Tratamiento de la bacteriemia por Staphylococcus aureus: evidencias y retos

Depósito de investigación de la Universidad de Sevilla https://idus.us.es/ Esta es la versión aceptada del artículo publicado en: This is an accepted manuscript of a paper published in: Enfermedades Infecciosas y Microbiología Clínica (2021): August 2021 DOI: 10.1016/j.eimc.2020.01.018 Copyright: © 2020 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved. El acceso a la versión publicada del artículo puede requerir la suscripción de la revista. Access to the published version may require subscription. “This is an Accepted Manuscript of an article published by Elsevier in Enfermedades Infecciosas y Microbiología Clínica on December 2020, available at: https://doi.org/10.1016/j.eimc.2020.01.018”. Enfermedades Infecciosas y Microbiologia Clinica Tratamiento de la bacteriemia por Staphylococcus aureus: evidencias y retos --Borrador del manuscrito-- Número del manuscrito: EIMC-D-19-00438R1 Tipo de artículo: Revision Palabras clave: Staphylococcus aureus; Bacteriemia; pronóstico; tratamiento antimicrobiano; tratamiento combinado. Autor correspondiente: Jesús Rodríguez-Baño, MD, PhD Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena / Departamento de Medicina, Universidad de Sevilla / Instituto de Biomedicina de Sevilla. Sevilla, SPAIN Primer autor: Luis Eduardo López-Cortés Orden de autores: Luis Eduardo López-Cortés Juan Gálvez-Acebal Jesús Rodríguez-Baño, MD, PhD Resumen: La bacteriemia por Staphylococcus aureus continúa siendo un reto diario para los clínicos. A pesar de todos los esfuerzos realizados, su mortalidad y morbilidad asociadas no han descendido de forma significativa en los últimos 20 años. Existe evidencia de que la adherencia a los indicadores de calidad para su manejo clínico es importante para mejorar el pronóstico de los pacientes, aunque su cumplimiento sigue siendo menor de lo deseado en muchos hospitales; en este sentido, la asistencia por especialistas en Enfermedades Infecciosas ha demostrado contribuir a reducir la mortalidad de estos pacientes. En este artículo se revisan los estudios clínicos más relevantes realizados en los últimos años con objeto de evaluar la eficacia y seguridad de fármacos alternativos a los clásicos. Sin embargo, éstos siguen siendo utilizados en un alto porcentaje de pacientes, ya que los prometedores resultados obtenidos por esos fármacos alternativos y determinadas combinaciones en estudios in vitro y modelos animales no se han traducido en una evidente superioridad en los estudios clínicos con la frecuencia que se hubiera esperado. Dicho esto, existen datos que sugieren que determinadas alternativas pueden ofrecer ventajas en situaciones concretas. En general, es necesario un manejo individualizado y experto de los pacientes para decidir la mejor terapia en base al foco, la gravedad y complicaciones, las características de los pacientes y los datos microbiológicos. Revisores sugeridos: Jose Miguel Cisneros [email protected] Miquel Pujol [email protected] Revisores a los que se opone: Respuesta a los revisores: Comentarios de los revisores: Revisor nº1: This article is a very well done and very well written review of the treatment of post S. aureus bacteraemia, which includes not only the most relevant published articles, but also the ongoing trials. I have only few minor (mainly typo) comments: -Line 76 and throughout the document: use bacteraemia instead of BSI to standardize the nomenclature used throughout the document. Respuesta: Hemos realizado el cambio para unificar la nomenclatura. -Line 123: replace "community-acquisition" for "community acquisition". Respuesta: Cambio realizado. -Lines 215-218: add allergy to beta-lactams as a frequent reason for the use of daptomycin. Con tecnología de Editorial Manager® y ProduXion Manager® de Aries Systems Corporation Respuesta: En caso de alergia a beta-lactámicos, las opciones de tratamiento deben ser similares a las existentes en caso de resistencia a meticilina. Incluímos un comentario al respecto. Revisor nº2: El contenido y la estructura del texto son correctos y revisan de forma adecuada los principales aspectos del tratamiento de la SAB. -En el primer párrafo los autores establecen que la evolución de la SAB depende de tres factores (bacteria, paciente y manejo clínico). Los dos primeros se presentan en el texto (líneas 69 y 95). Se debería indicar en el texto en qué momento se describen los aspectos relacionados con el manejo clínico (línea 110): concepto de bacteriemia complicada, papel de la ecocardiografía, aplicación del conjunto de medidas para mejorar su manejo ("bundle"), etc. Respuesta: Hemos incluido