Socioeconomic factors associated with antimicrobial resistance of Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli in Chilean hospitals (2008-2017).

OBJECTIVE: To identify socioeconomic factors associated with antimicrobial resistance of Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli in Chilean hospitals (2008-2017). METHODS: We reviewed the scientific literature on socioeconomic factors associated with the emergence and dissemination of antimicrobial resistance. Using multivariate regression, we tested findings from the literature drawing from a longitudinal dataset on antimicrobial resistance from 41 major private and public hospitals and a nationally representative household survey in Chile (2008-2017). We estimated resistance rates for three priority antibiotic-bacterium pairs, as defined by the Organisation for Economic Co-operation and Development; i.e., imipenem and meropenem resistant P. aeruginosa, cloxacillin resistant S. aureus, and cefotaxime and ciprofloxacin resistant E. coli. RESULTS: Evidence from the literature review suggests poverty and material deprivation are important risk factors for the emergence and transmission of antimicrobial resistance. Most studies found that worse socioeconomic indicators were associated with higher rates of antimicrobial resistance. Our analysis showed an overall antimicrobial resistance rate of 32.5%, with the highest rates for S. aureus (40.6%) and the lowest for E. coli (25.7%). We found a small but consistent negative association between socioeconomic factors (income, education, and occupation) and overall antimicrobial resistance in univariate (p < 0.01) and multivariate analyses (p < 0.01), driven by resistant P. aeruginosa and S. aureus. CONCLUSION: Socioeconomic factors beyond health care and hospital settings may affect the emergence and dissemination of antimicrobial resistance. Preventing and controlling antimicrobial resistance requires efforts above and beyond reducing antibiotic consumption

Comparative In Vitro Activity of Ceftolozane/Tazobactam against Clinical Isolates of Pseudomonas aeruginosa and Enterobacterales from Five Latin American Countries

Background: Ceftolozane/tazobactam (C/T) is a combination of an antipseudomonal oxyiminoaminothiazolyl cephalosporin with potent in vitro activity against Pseudomonas aeruginosa and tazobactam, a known β-lactamase inhibitor. The aim of this study was to evaluate the activity of C/T against clinical isolates of P. aeruginosa and Enterobacterales collected from five Latin American countries between 2016 and 2017, before its clinical use in Latin America, and to compare it with the activity of other available broad-spectrum antimicrobial agents. Methods: a total of 2760 clinical isolates (508 P. aeruginosa and 2252 Enterobacterales) were consecutively collected from 20 hospitals and susceptibility to C/T and comparator agents was tested and interpreted following the current guidelines. Results: according to the CLSI breakpoints, 68.1% (346/508) of P. aeruginosa and 83.9% (1889/2252) of Enterobacterales isolates were susceptible to C/T. Overall, C/T demonstrated higher in vitro activity than currently available cephalosporins, piperacillin/tazobactam and carbapenems when tested against P. aeruginosa, and its performance in vitro was comparable to fosfomycin. When tested against Enterobacterales, it showed higher activity than cephalosporins and piperacillin/tazobactam, and similar activity to ertapenem. Conclusions: these results show that C/T is an active β-lactam agent against clinical isolates of P. aeruginosa and Enterobacterales.Fil: García Betancur, Juan Carlos. Universidad El Bosque;Fil: De La Cadena, Elsa. Universidad El Bosque;Fil: Mojica, María F.. Universidad El Bosque; . Case Western Reserve University; Estados UnidosFil: Hernández Gómez, Cristhian. Universidad El Bosque;Fil: Correa, Adriana. Universidad Santiago de Cali; ColombiaFil: Radice, Marcela Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y BioquÍmica. Instituto de Investigaciones En Bacteriología y Virología Molecular (IBaViM); ArgentinaFil: Castañeda Méndez, Paulo. Fundacion Clinica Medica Sur; MéxicoFil: Jaime Villalon, Diego A.. Fundacion Clinica Medica Sur; MéxicoFil: Gales, Ana C.. Universidade Federal de Sao Paulo; BrasilFil: Munita, José M.. Universidad del Desarrollo; ChileFil: Villegas, María Virginia. Universidad El Bosque

