Open Forum Infectious Diseases Major Article Clinical Features and Outcomes of Streptococcus anginosus Group Infective Endocarditis: A Multicenter Matched Cohort Study Francesc Escrihuela-Vidal,1 Luis Eduardo López-Cortés,2 Laura Escolà-Vergé,3,4 Arístides De Alarcón González,5 Guillermo Cuervo,1, Antonio Sánchez-Porto,6 Nuria Fernández-Hidalgo,3,4 Rafael Luque,5 Miguel Montejo,7 José M. Miró,8 Miguel Ángel Goenaga,9 Patricia Muñoz,10 Maricela Valerio,10 Marco Ripa,11 Dolores Sousa-Regueiro,12 Mercé Gurguí,13 María Carmen Fariñas-Alvarez,14 Lourdes Mateu,15 Elisa García Vázquez,16 Juan Gálvez-Acebal,2,a and Jordi Carratalà1; for the Grupo de Apoyo al Manejo de la Endocarditis Infecciosa en España (GAMES) Cohort Investigators and the Barcelona Endocarditis Study Team (BEST)b 1 Department of Infectious Diseases, Hospital Universitari de Bellvitge, Institut d´Investigació Biomèdica de Bellvitge, University of Barcelona, Barcelona, Spain, 2Clinical Unit of Infectious Diseases and Microbiology, Hospital Universitario Virgen Macarena Institute of Biomedicine of Seville, Universidad de Sevilla, Sevilla, Spain, 3Department of Infectious Diseases, Hospital Universitari Vall d´Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain, 4Spanish Network for Research in Infectious Diseases, Madrid, Spain, 5Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine Infectious Diseases Research Group, Institute of Biomedicine of Seville, University of Seville/Centro Superior de Investigaciones Científicas (CSIC)/University Virgen del Rocío and Virgen Macarena, Sevilla, Spain, 6Department of Infectious Diseases, Hospital Servicio Andaluz de Salud (SAS) Línea de la Concepción, Cádiz, Spain, 7Unit of Infectious Diseases, Hospital Universitario de Cruces, Universidad del País Vasco, Bilbao, Spain, 8Infectious Diseases Service, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain, 9Department of Infectious Diseases, Hospital Universitario Donosti, San Sebastián, Spain, 10Clinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Centro de Investigación Biomédica en Red (CIBER) Enfermedades Respiratorias, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain, 11Unit of Infectious and Tropical Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy, 12Department of Infectious Diseases, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain, 13Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, Universidad Autónoma de Barcelona, Barcelona, Spain, 14Department of Infectious Diseases, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, Santander, Spain, 15Department of Infectious Diseases, Hospital Germans Trias i Pujol, Badalona, Spain, and 16Department of Infectious Diseases and Internal Medicine, Instituto Murciano de Investigación Biosanitaria (IMIB), Hospital Clínico Universitario Virgen de la Arrixaca, Facultad de Medicina, Universidad de Murcia, Murcia, Spain Background. Although Streptococcus anginosus group (SAG) endocarditis is considered a severe disease associated with abscess formation and embolic events, there is limited evidence to support this assumption. Methods. We performed a retrospective analysis of prospectively collected data from consecutive patients with definite SAG endocarditis in 28 centers in Spain and Italy. A comparison between cases due to SAG endocarditis and viridans group streptococci (VGS) or Streptococcus gallolyticus group (SGG) was performed in a 1:2 matched analysis. Results. Of 5336 consecutive cases of definite endocarditis, 72 (1.4%) were due to SAG and matched with 144 cases due to VGS/ SGG. SAG endocarditis was community acquired in 64 (88.9%) cases and affected aortic native valve in 29 (40.3%). When com- paring SAG and VGS/SGG endocarditis, no significant differences were found in septic shock (8.3% vs 3.5%, P = .116); valve dis- order, including perforation (22.2% vs 18.1%, P = .584), pseudoaneurysm (16.7% vs 8.3%, P = .108), or prosthesis