este aspecto como se nos sugiere. El párrafo se inicia de la siguiente forma: “Regarding the clinical management, a key aspect is the concept of “complicated bacteraemia…”. -En la figura se presenta un algoritmo para el manejo clínico de la SAB pero no se menciona en ninguna parte del texto que se trata de la estrategia propuesta por los autores. Quizá debería aparecer al final del apartado de "Outcome predictors" (después de línea 145). Respuesta: Estamos de acuerdo con el revisor, y así se especifica en la versión revisada. Agradecemos la sugerencia. -Tabla 1. Se debería eliminar la información referente a levofloxacino (no se recomienda en monoterapia para infecciones por S. aureus y puede llevar a confusión). De la misma manera, se debería añadir la información referente a teicoplanina, dado que es uno de los fármacos recomendados por los autores para el tratamiento de la infección por SAMR (Tabla 2). Respuesta: Hemos eliminado la referencia a levofloxacino y añadido una referente a teicoplanina siguiendo las recomendaciones del revisor. -Existen errores tipográficos en la tabla (2g = 2 g, Kg = kg, etc). Respuesta: Estos errores han sido corregidos. -Conclusiones: Son demasiado generales y deberían ser algo más concretas, en consonancia con lo que se resume en la Tabla 2 (p.e. indicación de monoterapia - beta-lactámicos en SAMS y vancomicina, daptomicina o teicoplanina en SAMR- para SAB no complicada, consideración de terapia combinada en SAB complicada, etc). Respuesta: Se han añadido varias frases al párrafo de conclusión, en el sentido que comenta el revisor. -Hubiera sido muy útil incluir una tabla en la que se resumieran los resultados más significativos de los principales ensayos o estudios observacionales mencionados en el texto (reconocemos que supondría un trabajo suplementario excesivo). Respuesta: Hemos incluido una tercera tabla con todos los estudios publicados a los que se hace referencia en el apartado de antibioterapia. Creemos que es una aportación muy útil a la revisión. Otros comentarios: - Línea 139: MSSA, early source removal > cambiar por early source control. Respuesta: Hemos corregido la errata. - Línea 142: aunque se acepta que la duración del tratamiento de la SAB no complicada puede ser de 10 días, la duración recomendada en el artículo citado (referencia 24, escrito por los autores) es de 14 días. Respuesta: Estamos de acuerdo con el revisor. Modificamos el texto en consecuencia. - Tabla 2. Aunque se menciona en el texto, debería aparecer en la tabla la definición de "infecciones de alto inóculo" (endocarditis y neumonía) (p.e. nota al pie de tabla). Respuesta: Hemos añadido la aclaración en la tabla señalada. - También se debería definir claramente el concepto de "lower susceptibility to vancomycin" (definido por CMI) si se refiere al valor elevado de CMI dentro del rango Con tecnología de Editorial Manager® y ProduXion Manager® de Aries Systems Corporation de sensibilidad (línea 220). Respuesta: la definición estaba incluida en la línea 223. La hemos incluido en la línea 220 y hemos cambiado “lower susceptibility to vancomycin” por “reduced susceptibility to vancomycin” para homogeneizar con el término empleado en la literatura. - Bacteriemia: utilizar la misma palabra en inglés en todo el texto (en la literatura se utiliza más bacteremia que bacteraemia), y eliminar bactereaemia en título de Tabla 2. Respuesta: “Bacteraemia” y “bacteremia” son los términos usados para la bacteriemia en el inglés del Reino Unido y en el de EEUU, respectivamente. Dado que todo el texto está redactado en inglés del Reino Unido, mantenemos bacteraemia salvo que el Editor nos indique lo contrario. - Línea 200: corregir sintaxis de la frase "Linezolid was associated with worse outcomes…" en las que aparece dos veces although. Respuesta: Corregido. Con tecnología de Editorial Manager® y ProduXion Manager® de Aries Systems Corporation Sevilla, 14 de Enero 2020 Estimado Editor, Le remitimos una nueva versión del artículo de revisión titulado “Tratamiento de la bacteriemia por Staphylococcus aureus: evidencias y retos" tras incluir cambios con todas las recomendaciones realizadas por los revisores. Agradecemos a los revisores y al Editor la revisión, que nos ha permitido mejorar el manuscrito. Las contestaciones a los comentarios de los revisores se incluyen en documento aparte. Un cordial saludo, Jesús Rodríguez-Baño En nombre del resto de autores Carta de presentación Acknowledgments: the authors received funds for research from Plan Nacional de I+D+i 2013‐2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0001) ‐ cofinanced by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014‐2020. Conflicts