Person: Munita, Jose M.
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Munita
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Jose M.
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Publication Dynamics of the MRSA Population in a Chilean Hospital: a Phylogenomic Analysis (2000-2016)(2023) Martínez, José; Planet, Paul; Spencer, Maria; Rivas, Lina; Díaz, Lorena; Moustafa, Ahmed; Riquelme, Roberto; Alcalde, Manuel; Hanson, Blake; Carvajal, Lina; Rincón, Sandra; Reyes, Jinnethe; Lam, Marusella; Calderon, Juan; Araos, Rafael; García, Patricia; Arias, César; Munita, Jose M.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. 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.Publication Ceftazidime/avibactam resistance is associated with PER-3-producing ST309 lineage in Chilean clinical isolates of non-carbapenemase producing Pseudomonas aeruginosa(2024) Soto, Katherine; Alcalde, Manuel; Ugalde, Juan; Olivares, Jorge; Quiroz, Valeria; Brito, Bárbara; Rivas Jiménez, Lina María; Munita, Jose M.; García, Patricia; Wozniak, AnielaIntroduction: Ceftazidime/avibactam (CZA) is indicated against multidrug-resistant Pseudomonas aeruginosa, particularly those that are carbapenem resistant. CZA resistance in P. aeruginosa producing PER, a class A extended-spectrum β-lactamase, has been well documented in vitro. However, data regarding clinical isolates are scarce. Our aim was to analyze the contribution of PER to CZA resistance in non-carbapenemase-producing P. aeruginosa clinical isolates that were ceftazidime and/or carbapenem non-susceptible. Methods: Antimicrobial susceptibility was determined through agar dilution and broth microdilution, while bla PER 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 bla PER-3 gene was induced in a PER-positive isolate by successive passages at 43°C without antibiotics. Results: Twenty-six of 287 isolates studied (9.1%) were CZA-resistant. Thirteen of 26 CZA-resistant isolates (50%) carried bla PER. One isolate carried bla PER 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 bla PER-3 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 bla PER-3 gene restored susceptibility to CZA, ceftolozane/tazobactam and other β-lactamsin the in vitro evolved isolate. Discussion: PER-3-producing ST309 P. aeruginosa is a successful multidrug-resistant clone with blaPER-3 gene implicated in resistance to CZA and other β-lactams.Publication Creación del primer biorrepositorio nacional de bacterias multirresistentes disponible para el estudio de la resistencia bacteriana en Chile(2022) García, Patricia; Rivas Jiménez, Lina María; Peters, Anne Sophie; Henríquez, Paola; Castillo, Loriana; Illesca, Vijna; Maripani, Andrea; Moreno, Juan; Mühlhause, Margareta; Porte, Lorena; Rioseco, María Luisa; Rojas, Pamela; Silva, Francisco; Suazo, Patricio; Munita, Jose M.La disponibilidad de cepas bacteriana para el estudio de la resis tencia bacteriana es clave para los avances en la investigación básica y clínica respecto del tema. Existen pocos biorrepositorios o bancos de bacterias con mecanismos de resistencia conocidos, aisladas de infecciones clínicamente significativas. Una revisión de la literatura revela que sólo en los Estados Unidos de América existe un biobanco de aislados resistentes disponibles para estudios. En esta publicación se cuenta cómo se creó el primer biorrepositorio de bacterias resistentes en Chile asociados a la Red de Laboratorios MICROB-R, con la participación de 11 centros distribuidos a lo largo del país, que a la fecha cuenta con más de 3.500 aislados bacterianos estudiados fenotípica y genotípicamente, disponibles para la comunidad científica chilenaPublication 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) Contreras-Gómez, María José; Martínez, José Rodrigo Waldemar; Rivas Jiménez, Lina María; Riquelme-Neira, Roberto; Ugalde, Juan A.; Wozniak, Aniela; García, Patricia; Munita, Jose M.; Olivares-Pacheco, Jorge; Alcalde-Rico, ManuelCarbapenem-resistant Pseudomonas aeruginosa (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 P. aeruginosa 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.Publication 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(2023) Allel, Kasim; Peters, Anne Sophie; Conejeros, José; Martínez, José; Spencer, Maria; Riquelme, Roberto; Rivas Jiménez, Lina María; Rojas, Pamela; Orellana, Cristian; García, Patricia; Araos Bralic, Rafael Ignacio; McGovern, Olivia; Patel, Twisha; Arias, Cesar; Lessa, Fernanda; Undurraga, Eduardo; Munita, Jose M.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.Publication Multispecies emergence of dual blaKPC/NDM carbapenemase-producing Enterobacterales recovered from invasive infections in Chile(2025) Quesille, Ana; Solar, Camila; Martínez, Jose; Rivas Jiménez, Lina María; Quiroz, Valeria; González, Ana; Riquelme, Roberto; Ugalde, Juan; Peters, Anne; Ortega, Oscar; Araos Bralic, Rafael Ignacio; García, Patricia; Lebreton, Francois; Munita, Jose M.; Diaz, LorenaCarbapenemase-producing carbapenem-resistant Enterobacterales (CP-CRE) represent a significant global threat. The emergence of dual CP-CRE is particularly alarming, as they can potentially compromise the efficacy of newer antibiotics, further decreasing therapeutic alternatives. Herein, we report the emergence of multiple species of CP-CRE recovered from invasive infections in Chile that simultaneously harbor blaKPC and blaNDM and provide an in-depth genomic characterization