Dynamics of the MRSA Population in a Chilean Hospital: a Phylogenomic Analysis (2000-2016)

La diseminación mundial de Staphylococcus aureus resistente a meticilina (SARM) está asociada a la aparición y el establecimiento de clones en zonas geográficas específicas. El clon chileno-cordobés (ChC) (ST5-SCCmecI) ha sido el clon de SARM predominante en Chile desde su primera descripción en 1998, a pesar del informe de otros clones de SARM emergentes en los últimos años. Aquí, caracterizamos la historia evolutiva de MRSA desde 2000 hasta 2016 en un centro de salud terciario chileno utilizando análisis filogenómicos. Secuenciamos 469 aislamientos de SARM recogidos entre 2000 y 2016. Evaluamos las tendencias temporales de los clones circulantes y realizamos una reconstrucción filogenómica para caracterizar la dinámica clonal. Encontramos un aumento significativo en la diversidad y riqueza de tipos de secuencia (STs; Spearman r = 0,8748, P , 0,0001) con un índice de diversidad de Shannon que aumentó de 0,221 en el año 2000 a 1,33 en 2016, y una diversidad efectiva (número de Hill; q = 2) que aumentó de 1,12 a 2,71. El análisis de la tendencia temporal reveló que en el periodo de 2000 a 2003 la mayoría de los aislados (94,2%; n = 98) pertenecían al clon ChC. Sin embargo, desde entonces, la frecuencia del clon ChC ha disminuido con el tiempo, representando el 52% de la colección en el período de 2013 a 2016. Este descenso estuvo acompañado por el aumento de dos linajes emergentes de SARM, ST105-SCCmecII y ST72-SCCmecVI. En conclusión, el clon ChC sigue siendo el linaje MRSA más frecuente, pero este linaje está siendo reemplazado gradualmente por varios clones emergentes, el más importante de los cuales es el clon ST105-SCCmecII. Hasta donde sabemos, éste es el mayor estudio de la dinámica clonal del SARM realizado en Sudamérica. © 2023 Martínez et al.The global dissemination of methicillin-resistant Staphylococcus aureus (MRSA) is associated with the emergence and establishment of clones in specific geographic areas. The Chilean-Cordobes clone (ChC) (ST5-SCCmecI) has been the predominant MRSA clone in Chile since its first description in 1998, despite the report of other emerging MRSA clones in recent years. Here, we characterize the evolutionary history of MRSA from 2000 to 2016 in a Chilean tertiary health care center using phylogenomic analyses. We sequenced 469 MRSA isolates collected between 2000 and 2016. We evaluated the temporal trends of the circulating clones and performed a phylogenomic reconstruction to characterize the clonal dynamics. We found a significant increase in the diversity and richness of sequence types (STs; Spearman r = 0.8748, P , 0.0001) with a Shannon diversity index increasing from 0.221 in the year 2000 to 1.33 in 2016, and an effective diversity (Hill number; q = 2) increasing from 1.12 to 2.71. The temporal trend analysis revealed that in the period 2000 to 2003 most of the isolates (94.2%; n = 98) belonged to the ChC clone. However, since then, the frequency of the ChC clone has decreased over time, accounting for 52% of the collection in the 2013 to 2016 period. This decline was accompanied by the rise of two emerging MRSA lineages, ST105-SCCmecII and ST72-SCCmecVI. In conclusion, the ChC clone remains the most frequent MRSA lineage, but this lineage is gradually being replaced by several emerging clones, the most important of which is clone ST105-SCCmecII. To the best of our knowledge, this is the largest study of MRSA clonal dynamics performed in South America. © 2023 Martínez et al

Dynamics of the Mrsa Population in a Chilean Hospital: a Phylogenomic analysis (2000-2016)