dehiscence (1.4% vs 6.3%, P = .170); paravalvular complications, including abscess (25% vs 18.8%, P = .264) and intracardiac fistula (5.6% vs 3.5%, P = .485); heart failure (34.7% vs 38.9%, P = .655); or embolic events (41.7% vs 32.6%, P = .248). Indications for surgery (70.8% vs 70.8%; P = 1) and mortality (13.9% vs 16.7%; P = .741) were similar between groups. Conclusions. SAG endocarditis is an infrequent but serious condition that presents a prognosis similar to that of VGS/SGG. Keywords. infective endocarditis; Streptococcus anginosus; viridans group streptococci; Streptococcus gallolyticus. Infective endocarditis is one of the most life-threatening infec- tions encountered in clinical practice and still represents a sig- nificant diagnostic and therapeutic challenge. About 40%–50% Received 26 January 2021; editorial decision 24 March 2021; accepted 25 March 2021. of patients with endocarditis require valve surgery at some a b Deceased 18 March 2020. point during the clinical course and mortality remains around Members of the GAMES and BEST study teams are listed in the Appendix at the end of this article. 20%–25% in the first year after diagnosis [1]. Correspondence: Guillermo Cuervo, MD, PhD, Department of Infectious Diseases, Hospital In recent years, epidemiological changes in endocarditis have Universitari de Bellvitge, Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, Spain (guillermo.cuervo@bellvitgehospital.cat). been documented in high-income countries, with an increasing Open Forum Infectious Diseases®2021 rate of episodes caused by staphylococci and enterococci [2, © The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases 3]. Nevertheless, streptococci are still a major cause of endo- Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ carditis, mostly in developing countries [4]. Concerning strep- by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any tococcal endocarditis, there is a clear predominance of cases medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com due to viridans group streptococci (VGS), whereas β-hemolytic DOI: 10.1093/ofid/ofab163 streptococci [5] and Streptococcus anginosus group (SAG) Streptococcus anginosus Group Endocarditis • ofid • 1 [1] are identified less often as causative agents. The species or asymptomatic. Request for imaging tests was made at the dis- encompassing SAG (Streptococcus anginosus, Streptococcus cretion of the treating physicians. Acute kidney injury was de- intermedius, and Streptococcus constellatus) are known for their fined as an abrupt decrease in kidney function with an increase propensity to cause pyogenic infection and abscess formation of at least 1.5-fold in serum creatinine levels. Heart conduction in the head, neck, or abdomen. SAG can also cause bacteremia disorders were defined as newly identified auriculoventricular and, more rarely, endocarditis [6, 7]. blockage or heart bundle blockage. Septic shock was defined as Although endocarditis caused by SAG is thought to be asso- hypotension persisting despite adequate fluid resuscitation [13, ciated with valve destruction, abscess formation, and embolic 14]. Indication for surgery was considered for heart failure due events [8], little information is available to support the assump- to valve regurgitation, intracardiac complications, or signs of tion that it is more severe than other causes. We therefore aimed uncontrolled infection, as listed in both the European and US to characterize the main clinical features and outcomes of en- guidelines [11, 15]. Overall mortality was defined as all-cause docarditis caused by SAG and compared this with endocarditis death during follow-up. Endocarditis-related mortality was de- and cases due to VGS or Streptococcus gallolyticus group (SGG) fined as death during active antibiotic treatment at initial hospi- in a large cohort of patients with infective endocarditis. talization or when