of interest: LELC has served as scientific advisor for Novartis, speaker for MSD, Pfizer, Angelini, and ViiV, and has served as trainer for MSD and ViiV. JGA has received grants for attending meetings from Angelini, Pfizer and Gilead, and has participated in accredited educational activities funded by MSD. JRB has participated in unrestricted accredited educational activities funded by MSD. Responsabilidades éticas/Ethical disclosures Sevilla, 14 de Enero 2020 Estimado Editor, Le remitimos una nueva versión del artículo de revisión titulado “Tratamiento de la bacteriemia por Staphylococcus aureus: evidencias y retos" tras incluir cambios con todas las recomendaciones realizadas por los revisores. Agradecemos a los revisores y al Editor la revisión, que nos ha permitido mejorar el manuscrito. Un cordial saludo, Jesús Rodríguez-Baño En nombre del resto de autores Comentarios de los revisores: Revisor nº1: This article is a very well done and very well written review of the treatment of post S. aureus bacteraemia, which includes not only the most relevant published articles, but also the ongoing trials. I have only few minor (mainly typo) comments: -Line 76 and throughout the document: use bacteraemia instead of BSI to standardize the nomenclature used throughout the document. Respuesta: Hemos realizado el cambio para unificar la nomenclatura. -Line 123: replace "community-acquisition" for "community acquisition". Respuesta: Cambio realizado. -Lines 215-218: add allergy to beta-lactams as a frequent reason for the use of daptomycin. Respuesta: En caso de alergia a beta-lactámicos, las opciones de tratamiento deben ser similares a las existentes en caso de resistencia a meticilina. Incluímos un comentario al respecto. Revisor nº2: El contenido y la estructura del texto son correctos y revisan de forma adecuada los principales aspectos del tratamiento de la SAB. -En el primer párrafo los autores establecen que la evolución de la SAB depende de tres factores (bacteria, paciente y manejo clínico). Los dos primeros se presentan en el texto (líneas 69 y 95). Se debería indicar en el texto en qué momento se describen los aspectos relacionados con el manejo clínico (línea 110): concepto de bacteriemia complicada, papel de la ecocardiografía, aplicación del conjunto de medidas para mejorar su manejo ("bundle"), Respuesta a los revisores (Response to reviewers) etc. Respuesta: Hemos incluido este aspecto como se nos sugiere. El párrafo se inicia de la siguiente forma: “Regarding the clinical management, a key aspect is the concept of “complicated bacteraemia…”. -En la figura se presenta un algoritmo para el manejo clínico de la SAB pero no se menciona en ninguna parte del texto que se trata de la estrategia propuesta por los autores. Quizá debería aparecer al final del apartado de "Outcome predictors" (después de línea 145). Respuesta: Estamos de acuerdo con el revisor, y así se especifica en la versión revisada. Agradecemos la sugerencia. -Tabla 1. Se debería eliminar la información referente a levofloxacino (no se recomienda en monoterapia para infecciones por S. aureus y puede llevar a confusión). De la misma manera, se debería añadir la información referente a teicoplanina, dado que es uno de los fármacos recomendados por los autores para el tratamiento de la infección por SAMR (Tabla 2). Respuesta: Hemos eliminado la referencia a levofloxacino y añadido una referente a teicoplanina siguiendo las recomendaciones del revisor. -Existen errores tipográficos en la tabla (2g = 2 g, Kg = kg, etc). Respuesta: Estos errores han sido corregidos. -Conclusiones: Son demasiado generales y deberían ser algo más concretas, en consonancia con lo que se resume en la Tabla 2 (p.e. indicación de monoterapia -beta- lactámicos en SAMS y vancomicina, daptomicina o teicoplanina en SAMR- para SAB no complicada, consideración de terapia combinada en SAB complicada, etc). Respuesta: Se han añadido varias frases al párrafo de conclusión, en el sentido que comenta el revisor. -Hubiera sido muy útil incluir una tabla en la que se resumieran los resultados más significativos de los principales ensayos o estudios observacionales mencionados en el texto (reconocemos que supondría un trabajo suplementario excesivo). Respuesta: Hemos incluido una tercera tabla con todos los estudios publicados a los que se hace referencia en el apartado de antibioterapia. Creemos que es una aportación muy útil a la revisión. Otros comentarios: - Línea 139: MSSA, early source removal > cambiar por early source control. Respuesta: Hemos corregido la errata. - Línea 142: aunque se acepta que la duración del tratamiento de la SAB no complicada