is a major human pathogen causing a wide range of infections, including bacteremia, infective endocarditis, and osteoarticular, skin and soft tissue, pleuropulmonary, and device-related infections (1
). S. aureus
is a leading cause of hospital-associated infections and is the most common cause of soft tissue infections requiring visits to emergency services in the United States (2
). Bloodstream infection (BSI) is a potentially fatal complication of S. aureus
disease, with an estimated incidence of 80 to 190 cases/100,000 inhabitants per year in developed countries (3–5
). For example, in the United States and France, it is estimated that ca. 600,000 and 125,000 cases of S. aureus
BSIs occur per year, respectively (3–5
The emergence of methicillin-resistant S. aureus
(MRSA) poses important therapeutic challenges (6
). Although initially identified as an important nosocomial pathogen, MRSA is now endemic in the community (7
). The Centers for Disease Control and Prevention (CDC) estimates that 80,461 invasive MRSA infections and 11,285 related deaths occurred in the United States in 2011 (8
). Community-associated MRSA (CA-MRSA) strains were first described among healthy individuals with no health care contact or hospital-associated risk factors (8
). In North America (NA), the CA-MRSA epidemic is widely attributed to the spread of a clone designated USA300-ST8 (9
). Interestingly, a USA300-related genetic lineage (designated USA-300 Latin American variant [USA300-LV]) has emerged in the northern part of South America (SA) and appears to have become endemic in hospitals in the region (Colombia, Venezuela, and Ecuador) (11–14
). Recent phylogenetic analyses of USA300 and USA300-LV MRSA revealed that the two genetic lineages are closely related and that the NA and SA clades segregated geographically. Molecular clock analyses suggested that both clades had a common ancestor that may have emerged in the mid-1970s with individual segregation occurring by 1989 and 1985 for the NA and SA clades, respectively (14
). Geographic segregation of these parallel epidemics coincided with the independent acquisition of the arginine catabolic mobile element (ACME) in NA isolates and a copper and mercury resistance (COMER) mobile element in SA isolates (14
Apart from the introduction of the USA300-LV in the northern countries of SA, important changes in the population structure of MRSA have also occurred in Argentina and Brazil (15–17
). However, a comprehensive molecular analysis of S. aureus
bacteremia in Latin America has not been attempted before. Here, we sought to characterize the population structure of S. aureus
bacteremia and the changing molecular epidemiology of MRSA in a prospective multicenter cohort study of S. aureus
bacteremia spanning 3.5 years (2011 to 2014) in selected hospitals from nine Latin-American countries.
In this work, we have assembled the largest cohort of patients with S. aureus
bacteremia in Latin America to date. The study included patients enrolled in selected hospitals from nine countries, from Mexico to Argentina. Our main objective was to understand the clinical and molecular characteristics of S. aureus
bacteremia on a large scale. Although we understand that the hospitals enrolled may not represent the situation of other hospitals in the countries included in this study, it is important to note that our findings are supported by many previous local studies (11–19
). Thus, our results may actually reflect an accurate picture of circulating S. aureus
lineages causing bloodstream infections in the region.
One of the most interesting findings of our study is that the proportion of MRSA strains remains high in the region but exhibits important regional variations. Indeed, rates of MRSA higher than 40% were found in the majority of countries, with the highest prevalence in the participating hospitals in Brazil (62%), a finding that is consistent with those of recently reported surveillance studies (11–19
). A notable exception to the above appears to be in the included hospitals from both Colombia and Ecuador. In these centers, the rates of MRSA appear to have markedly decreased compared with those from previous studies. Indeed, in a multicenter surveillance carried out by our group in Colombia from 2006 to 2008 (which included the three hospitals of the current study), methicillin resistance in S. aureus
was documented in ca. 50% of hospital-associated isolates (13
). By contrast, in the present study, <30% of S. aureus
isolates from these hospitals were MRSA. Although the former study included isolates from clinical samples other than blood, the decrease in the rates of MRSA seems significant compared with previous reports of hospitals in Peru and Venezuela (19
). Although we cannot exclude that such reductions in MRSA prevalence could be due to major changes in infection control practices in the participating hospitals, the lower rates of MRSA seem to be associated with the shift in the population structure.
In 2005, we characterized the first strains of CA-MRSA reported in Colombia and found that, in contrast to in other parts of the world, the majority of these infections were caused by MRSA isolates that belonged to a genetic lineage closely related to the USA300 strain prevalent in NA (we designated this lineage USA300-LV) (11–14
). Both USA300 genetic lineages encompass ST8 isolates harboring SCCmec
IV and genes encoding the PVL toxin. However, the most important genetic distinction between these two is the absence of the ACME island in USA300-LV, which is replaced by a gene cluster encoding proteins involved in the metabolism of copper and mercury (14
). The results of our study, which are supported by several other local findings, indicate that in stark contrast with USA300, USA300-LV strains have been able to completely replace previously prevalent hospital-associated clones in Colombia and Ecuador (11–19
). The reasons for such remarkable clonal switch in a relatively short time span are not known. Thus, the understanding of the pathogenic properties of this genetic lineage and the role of the COMER island in virulence and the ability to disseminate has become a priority of our future studies.
To dissect the population genetics of isolates from our studies, we selected isolates for whole-genome sequencing (WGS) based on our initial molecular characterization to offer a more detailed picture of the molecular epidemiology and population structure of MRSA. Our genomic analyses indicate that three major clades are likely to circulate in the Latin American centers included in this study, which in general, clustered in previous MLST analyses. The most multidrug-resistant of these clades is clade A, which encompasses the majority of MRSA strains of the region (except in Colombia and Ecuador). The strains are grouped within the CC5 (Chilean/Cordobes and NY/Japan-USA100 clones) and exhibit high rates of resistance to quinolones, MLSB
, and aminoglycosides associated with the presence of SCCmec
I and II. An exception to the above characteristics is a cluster of ST5 isolates recovered in Argentina (ARG) and Brazil (BRA) that carry SCCmec
IVa and IVg and have been associated with community infections in these countries (15
), suggesting that a novel ST5 CA-MRSA lineage is in its ascendency in the southern parts of SA.