occurring as a complication of valve surgery. Microbiological Identification METHODS Identification of microorganisms to the species level was per- Patient Population and Data Collection formed according to standard methods in each participating This was a large multicenter cohort study of consecutive adult center [16]. Before 2011, bacteria isolated from blood culture patients with a definite diagnosis of endocarditis at 27 dif- isolates were identified using conventional biochemical tests or ferent Spanish hospitals (24 of them included within the Grupo by 16S polymerase chain reaction and sequencing in cases of in- de Apoyo al Manejo de la Endocarditis Infecciosa en España conclusive results. Since 2011, isolates have been identified using [GAMES] prospective cohort) and 1 Italian hospital. GAMES is matrix-assisted laser desorption/ionization–time of flight in the a prospective registry into which multidisciplinary teams pro- majority of the participant hospitals. Viridans group streptococci spectively record all consecutive episodes of endocarditis since included Streptococcus mitis group (S mitis, S oralis, S sanguinis, 2008 [9]. We therefore performed a retrospective analysis of S parasanguinis, S gordonii), Streptococcus mutans group (S prospectively collected data for the period 2008–2017, using a mutans), and Streptococcus salivarius group (S salivarius). standardized case report form. Data included demographic and Streptococcus gallolyticus group included 4 subspecies: gallolyticus, clinical variables, echocardiography findings, treatment, and pasteurianus, infantarius, and lutetiensis. Streptococcus anginosus outcomes, namely septic shock, valvular and paravalvular com- group included S anginosus, S constellatus, and S intermedius. plications, heart failure, embolic events, indication for surgery, Antibiotic susceptibility was evaluated according to the Clinical and mortality. and Laboratory Standards Institute recommendations. We analyzed all cases of definite endocarditis due to SAG and compared these with cases due to VGS or SGG using a 1:2 Statistical Analysis matched analysis. Matching was performed according to the Categorical variables are expressed as frequencies and percent- type of valve (native or prosthetic), patient’s sex, age (±5 years), ages. Continuous variables are expressed as mean and standard year of diagnosis, and when feasible, hospital. Episodes of deviation (SD). Qualitative variables were compared using χ 2 device-related infection (pacemaker and implantable defibril- or Fisher exact tests, and quantitative variables were compared lators) and isolated right-side valve endocarditis were excluded. using the Student t test or Mann-Whitney U test, as appropriate. Statistical significance was set at P < .05, and all P values were Definitions 2-sided. Analyses were performed using IBM SPSS version 20 Definite infective endocarditis was defined according to the (IBM Corporation, Armonk, New York). modified Duke criteria [10, 11]. Acquisition was categorized as community-acquired or non-community-acquired, with the Ethical Considerations latter including nosocomial-acquired and health care–asso- This observational study was conducted in accordance with ciated infections [12]. All patients were followed up for up to the Declaration of Helsinki and was approved by the regional 1 year and were considered cured in the absence of relapse or ethics committee (Comité Ético de Investigación Clínica death. Relapse during follow-up was defined as positive blood Regional de la Comunidad de Madrid, approval code 07/18). cultures with the same microorganism. A new episode of endo- To protect personal privacy, identifying information in the carditis caused by a different microorganism was classified as a electronic database was encrypted for each patient. Written reinfection. Embolic events were defined as radiological findings informed consent was obtained