puede ser de 10 días, la duración recomendada en el artículo citado (referencia 24, escrito por los autores) es de 14 días. Respuesta: Estamos de acuerdo con el revisor. Modificamos el texto en consecuencia. - Tabla 2. Aunque se menciona en el texto, debería aparecer en la tabla la definición de "infecciones de alto inóculo" (endocarditis y neumonía) (p.e. nota al pie de tabla). Respuesta: Hemos añadido la aclaración en la tabla señalada. - También se debería definir claramente el concepto de "lower susceptibility to vancomycin" (definido por CMI) si se refiere al valor elevado de CMI dentro del rango de sensibilidad (línea 220). Respuesta: la definición estaba incluida en la línea 223. La hemos incluido en la línea 220 y hemos cambiado “lower susceptibility to vancomycin” por “reduced susceptibility to vancomycin” para homogeneizar con el término empleado en la literatura. - Bacteriemia: utilizar la misma palabra en inglés en todo el texto (en la literatura se utiliza más bacteremia que bacteraemia), y eliminar bactereaemia en título de Tabla 2. Respuesta: “Bacteraemia” y “bacteremia” son los términos usados para la bacteriemia en el inglés del Reino Unido y en el de EEUU, respectivamente. Dado que todo el texto está redactado en inglés del Reino Unido, mantenemos bacteraemia salvo que el Editor nos indique lo contrario. - Línea 200: corregir sintaxis de la frase "Linezolid was associated with worse outcomes…" en las que aparece dos veces although. Respuesta: Corregido. 6 associated with lower mortality in a quasi-experimental multicentre study;24 this approach 145 has been validated in later studies.25, 26 A proposal for the clinical management of S. 146 aureus bacteremia is included in Figure 1. 147 148 Antimicrobial therapy 149 150 Until recently, the preferred options for the treatment of SAB had remained 151 unchanged for decades. The fact that SAB-associated morbidity and mortality continue 152 to be high had triggered the search for new alternatives; in fact, there are many published 153 studies with in vitro and in vivo evaluation of the activity of new drugs and new 154 combinations. However, the promising results of these models did not always translate to 155 improved outcomes in clinical studies. Therefore, in this review we will mainly discuss 156 the results of clinical studies. The different drugs used for SAB are specified in Table 1, 157 and a summary of the recommended regimens in Table 2. The published studies included 158 in this review are included in Table 3. 159 160 Monotherapy 161 162 Penicillinase-resistant penicillins (cloxacillin, oxacillin) are usually considered 163 the drugs of choice for MSSA bacteremia. However, cefazolin, a first generation 164 cephalosporin, has several potential advantages: available data suggest it may have lower 165 liver and renal toxicity, lower rate of phlebitis, and better stability at room temperature, 166 making it more convenient for outpatient parenteral antimicrobial therapy (OPAT).27 In 167 case of patients under hemodialysis, the longer half-life of cefazolin (1 g/day or 2 gr after 168 the dialysis session) allows to reduce the manipulation of the dialysis catheter. Despite it 169 was traditionally considered a less efficacious drug because of showing lower in vitro 170 activity when exposed to higher bacterial concentrations (the so-called inoculum effect), 171 the results of several recent meta-analysis have challenged that idea by showing similar 172 efficacy and lower renal toxicity.28-30 The inoculum effect seems to be related to the 173 inactivation of the drug by a type A beta-lactamase codified by blaZ gene. An 174 observational study including 185 isolates from 5 centres in USA found the blaZ gene in 175 77% of them; 27% had a >4-fold increase in the cefazolin MIC when exposed to a high 176 inoculum, and 4% were not-susceptible to cefazolin, all of which harboured blaZ genes.31 177 Some data support a clinical impact of the inoculum effect;30 if this is confirmed in future 178 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 7 studies, it might be useful to develop a rapid technique to detect such isolates. At this 179 moment and until the results of an ongoing randomised trial are available,32 it seems 180 prudent to avoid the use of cefazolin in severe infections with high bacterial load such as 181 endocarditis or pneumonia. The use of other cephalosporins or penicillins do not seem to 182 provide any advantage over cefazolin. For penicillin-allergic patients, and contrary to 183 what is frequently believed, there is no evidence for an increased risk of anaphylaxis when 184 exposed to cefazolin.33 Also, switching to cefazolin in patients with non-IgE, immune 185 mediated reactions to nafcillin seems to be safe.34 It should be reminded that vancomycin 186 is less efficacious than antistaphylococcal penicillins. Whenever cefazolin is not 187 considered suitable in penicillin-allergic patients, the therapeutic options are similar to 188 those in case of MRSA (see below). 