Clade B encompasses isolates from CC8 and CC239, including those belonging to USA300-LV and NA-USA300. In general, the CC8 isolates harbor the PVL genes, carry SCCmec IV, and are less enriched in antibiotic resistance genes than those of clade A, with the exception of isolates belonging to the Brazilian clone which harbor SCCmec III and harbor resistance profiles similar to those of clade A. Of note, 18% of Mexican MRSA isolates from a tertiary hospital (grouped in clade B) display the pattern typical of that of NA-USA300, suggesting that this strain is likely to be circulating in Mexico. Finally, clade C groups most of ST30 CA strains, which are found mainly in the ARG hospitals and are related to the Oceania-Pacific ST30 clone initially described in Australia. These strains also carry SCCmec IVc/E, with genes encoding PVL present in 61% of them. Of note, the Argentinian hospitals harbored the most highly diverse population of MRSA, and the reasons for such heterogeneity in the population genetics of MRSA are unclear.
As mentioned above, an important limitation of our study is that we only included a few participating centers in each country, and our results may not reflect the situation of the entire region. However, this is an inherent limitation of studies similar to ours, and a more comprehensive inclusion of hospitals with such diversity and different social and economic realities is challenging. Moreover, the results from many local studies seem to support our findings, making them more generalizable (11–19
). Also, we did not have the support to perform WGS on the entire collection, which would have provided a deeper understanding of the population structure of the MRSA isolates. Nonetheless, our genomic selection strategy was robust (96 isolates), with the objective of including isolates that may accurately represent the phylogenetic picture of MRSA bacteremia in the participating centers. Indeed, our genomic findings are also supported by results from other studies and point to specific clonal changes that may contribute to the understanding of the dissemination and dynamics of bacteremic S. aureus
infections in the region.
In summary, we presented a comprehensive characterization of S. aureus bacteremia in Latin America, providing strong evidence that clonal replacement is frequent and that the population structure is in continuous evolution. The identification of newly emerged genetic lineages would help in defining specific therapeutic approaches for MRSA infections in the region.
We dedicate the manuscript to the memory of Carlos Mejia-Villatoro. We thank Juan David Garavito, Natalia Rojas, and Paola Porras for technical assistance in the characterization of the isolates. We also thank the following members of the Latin-America Working Group on Bacterial Resistance. From Argentina, Didier Bruno, Hospital de Clinicas, Buenos Aires; Ernesto Efron, Hospital Británico, Buenos Aires; and Marcelo Del Castillo, Sanatorio Mater Dei, Buenos Aires. From Brazil, Thaís Guimarães, Hospital do Servidor Publico Estadual de São Paulo, São Paulo. From Chile, María Elena Ceballos, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago; Isabel Domínguez and Daniela Beltrán, Hospital Sótero del Río, Santiago; and Gisela Riedel, Hospital Guillermo Grant Benavente, Concepción. From Colombia, Sandra Liliana Valderrama, Unidad de Enfermedades Infecciosas, Hospital Universitario San Ignacio, Pontificia Universidad Javeriana, Bogota; Sandra Milena Gualtero, Hospital Universitario San Ignacio, Clínica Shaio; and Carlos Humberto Saavedra, Unidad Infectologia, Hospital Universitario Clínica San Rafael, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá. From Ecuador, Betzabé Tello, Hospital Vozandes, Quito; Juan Carlos Aragón, Hospital General de las Fuerzas Armadas, Quito; and Fausto Guerrero, Hospital Carlos Andrade Marín, Quito. From Guatemala, María Mónica Silvestre, Hospital Roosevelt. From Mexico, Rayo Morfin-Otero, Hospital Civil de Guadalajara, Fray Antonio Alcalde, Centro Universitario Ciencias de la Salud, Universidad de Guadalajara, Guadalajara. From Peru, Jose Hidalgo, Hospital Guillermo Almenara, Lima; and Luis Hercilla, Hospital Alberto Sabogal, Lima. From Venezuela, Ana María Cáceres Hernández, Clinica La Floresta, Caracas; Marisela Silva, Hospital Universitario de Caracas, Caracas; and Alfonso José Guzmán, Centro Médico de Caracas, Caracas.
This work was supported by an independent investigator-initiated grant to E.G. and C.S. C.A.A. is supported by the National Institutes of Health–National Institute of Allergy and Infectious Diseases (NIH/NIAID) (grants K24-AI114818, R01-AI093749, R21-AI114961, and R21/R33 AI121519). DNA sequencing was supported in part by Departamento de Ciencia, Tecnologia e Innovacion (COLCIENCIAS) (grant 130871250417/906-2015 to J.R.). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
All authors have completed and submitted the ICMJE form for the disclosure of potential conflicts of interest. Cesar A. Arias has received grant support, consulted for or provided lectures for Pfizer, Merck, Bayer, Allergan Pharmaceuticals, Novartis, Theravance, and the Medecins Company. Mauro J. Salles has received grant support from Pfizer and Novartis, and lecture and consulting fees from Pfizer, Novartis, Bayer, MSD, Sanofi-Aventis, and Astra-Zeneca. Paul J. Planet and Eduardo Rodríguez-Noriega have received lecture and consulting fees from Pfizer. Carlos Seas has received fees and grant support from Pfizer and grant support from Glaxo Smith Kline and Bristol Myers Squibb. No other conflict of interest was reported.