from all patients reviewed consistent with ischemia of a major organ, either symptomatic in the GAMES cohort. Informed consent was waived by the 2 • ofid • Escrihuela-Vidal et al ethics committee in each of the Barcelona Endocarditis Study occurred in 20.8%, heart conduction disorders in 15.3%, and Team (BEST) participating hospitals because no intervention septic shock in 8.3%, but there were no cases of symptomatic was involved and no patient-identifying information was osteoarticular involvement. included. All patients received β-lactams as backbone antibiotic therapy, in 37 cases (51%) in synergic combination with genta- RESULTS micin. The mean antibiotic treatment length was 34.5 days (SD, 12.6 days). Although more than two-thirds of cases had an in- Clinical Characteristics and Outcomes of SAG Endocarditis dication for surgery, it was eventually not performed in 14% due During the study period, 5336 episodes of definite endocar- to a poor prognosis and/or lack of patient consent. There was an ditis were recorded in the participating hospitals. Of these, 72 elective indication in 33% of surgeries. Ultimately, 83% of cases cases (1.4%) were due to SAG, and these cases were matched were deemed to have been cured. Overall mortality occurred with 144 controls of patients with VGS or SGG endocarditis. in 10 patients (14%), all cases considered endocarditis-related Characteristics by infective agent are detailed in Tables 1 and mortality due to peri- or postoperative complications, severe 2. Most cases of SAG (76%) occurred in men, and the mean bleeding, multiorgan failure, and septic or cardiogenic shock. age was 67 years (SD, 16 years). Most cases were community- acquired (90%) and affected native valves (80.6%). The aortic valve was involved most often (40.3%), followed by the mi- Microbiology tral valve (38.9%) and the aortic and mitral valves combined The most frequently isolated microorganism in SAG endocar- (19.4%). ditis was S anginosus (n = 40 [55%]), followed by S constellatus New valve regurgitation developed in 20 (27.8%) patients, (n = 15 [20%]) and S intermedius (n = 7 [10%]). In 10 (14%) with severe mitral regurgitation being the most frequent. cases, a SAG microorganism was isolated but not identified to Notably, 15 patients (20.9%) suffered some form of intracra- the species level. Among the cases of VGS/SGG endocarditis, S nial hemorrhage and 14 (19.4%) suffered splenic emboli. Acute mitis was the most commonly isolated microorganism (n = 40 heart failure occurred in 34.7%, with 26.4% of cases having a [28%]), followed by S oralis (n = 22 [15%]), S sanguinis (n = 20 New York Heart Classification III or IV. Acute kidney injury [14%]), and other species (Table 3). In 29 (20%) cases of VGS/ Table 1. Comparative Analysis of General Characteristics and Clinical Manifestations of Infective Endocarditis Caused by Streptococcus anginosus Group and Viridans Group Streptococci/Streptococcus gallolyticus Group Characteristic SAG Endocarditis (n = 72) VGS or SGG Endocarditis (n = 144) P Value Male sex 55 (76.4) 106 (73.6) .846 Mean age, y (SD) 67 (16) 68 (15) .845 Chronic lung disease 12 (16.7) 23 (16) 1.000 Diabetes mellitus 16 (22.2) 22 (15.3) .283 Chronic kidney disease 6 (8.3) 18 (12.5) .491 Age-adjusted Charlson index, y, mean (SD) 3.8 (2.6) 3.7 (2.5) .960 Acquisition .834 Community-acquired 64 (88.9) 133 (92.4) .552 Non-community-acquired 6 (8.4) 9 (6.3) .776 Type of endocarditis .951 Native 58 (80.6) 118 (81.9) .951 Prosthetic 14 (19.4) 26 (18.1) .951 Affected valve .876 Aortic 29 (40.3) 60 (41.7) .961 Mitral 28 (38.9) 52 (36.1) .803 Mitral and aortic 14 (19.4) 26 (18.1) .950 Embolic phenomena 30 (41.7) 47 (32.6) .248 Central nervous system emboli 18 (25) 22 (15.3) .122 Echocardiographic findings Perforation or valve rupture 16 (22.2) 26 (18.1) .584 Pseudoaneurysm 12 (16.7) 12 (8.3) .108 Abscess 18 (25) 27 (18.8) .264 Intracardiac fistula 4 (5.6) 5 (3.5) .485 Prosthesis dehiscence 1 (1.4) 9 (6.3) .170 Data are presented as No. (%) unless otherwise indicated. Abbreviations: SAG, Streptococcus anginosus group; SD, standard deviation; SGG, Streptococcus gallolyticus group; VGS, viridans group streptococci. Streptococcus anginosus Group Endocarditis • ofid • 3 Table 2. Comparative Analysis of Treatment and Outcomes of Infective Endocarditis Caused by Streptococcus anginosus Group and Viridans Group Streptococci/Streptococcus gallolyticus Group Characteristic SAG Endocarditis (n = 72) VGS or SGG Endocarditis (n = 144) P Value Treatment duration, d, mean (SD) 34.5 (12.6) 33.8 (10.8) .854 Combination treatment with gentamicin 37 (51) 82 (56.9) .494 Complications Acute heart failure 25 (34.7) 56 (38.9) .655 Persistent bacteremia 4 (5.6) 8 (5.6) .602 Heart conduction disorder 11 (15.3) 18 (12.5) .739 Acute kidney injury 15 (20.8) 44 (30.6) .177 Septic shock 6 (8.3) 5 (3.5) .116 Surgery Surgery indicated 51 (70.8) 102 (70.8) 1 Elective 24 (33.3) 47 (32.6) 1 Urgent 12 (16.7) 19 (13.2) .618 Emergent 5 (6.9) 7 (4.9) .749 Surgery indicated but not performed 10 (13.9) 29 (20.1) .348 Prognosisa Definitely cured 60 (83.3) 114 (79.2) .584 Overall mortality 10 (13.9) 24 (16.7) .741   Endocarditis-related mortality 10 (13.9) 16 (11.1) .711 Relapse 0 1 (0.7) Reinfection 0 2 (1.4) Data are presented as No. (%) unless otherwise indicated. Abbreviations: SAG, Streptococcus anginosus group; SD, standard deviation; SGG, Streptococcus gallolyticus group; VGS, viridans group streptococci. a There were 2 and 3 losses to follow-up among SAG and VSG/SGG endocarditis, respectively. SGG endocarditis, identification was not performed to the shock (8.3% vs 3.5%, P = .116), indication for surgery (70.8% vs species level. 70.8%, P = 1), or overall mortality (13.9% vs 16.7%, P = .741). There was 1 case of relapse due to S oralis. No molecular typing Comparative Analysis of SAG and VGS/SGG Endocarditis was performed. Tables 1 and 2 show the comparison between SAG and VGS/ SGG endocarditis. There were no statistically significant differ- DISCUSSION ences in either valve involvement (perforation: 22.2% vs 18.1%, In this largest study of SAG endocarditis to date, we found P = .584; pseudoaneurysm: 16.7% vs 8.3%, P = .108; prosthesis that SAG accounted for 1.4% of all definite cases of endocar- dehiscence: 1.4% vs 6.3%, P = .170) or paravalvular complica- ditis in our cohort. This figure concurs with that reported in tions (abscess: 25% vs 18.8%, P = .264; intracardiac fistula: 5.6% a previous study of 18 patients [17]. Also in accordance with vs 3.5%, P = .485). Equally, no significant differences were de- previous observations, we found that S. anginosus was the tected between SAG and VGS/SGG endocarditis when com- most commonly identified causative species in SAG endo- paring the rate of acute heart failure (34.7% vs 38.9%, P = .655), carditis [8, 18]. heart conduction disorders (15.3% vs 12.5%, P = .739), septic Controversy remains about the true virulence of SAG in in- fective endocarditis. Some sporadic case reports depict SAG en- Table 3. Distribution of Viridans Group Streptococci or Streptococcus docarditis as an aggressive infection with frequent intracardiac gallolyticus Group Isolates Causing Endocarditis, by Species complications, embolic events, and abscess formation [19–21]. In a retrospective study of 56 cases of endocarditis caused by Species of Microorganism Frequency (%) β-hemolytic streptococci, 29 cases of SAG endocarditis had a Streptococcus mitis 40 (27.8) less aggressive presentation and fewer extracardiac complica- Nonidentified Streptococcus viridans group 29 (20.1) tions [1]. However, the conclusions in previous studies are lim- Streptococcus oralis 22 (15.3) ited by the limited by the small number of cases of endocarditis Streptococcus sanguinis 20 (13.9) caused by SAG. Streptococcus salivarius 12 (8.3) Streptococcus mutans 9 (6.3) We observed no statistically significant differences when com- Streptococcus gordonii 8 (5.6) paring SAG with VGS/SGG endocarditis regarding either local Streptococcus gallolyticus group 3 (2.1) complications (valve perforation or abscess, pseudoaneurysm, Streptococcus parasanguinis 1 (0.7) prosthesis dehiscence, or intracardiac fistula) or systemic 4 • ofid • Escrihuela-Vidal et al complications (heart failure and septic shock). Similarly, we Esperanza Merino, Joaquín Plazas, Sergio Reus; Complejo Hospitalario Universitario A Coruña (A Coruña): Nemesio Álvarez, José María Bravo- found no differences in the proportion of patients with sur- Ferrer, Laura Castelo, José Cuenca, Pedro Llinares, Enrique Miguez Rey, gical indications nor in mortality. These results are consistent María Rodríguez Mayo, Efrén Sánchez, Dolores Sousa Regueiro; Complejo with those of a previous study in which SAG endocarditis had a Hospitalario Universitario de Huelva (Huelva): Francisco Javier Martínez; comparable prognosis to VGS/SGG endocarditis [17]. It could Hospital Universitario de Canarias, (Canarias): Mª del Mar Alonso, Beatriz Castro, Teresa Delgado Melian, Javier Fernández Sarabia, be hypothesized that prior observations reporting a higher Dácil García Rosado, Julia González González, Juan Lacalzada, virulence of SAG endocarditis may have been biased toward Lissete Lorenzo de la Peña, Alina Pérez Ramírez, Pablo Prada Arrondo, describing the most severe cases. It should be noted, however, Fermín Rodríguez Moreno; Hospital Regional Universitario de Málaga (Málaga): Antonio Plata Ciezar, José Mª Reguera Iglesias; Hospital that higher rates of pseudoaneurysms, intracardiac abscess, Universitario Central Asturias (Oviedo): Víctor Asensi Álvarez, and central nervous system emboli were actually identified, Carlos Costas, Jesús de la Hera, Jonnathan Fernández Suárez, although without achieving statistical significance. Anatomic Lisardo Iglesias Fraile, Víctor León Arguero, José López Menéndez, Pilar Mencia Bajo, Carlos Morales, Alfonso Moreno Torrico, damage and prognostic differences may ultimately be subtle Carmen Palomo, Begoña Paya Martínez, Ángeles Rodríguez Esteban, and difficult to detect; thus, the non–statistically significant dif- Raquel Rodríguez García, Mauricio Telenti Asensio; Hospital Clínic- ferences observed could reflect a type II statistical error due to IDIBAPS, Universidad de Barcelona (Barcelona): Manuel Almela, the limited number of SAG endocarditis cases in our cohort. Juan Ambrosioni, Manuel Azqueta, Mercè Brunet, Marta Bodro, Ramón Cartañá, Carlos Falces, Guillermina Fita, David Fuster, Our study has some limitations that should be acknowl- Cristina García de la Mària, Delia García-Pares, Marta Hernández-Meneses, edged. Due to its retrospective design, some information such Jaume Llopis Pérez, Francesc Marco, José M. Miró, Asunción Moreno, as the formation of extracardiac abscesses was not available for David Nicolás, Salvador Ninot, Eduardo Quintana, Carlos Paré, Daniel Pereda, Juan M. Pericás, José L. Pomar, José Ramírez, Irene Rovira, comparison between groups. Moreover, the small number of Elena Sandoval, Marta Sitges, Dolors Soy, Adrián Téllez, José M. Tolosana, cases with certain complications, such as prosthesis dehiscence Bárbara Vidal, Jordi Vila; Hospital General Universitario Gregorio Marañón or intracardiac fistula, diminishes the power of these analyses. (Madrid): Iván Adán, Juan Carlos Alonso, Ana Álvarez-Uría, Javier Bermejo, Emilio Bouza, Gregorio Cuerpo Caballero, Antonia Delgado Montero, On the other hand, the well-known difficulties for the accurate Ana González Mansilla, Mª Eugenia García Leoni, Esther Gargallo, identification of streptococcal species and some changes in the Víctor González Ramallo, Martha Kestler Hernández, Amaia Mari Hualde, microbiological tools used for this task throughout the study Marina Machado, Mercedes Marín, Manuel