189 190 In the case of MRSA bacteraemia, vancomycin has been the reference drug for 191 years. The issue of vancomycin dosing has been extensively reviewed before and will not 192 be discussed here. Two reasons triggered the investigation of alternatives to vancomycin: 193 the fact that has been shown to be less efficacious than penicillins when used for MSSA 194 and the emergence of MRSA isolates with low susceptibility to vancomycin. Some 195 advantages of vancomycin are the long experience gained with its use, and the possibility 196 of measuring blood levels in most centres. 197 198 Teicoplanin and linezolid were early candidates for becoming alternatives to 199 vancomycin. Teicoplanin is also a glycopeptide active against MRSA; the accumulated 200 experience in SAB is lower than with vancomycin, but it seems to have lower vascular 201 and renal toxicity than vancomycin. Due to its difficulty to rapidly achieve adequate 202 serum levels, administration of a loading dose of 6 mg/kg followed by 3 mg/kg once daily 203 is recommended. Measurement of blood levels is not available in most centres. In a 204 randomised trial of patients with suspected catheter-related bacteraemia and skin- 205 structure infections (SSTI), linezolid was non-inferior to vancomycin overall, but was 206 associated with higher mortality in the subgroups of patients with negative cultures and 207 in those with gram negative pathogens only;35 in a previous pooled analysis of five 208 randomised studies including 53 patients with MRSA bacteraemia, no significant 209 differences in clinical or microbiological cure rates versus vancomycin could be found 210 (OR, 1.47; 95% CI, 0.50-4.34; and 0.83; 95% CI, 0.37-1.87, respectively).36 Linezolid 211 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 8 might be preferred over vancomycin in cases of bacteraemic pneumonia due to MRSA, 212 but its superiority is controversial. 213 214 Daptomycin was shown to be non-inferior to standard therapy in MSSA and 215 MRSA bacteraemia in a randomised trial,37 which was criticised because it included right- 216 side endocarditis cases and allowed treating patients with MSSA with vancomycin. 217 Despite the theoretical advantages of daptomycin over vancomycin (faster bactericidal 218 and anti-biofilm activity, favourable pharmacokinetic profile or lower nephrotoxicity), 219 comparative studies performed so far are flawed by important limitations and therefore, 220 whether it is truly superior is controversial. The recommended dose of daptomycin for 221 SAB have been increased since its approval from 6 to 8-10 mg/kg/d in order to avoid the 222 emergence of resistance during treatment. Most experts consider that daptomycin would 223 be the drug of choice for MRSA bacteraemia in patients with impaired renal function, 224 high risk of nephrotoxicity, reduced susceptibility to vancomycin (defined as high MIC 225 within the range of susceptibility), and whenever achieving appropriate vancomycin 226 trough levels is difficult.37-39 Daptomycin should not be used for S. aureus pneumonia 227 since it is inactivated by pulmonary surfactant. Of note, whether there is an association 228 of worse outcomes in patients treated with vancomycin when their isolates show reduced 229 susceptibility to vancomycin is debatable (see above), since the determination of MIC is 230 not highly reproducible, particularly when gradient strips are used. In other 231 circumstances, there is not a clear consensus: while some experts consider that 232 vancomycin should be abandoned in all or most circumstances, we think that it still has a 233 role in many patients, particularly in those with uncomplicated bacteremia caused by fully 234 susceptible isolates. Trimetoprim-sulfamethoxazole is frequently active against MRSA 235 isolates; however, it did not achieve non-inferiority to vancomycin in a randomised trial 236 of serious MRSA infection including bacteraemia.40 Data on clindamycin in bacteraemia 237 are scarce. 