of these worrisome pathogens. We collected carbapenem-resistant Enterobacterales (CRE) isolates from invasive infections over a 4-year period, across 11 healthcare centers in Chile. Bacterial species and the presence of carbapenemase genes were confirmed using MALDI-TOF and PCR assays, respectively. Antimicrobial susceptibility testing was conducted through disk diffusion and broth microdilution methods. Dual CP-CRE isolates were subjected to short- and long-read whole genome sequencing to perform a detailed genomic characterization of the isolates and of the mobile genetic elements harboring the enzymes. From a total of 1,335 CRE isolates, we observed an increase in the prevalence of CP-CRE, from 11% in 2019 to 38% in 2022. A total of 11 dual CP-CRE isolates were recovered, all of them harboring blaKPC and blaNDM. Species corresponded to Escherichia coli (n = 6), Klebsiella pneumoniae (n = 2), Klebsiella oxytoca (n = 2), and Citrobacter freundii (n = 1). Dual CP-CRE isolates exhibited resistance to all tested β-lactams except for cefiderocol. The blaKPC and blaNDM encoding genes were located on independent plasmids. Platforms harboring blaKPC were diverse and included IncN, IncF, and IncFIB plasmids. In contrast, blaNDM-7 was only found on fairly conserved IncX3 plasmids. We report that a rapid increase of CP-CRE in Chile, alongside with the emergence of multiple bacterial species of CP-CRE co-harboring blaKPC-2/3 and blaNDM-7, underscores a critical public health challenge. Our data suggest that the dissemination of blaNDM-7 was predominantly facilitated by IncX3 plasmids, whereas the spread of blaKPC involved multiple plasmid backbones. Active surveillance and genomic monitoring are critical to inform public policy and curtail the spread of these highly resistant pathogens.Publication Geographic divergence of methicillin-resistant Staphylococcus aureus ST5-SCCmecI in the aftermath of a major earthquake and tsunami: impact of a plasmid harboring heavy metal resistance genes(2025) Martínez, Jose; Alcalde, Manuel; Jara, Estefanía; Reyes, Jinnethe; Carvajal, Lina; Rincon, Sandra; Ríos, Rafael; Diaz, Lorena; Quesille, Ana; Riquelme, Roberto; Rivas Jiménez, Lina María; Moustafa, Ahmed; Hanson, Blake; Undurraga, Eduardo; Olivares, Jorge; García, Patricia; Araos Bralic, Rafael Ignacio; Planet, Paul; Arias, César; Munita, Jose M.El Staphylococcus aureus resistente a la meticilina (SARM) es una importante amenaza para la salud pública. La propagación global del SARM se caracteriza por sucesivas oleadas de clones epidémicos que dominan regiones geográficas específicas. Se cree que la adquisición de genes que codifican la resistencia a metales pesados (GMMP) es una característica clave en la divergencia geográfica del SARM. Sin embargo, la relación causa-efecto entre la presencia de GMMP y la divergencia de los clones de SARM aún no se ha dilucidado. En este estudio, evaluamos el papel que los GMMP pudieron haber desempeñado en la divergencia evolutiva del linaje ST5-SCC mec I del SARM en Latinoamérica. Realizamos una caracterización genómica de 113 aislamientos clínicos de SARM de seis centros de salud latinoamericanos, incluyendo 53 aislamientos recolectados en dos ciudades de Chile (Santiago y Concepción). Encontramos un plásmido (pSCL4752) que alberga genes de resistencia al arsénico, cadmio y mercurio en el 65% ( n = 71) de los aislados ST5-SCC mec I. También observamos una divergencia geográfica asociada a la presencia de pSCL4752 en aislados chilenos, con una mayor frecuencia en aislados de Concepción (88%) en comparación con Santiago (29%). Curiosamente, un análisis de reloj molecular reveló que esta divergencia se produjo tras el terremoto y tsunami de magnitud 8,8 Mw que azotó la zona de Concepción en 2010. Además, nuestros resultados demuestran que la presencia de pSCL4752 puede ser beneficiosa o perjudicial para los aislados ST5-SCC mec I, dependiendo de la disponibilidad ambiental de estos metales pesados. Nuestros resultados sugieren que la divergencia del linaje ST5-SCC mec I MRSA en América Latina podría haber sido fomentada por desastres ambientales e influenciada por la presencia/ausencia de HMRG albergados en un plásmido. IMPORTANCIA El Staphylococcus aureus resistente a la meticilina (MRSA) es una de las principales causas de infecciones potencialmente mortales en todo el mundo y una creciente preocupación para la salud pública. El aumento de bacterias resistentes a los antibióticos, como el MRSA, a menudo está vinculado a adaptaciones genéticas que mejoran su supervivencia. Nuestra investigación arroja luz sobre cómo los cambios ambientales, como los desencadenados por un desastre natural, pueden influir en la evolución y la propagación geográfica de un linaje de MRSA altamente resistente en América Latina. Identificamos un plásmido que porta genes de resistencia al arsénico, cadmio y mercurio, el cual se asoció con la divergencia geográfica del ST5-SCC mec.Se ha identificado un linaje de SARM con diferencias notables en su prevalencia entre las regiones afectadas por un gran terremoto y tsunami. Al vincular los eventos ambientales con la evolución del patógeno, nuestro estudio destaca el papel de las presiones ecológicas en la propagación del SARM. Estos hallazgos subrayan la necesidad de integrar el monitoreo ambiental en las estrategias de salud pública para comprender mejor el desafío global de la resistencia a los antimicrobianos.