Martínez-Sellés, period should be recognized as another potential limitation. Patricia Muñoz, María Olmedo, Álvaro Pedraz, Blanca Pinilla, Ángel Pinto, Cristina Rincón, Hugo Rodríguez-Abella, Maricela Valerio, We believe, however, that the multicenter nature of this study Pilar Vázquez, Eduardo Verde Moreno; Hospital Universitario La Paz, and the contemporary period of data collection strengthen our (Madrid): Isabel Antorrena, Belén Loeches, Mar Moreno, Ulises Ramírez, results. Verónica Rial Bastón, María Romero, Sandra Rosillo; Hospital Universitario Marqués de Valdecilla (Santander): Jesús Agüero Balbín, Cristina Amado, In conclusion, SAG endocarditis is an infrequent but serious Carlos Armiñanzas Castillo, Ana Arnaiz, Francisco Arnaiz de las Revillas, condition that follows a similar clinical course to VGS/SGG Manuel Cobo Belaustegui, María Carmen Fariñas, Concepción Fariñas- endocarditis, regarding valvular complications and prognostic Álvarez, Marta Fernández Sampedro, Iván García, Claudia González Rico, variables such as indication for surgery or endocarditis-related Laura Gutierrez-Fernandez, Manuel Gutiérrez-Cuadra, José Gutiérrez Díez, Marcos Pajarón, José Antonio Parra, Ramón Teira, Jesús Zarauza; Hospital mortality. Universitario Puerta de Hierro (Madrid): Jorge Calderón Parra, Marta Cobo, Fernando Domínguez, Alberto Fortaleza, Pablo García Pavía, Appendix Jesús González, Ana Fernández Cruz, Elena Múñez, Antonio Ramos, Members of the GAMES prospective registry. Hospital Costa del Sol Isabel Sánchez Romero; Hospital Universitario Ramón y Cajal, (Madrid): (Marbella): Fernando Fernández Sánchez, Mariam Noureddine, Tomasa Centella, José Manuel Hermida, José Luis Moya, Pilar Martín- Gabriel Rosas, Javier de la Torre Lima; Hospital Universitario de Cruces Dávila, Enrique Navas, Enrique Oliva, Alejandro del Río, Jorge Rodríguez- (Bilbao): Elena Bereciartua, Roberto Blanco, María Victoria Boado, Roda Stuart, Soledad Ruiz; Hospital Universitario Virgen de las Nieves Marta Campaña Lázaro, Alejandro Crespo, Laura Guio Carrión, Mikel Del (Granada): Carmen Hidalgo Tenorio; Hospital Universitario Virgen Álamo Martínez de Lagos, Gorane Euba Ugarte, Josune Goikoetxea, Macarena (Sevilla): Manuel Almendro Delia, Omar Araji, Marta Ibarrola Hierro, José Ramón Iruretagoyena, Josu Irurzun Zuazabal, José Miguel Barquero, Román Calvo Jambrina, Marina de Cueto, Leire López-Soria, Miguel Montejo, Javier Nieto, David Rodrigo, Juan Gálvez Acebal, Irene Méndez, Isabel Morales, Luis Eduardo López- Regino Rodríguez, Yolanda Vitoria, Roberto Voces; Hospital Universitario Cortés; Hospital Universitario Virgen del Rocío (Sevilla): Virgen de la Victoria (Málaga): Mª Victoria García López, Arístides de Alarcón, Emilio García, Juan Luis Haro, José Antonio Lepe, Radka Ivanova Georgieva, Guillermo Ojeda, Isabel Rodríguez Bailón, Francisco López, Rafael Luque; Hospital San Pedro (Logroño): Josefa Ruiz Morales; Hospital Universitario Donostia-Poliklínica Gipuzkoa- Luis Javier Alonso, Pedro Azcárate, José Manuel Azcona Gutiérrez, IIS Biodonostia (San Sebastián): Harkaitz Azkune Galparsoro, José Ramón Blanco, Antonio Cabrera Villegas, Lara García-Álvarez, Elisa Berritu Boronat, Mª Jesús Bustinduy Odriozola, Concepción García García, José Antonio Oteo; Hospital de la Santa Creu i Cristina del Bosque Martín, Tomás Echeverría, Alberto Eizaguirre Yarza, Sant Pau (Barcelona): Natividad de Benito, Mercé Gurguí, Cristina Pacho, Ana Fuentes, Miguel Ángel Goenaga, Muskilda Goyeneche del Río, Roser Pericas, Guillem Pons; Complejo Hospitalario Universitario de Ángela Granda Bauza, José Antonio Iribarren, Xabier Kortajarena Urkola, Santiago de Compostela (A Coruña): M. Álvarez, A. L. Fernández, José Ignacio Pérez-Moreiras López, Ainhoa Rengel Jiménez, Karlos Reviejo, Amparo Martínez, A. Prieto, Benito Regueiro, E. Tijeira, Marino Vega; Alberto Sáez Berbejillo, Elou Sánchez Haza, Rosa Sebastián Alda, Hospital