The global dissemination of methicillin-resistant Staphylococcus aureus (MRSA) is associated with the emergence and establishment of clones in specific geographic areas. The Chilean-Cordobes clone (ChC) (ST5-SCCmecI) has been the predominant MRSA clone in Chile since its first description in 1998, despite the report of other emerging MRSA clones in recent years. Here, we characterize the evolutionary history of MRSA from 2000 to 2016 in a Chilean tertiary health care center using phylogenomic analyses. We sequenced 469 MRSA isolates collected between 2000 and 2016. We evaluated the temporal trends of the circulating clones and performed a phylogenomic reconstruction to characterize the clonal dynamics. We found a significant increase in the diversity and richness of sequence types (STs; Spearman r = 0.8748, P \u3c 0.0001) with a Shannon diversity index increasing from 0.221 in the year 2000 to 1.33 in 2016, and an effective diversity (Hill number; q = 2) increasing from 1.12 to 2.71. The temporal trend analysis revealed that in the period 2000 to 2003 most of the isolates (94.2%; n = 98) belonged to the ChC clone. However, since then, the frequency of the ChC clone has decreased over time, accounting for 52% of the collection in the 2013 to 2016 period. This decline was accompanied by the rise of two emerging MRSA lineages, ST105-SCCmecII and ST72-SCCmecVI. In conclusion, the ChC clone remains the most frequent MRSA lineage, but this lineage is gradually being replaced by several emerging clones, the most important of which is clone ST105-SCCmecII. to the best of our knowledge, this is the largest study of MRSA clonal dynamics performed in South America. IMPORTANCE Methicillin-resistant Staphylococcus aureus (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. We used whole-genome sequencing to study 469 MRSA isolates collected between 2000 and 2016 in Chile providing the largest and most detailed study of clonal dynamics of MRSA in South America to date. We found a significant increase in the diversity of MRSA clones circulating over the 17-year study period. Additionally, we describe the emergence of two novel clones (ST105-SCCmecII and ST72-SCCmecVI), which have been gradually increasing in frequency over time. Our results drastically improve our understanding of the dissemination and update our knowledge about MRSA in Latin America

Mecanismos Moleculares de Resistencia a Ceftazidima/Avibactam en Aislados Clínicos de Enterobacterales y Pseudomonas aeruginosa en Hospitales Latinoamericanos

Ceftazidima-avibactam (CZA) es la combinación de una cefalosporina de tercera generación y un nuevo inhibidor de β-lactamasas no β-lactámico capaz de inactivar β-lactamasas de clase A, C y algunas D. A partir de una colección de 2.727 aislamientos clínicos de Enterobacterales (n = 2.235) y P. aeruginosa (n = 492) que se recogieron entre 2016 y 2017 de cinco países latinoamericanos, investigamos los mecanismos moleculares de resistencia a CZA de 127 (18/2.235 [0,8%] Enterobacterales y 109/492 [22,1%] P. aeruginosa). En primer lugar, mediante qPCR para detectar la presencia de genes que codifican las carbapenemasas KPC, NDM, VIM, IMP, OXA-48-like y SPM-1, y en segundo lugar, mediante secuenciación del genoma completo (WGS). De los aislados resistentes a la CZA, se detectaron genes codificadores de MBL en los 18 Enterobacterales y los 42/109 aislados de P. aeruginosa, lo que explica su fenotipo resistente. Los aislados resistentes que dieron un resultado negativo en la qPCR para cualquiera de los genes codificadores de MBL se sometieron a WGS. El análisis WGS de los 67 aislados de P. aeruginosa restantes mostró mutaciones en genes previamente asociados con una susceptibilidad reducida a la CZA, como los implicados en la bomba de eflujo MexAB-OprM y la hiperproducción de AmpC (PDC), PoxB (blaOXA-50-like), FtsI (PBP3), DacB (PBP4) y OprD. Los resultados aquí presentados ofrecen una instantánea del panorama epidemiológico molecular para la resistencia a CZA antes de la introducción de este antibiótico en el mercado latinoamericano. Por lo tanto, estos resultados sirven como una valiosa herramienta de comparación para rastrear la evolución de la resistencia a CZA en esta región geográfica endémica de carbapenemasas.Ceftazidime-avibactam (CZA) is the combination of a third-generation cephalosporin and a new non-β-lactam β-lactamase inhibitor capable of inactivating class A, C, and some D β-lactamases. From a collection of 2,727 clinical isolates of Enterobacterales (n = 2,235) and P. aeruginosa (n = 492) that were collected between 2016 and 2017 from five Latin American countries, we investigated the molecular resistance mechanisms to CZA of 127 (18/2,235 [0.8%] Enterobacterales and 109/492 [22.1%] P. aeruginosa). First, by qPCR for the presence of genes encoding KPC, NDM, VIM, IMP, OXA-48-like, and SPM-1 carbapenemases, and second, by whole-genome sequencing (WGS). From the CZA-resistant isolates, MBL-encoding genes were detected in all 18 Enterobacterales and 42/109 P. aeruginosa isolates, explaining their resistant phenotype. Resistant isolates that yielded a negative qPCR result for any of the MBL encoding genes were subjected to WGS. The WGS analysis of the 67 remaining P. aeruginosa isolates showed mutations in genes previously associated with reduced susceptibility to CZA, such as those involved in the MexAB-OprM efflux pump and AmpC (PDC) hyperproduction, PoxB (blaOXA-50-like), FtsI (PBP3), DacB (PBP4), and OprD. The results presented here offer a snapshot of the molecular epidemiological landscape for CZA resistance before the introduction of this antibiotic into the Latin American market. Therefore, these results serve as a valuable comparison tool to trace the evolution of the resistance to CZA in this carbapenemase-endemic geographical region

