for C/T), are lacking. Here, we evaluated performance of gradient strips (Etest and MIC test strip (MTS), and disk diffusion (DD) using CLSI breakpoints. Additionally, we assessed the performance of DD using EUCAST breakpoints. For all susceptibility tests, we used a collection of 97 non-CP-CR-PA clinical isolates recovered from 11 Chilean hospitals. Both gradient strips and DD had acceptable performance when using CLSI breakpoints, yielding a categorical agreement (CA) of >90% and 92%, respectively. In contrast, DD using EUCAST breakpoints performed sub-optimally (CA 81%). MTS yielded a higher essential agreement (EA, >90%) than Etest (84%). Importantly, the performance of all methods varied significantly when the isolates were stratified by their degree of susceptibility to other anti-pseudomonal β-lactams. All methods had 100% CA when testing isolates that were pan-susceptible to all β-lactams (Pan-β-S). However, the CA markedly decreased when testing isolates resistant to all β-lactams (Pan-β-R). Indeed, the CA was 81% for Etest (6 errors), 78% for MTS (7 errors) and 78% and 56% for DD when using CLSI (7 errors) or EUCAST breakpoints (14 errors), respectively. Our results suggest that all manual AST methods have strikingly decreased performance in the context of Pan-β-R P. aeruginosa with potentially major clinical implications.

Browsing by Author "Arias, Cesar A."

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