Santiago Apóstol, (Vitoria): Andrés Canut Blasco, Itziar Solla Ruiz, Irati Unamuno Ugartemendia, Diego Vicente Anza, José Cordo Mollar, Juan Carlos Gainzarain Arana, Oscar García Uriarte, Iñaki Villanueva Benito, Mar Zabalo Arrieta; Hospital General Universitario Alejandro Martín López, Zuriñe Ortiz de Zárate, José Antonio Urturi Matos; de Alicante (Alicante): Rafael Carrasco, Vicente Climent, Patricio Llamas, Hospital SAS Línea de la Concepción (Cádiz): Sánchez-Porto Antonio, Streptococcus anginosus Group Endocarditis • ofid • 5 Úbeda Iglesias Alejandro; Hospital Clínico Universitario Virgen de la Marco Ripa, Paolo Scarpellini, Michele De Bonis, Eustachio Agricola, Silvia Arrixaca (Murcia): José Mª Arribas Leal, Elisa García Vázquez, Carletti, Elena Busnardo. Alicia Hernández Torres, Ana Blázquez, Gonzalo de la Morena Valenzuela; Hospital de Txagorritxu (Vitoria): Ángel Alonso, Javier Aramburu, Notes Felicitas Elena Calvo, Anai Moreno Rodríguez, Paola Tarabini-Castellani; Disclaimer. The funding agencies had no involvement in the preparation Hospital Virgen de la Salud (Toledo): Eva Heredero Gálvez, of the manuscript. Carolina Maicas Bellido, José Largo Pau, Mª Antonia Sepúlveda, Financial support. This work was supported by Plan Nacional de I+D+i Pilar Toledano Sierra, Sadaf Zafar Iqbal-Mirza; Hospital Rafael Méndez 2013‐2016 and Instituto de Salud Carlos III, Subdirección General de Redes (Lorca-Murcia):, Eva Cascales Alcolea, Ivan Keituqwa Yañez, y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Julián Navarro Martínez, Ana Peláez Ballesta; Hospital Universitario San Universidades, Spanish Network for Research in Infectious Diseases (REIPI Cecilio (Granada): Eduardo Moreno Escobar, Alejandro Peña Monje, RD16/0016/0005), co‐financed by the European Development Regional Valme Sánchez Cabrera, David Vinuesa García; Hospital Son Llátzer (Palma Fund “A way to achieve Europe,” Operative Program Intelligent Growth de Mallorca): María Arrizabalaga Asenjo, Carmen Cifuentes Luna, 2014–2020. We thank CERCA Programme/Generalitat de Catalunya for Juana Núñez Morcillo, Mª Cruz Pérez Seco, Aroa Villoslada Gelabert; institutional support. J. M. M. received a personal 80:20 research grant Hospital Universitario Miguel Servet (Zaragoza): Carmen Aured Guallar, from Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Nuria Fernández Abad, Pilar García Mangas, Marta Matamala Adell, Barcelona, Spain, during 2017–2021. Mª Pilar Palacián Ruiz, Juan Carlos Porres; Hospital General Universitario Potential conflicts of interest. J. M. M. has received consulting honor- Santa Lucía (Cartagena): Begoña Alcaraz Vidal, Nazaret Cobos Trigueros, aria and/or research grants from AbbVie, Angelini, Contrafect, Cubist, María Jesús Del Amor Espín, José Antonio Giner Caro, Genentech, Gilead Sciences, Janssen, Medtronic, MSD, Novartis, Pfizer, and Roberto Jiménez Sánchez, Amaya Jimeno Almazán, Alejandro Ortín Freire, ViiV Healthcare, outside the submitted work. All other authors report no Monserrat Viqueira González; Hospital Universitario Son Espases (Palma potential conflicts of interest. de Mallorca): Pere Pericás Ramis, Mª Ángels Ribas Blanco, All authors have submitted the ICMJE Form for Disclosure of Potential Enrique Ruiz de Gopegui Bordes, Laura Vidal Bonet; Complejo Hospitalario Conflicts of Interest. Conflicts that the editors consider relevant to the con- Universitario de Albacete (Albacete): Mª Carmen Bellón Munera, tent of the manuscript have been disclosed. Elena Escribano Garaizabal, Antonia Tercero Martínez, Juan Carlos Segura Luque; Hospital Universitario Terrassa: Cristina Badía, References Lucía Boix Palop, Mariona Xercavins, Sónia Ibars. Hospital Universitario 1. Lefort A, Lortholary O, Casassus P, et al; Beta-Hemolytic Streptococci Infective Dr. Negrín (Gran Canaria): Xerach Bosch, Eloy Gómez Nebreda, Endocarditis Study Group. 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