Antibiotic Consumption During the Coronavirus Disease 2019 Pandemic and Emergence of Carbapenemase-Producing Klebsiella pneumoniae Lineages Among Inpatients in a Chilean Hospital: A Time-Series Study and Phylogenomic Analysis.

BACKGROUND: The impact of coronavirus disease 2019 (COVID-19) on antimicrobial use (AU) and resistance has not been well evaluated in South America. These data are critical to inform national policies and clinical care. METHODS: At a tertiary hospital in Santiago, Chile, between 2018 and 2022, subdivided into pre- (3/2018-2/2020) and post-COVID-19 onset (3/2020-2/2022), we evaluated intravenous AU and frequency of carbapenem-resistant Enterobacterales (CRE). We grouped monthly AU (defined daily doses [DDD]/1000 patient-days) into broad-spectrum β-lactams, carbapenems, and colistin and used interrupted time-series analysis to compare AU during pre- and post-pandemic onset. We studied the frequency of carbapenemase-producing (CP) CRE and performed whole-genome sequencing analyses of all carbapenem-resistant (CR) Klebsiella pneumoniae (CRKpn) isolates collected during the study period. RESULTS: Compared with pre-pandemic, AU (DDD/1000 patient-days) significantly increased after the pandemic onset, from 78.1 to 142.5 (P < .001), 50.9 to 110.1 (P < .001), and 4.1 to 13.3 (P < .001) for broad-spectrum β-lactams, carbapenems, and colistin, respectively. The frequency of CP-CRE increased from 12.8% pre-COVID-19 to 51.9% after pandemic onset (P < .001). The most frequent CRE species in both periods was CRKpn (79.5% and 76.5%, respectively). The expansion of CP-CRE harboring blaNDM was particularly noticeable, increasing from 40% (n = 4/10) before to 73.6% (n = 39/53) after pandemic onset (P < .001). Our phylogenomic analyses revealed the emergence of two distinct genomic lineages of CP-CRKpn: ST45, harboring blaNDM, and ST1161, which carried blaKPC. CONCLUSIONS: AU and the frequency of CP-CRE increased after COVID-19 onset. The increase in CP-CRKpn was driven by the emergence of novel genomic lineages. Our observations highlight the need to strengthen infection prevention and control and antimicrobial stewardship efforts

A Natural Deep Eutectic Solvent Formulated to Stabilize β-Lactam Antibiotics

Abstract β-lactam antibiotics, such as penicillin share a very unstable chemical structure. In water-based solutions, such as those used for clinical applications, the β-lactam ring is readily opened due to a nucleophilic or electrophilic attack, leading to the loss of antimicrobial activity. Since the achievement and maintenance of optimum therapeutic levels of β-lactam antibiotics is critical for the resolution of many infectious clinical situations, and to avoid antibiotic resistance generation, the design of new non-aqueous dosage forms is urgent. Recently, natural deep eutectic solvents (NADES) have emerged as alternative non-toxic and non-aqueous solvents for different biomedical applications. In this work, we formulated and characterized a NADES composed by betaine and urea (BU). Using this solvent, we evaluated the stability of clavulanic acid (CLV) and imipenem (IMP) and characterized their antimicrobial activities calculating the minimal inhibitory concentration. Characterization of BU solvent by infrared spectroscopy (IR) and nuclear magnetic resonance spectroscopy (NMR) indicated that the obtained solvent has a microstructure mainly based on hydrogen bonding interactions and water addition strongly affects its dynamic. The stability of β-lactam antibiotic IMP and CLV using this solvent was increased by 7 fold and 2.5 fold respectively compared to water when analysed seven days after being dissolved. Microbiological assays showed that antibacterial activity at day seven was significantly decreased for both CLV and IMP when dissolved in water, while no change in their antibacterial properties was observed when antibiotics were dissolved in BU. The increased stability of IMP and CLV in BU may be related to the inert behaviour of the solvent and the higher dynamic restriction that helps antibiotics to maintain a more stable conformation. These data suggest the potential use of BU as a solvent to prevent degradation of β-lactam antibiotics

Trends and socioeconomic, demographic, and environmental factors associated with antimicrobial resistance: a longitudinal analysis in 39 hospitals in Chile 2008-2017.

BACKGROUND: Antimicrobial resistance (AMR) is among the most critical global health threats of the 21st century. AMR is primarily driven by the use and misuse of antibiotics but can be affected by socioeconomic and environmental factors. Reliable and comparable estimates of AMR over time are essential to making public health decisions, defining research priorities, and evaluating interventions. However, estimates for developing regions are scant. We describe the evolution of AMR for critical priority antibiotic-bacterium pairs in Chile and examine their association with hospital and community-level characteristics using multivariate rate-adjusted regressions. METHODS: Drawing on multiple data sources, we assembled a longitudinal national dataset to analyse AMR levels for critical priority antibiotic-bacterium combinations in 39 private and public hospitals (2008-2017) throughout the country and characterize the population at the municipality level. We first described trends of AMR in Chile. Second, we used multivariate regressions to examine the association of AMR with hospital characteristics and community-level socioeconomic, demographic, and environmental factors. Last, we estimated the expected distribution of AMR by region in Chile. FINDINGS: Our results show that AMR for priority antibiotic-bacterium pairs steadily increased between 2008 and 2017 in Chile, driven primarily by Klebsiella pneumoniae resistant to third-generation cephalosporins and carbapenems, and vancomycin-resistant Enterococcus faecium. Higher hospital complexity, a proxy for antibiotic use, and poorer local community infrastructure were significantly associated with greater AMR. INTERPRETATION: Consistent with research in other countries in the region, our results show a worrisome increase in clinically relevant AMR in Chile and suggest that hospital complexity and living conditions in the community may affect the emergence and spread of AMR. Our results highlight the importance of understanding AMR in hospitals and their interaction with the community and the environment to curtail this ongoing public health crisis. FUNDING: This research was supported by the Agencia Nacional de Investigación y Desarrollo (ANID), Fondo Nacional de Desarrollo Científico y Tecnológico FONDECYT, The Canadian Institute for Advanced Research (CIFAR), and Centro UC de Políticas Públicas, Pontificia Universidad Católica de Chile