238 239 Some newer drugs active against MRSA such as the lipoglycopeptides 240 dalbavancin and oritavancin, or the anti-MRSA cephalosporins ceftaroline and 241 ceftobiprole, are now available. Curiously, none of them have been specifically approved 242 for MRSA bacteraemia despite it is probably the indication where new drugs are more 243 needed. Due to its intrinsic characteristics (one weekly intravenous dose), dalbavancin 244 may be particularly useful as sequential treatment allowing early discharge of patients in 245 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 9 the absence of OPAT programmes. It showed promising results in multicentre, 246 observational, retrospective study including 83 patients with bacteraemia caused by gram 247 positive bacteria (59%) and infective endocarditis (49%), as sequential therapy; crude 248 mortality at 12 months was 8.8%, and the rate of therapeutic failure was 2.9%.41 249 However, adequate comparative studies are needed. Regarding ceftaroline, a 250 multicentre, case-control matched study compared the outcomes of patients receiving 251 ceftaroline as rescue therapy after vancomycin failure with those treated with 252 vancomycin; patients treated with ceftaroline cleared the bacteremia more rapidly and 253 had a higher rate of clinical success.42 An analysis of the registry of patients treated with 254 ceftaroline included 48 patients with SAB from SSTI or community-acquired pneumonia 255 (CAP).43 The clinical success was 58% (52% for SSTI, and 67% for CAP); in those with 256 MRSA bacteremia, the figures were 50% and 63%, respectively. The published 257 experience with ceftobiprole as monotherapy in SAB is limited; a recent report provided 258 a post-hoc analysis of 95 patients with bacteraemia included in four randomised trials;44 259 30-day mortality were similar to the different comparators; the number of patients with 260 MRSA bacteremia (18) is too low to draw any conclusion. Therefore, more data are 261 needed for these new drugs. 262 263 Combination therapy 264 265 The combination of cloxacillin and vancomycin has been recommended for 266 patients in whom S. aureus is isolated from blood cultures, pending susceptibility results, 267 particularly if risk factors for MRSA are present.45 Initially, this recommendation was 268 based on the higher efficacy of cloxacillin for MSSA, and in order to avoid a delay in 269 administering an active drug in the case of MRSA. Beyond that, definitive combination 270 therapy has been investigated as a potential way to improve the outcome of SAB, both 271 for MSSA and MRSA, particularly in the case of complicated SAB or failure of 272 monotherapy.45 273 274 The use of aminoglycosides in combination with cloxacillin or vancomycin has 275 been abandoned as they increase toxicity without any evident benefit. Rifampin has long 276 been considered a good candidate for combination due to its in vitro synergy, antibiofilm 277 activity, intracellular penetration and rapid bactericidal action. However, a recent 278 landmark double-blind randomised trial evaluated the benefits of adding rifampin (600 279 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 10 mg or 900 mg per day according to weight, oral or intravenous) for 2 weeks to standard 280 therapy, and found no differences in the rate of treatment failure, disease recurrence, or 281 mortality.46 However, rifampin might still be considered in patients with cases of valve, 282 endovascular or joint prosthesis, who were underrepresented in the trial. 283 284 For MSSA, different combinations have shown synergy in vitro and in vivo; 285 however, data from clinical studies are scarce or limited so far, and have not shown a 286 consistent benefit. The combination of beta-lactams with vancomycin did not show lower 287 mortality than monotherapy with vancomycin for bacteraemia due to MSSA (in any case, 288 vancomycin is not the drug of choice for MSSA), in a retrospective cohort study.47 An 289 analysis of the registry of patients treated with daptomycin including patients with 290 moderate renal impairment suggested that the combination of daptomycin and a beta- 291 lactam might be beneficial in patients with SAB with endocarditis or a bone/joint 292 infection or unknown source.48 However, a later propensity score–matched analysis could 293 not find significant difference in mortality between patients treated with a beta-lactam 294 (cloxacillin or cefazolin) in monotherapy or in combination with daptomycin at 10 295 mg/kg/day, even in the subset of patients with high risk source of infection.49 Fosfomycin 296 is active against most S. aureus isolates, and is an attractive drug for combinations 297 according to in vivo studies and animal models; a randomised trial comparing cloxacillin 298 and fosfomycin versus cloxacillin monotherapy will soon start recruitment.50 299 300 Also, different combinations are being studied for MRSA bacteremia. The 301 combination of beta-lactams, trimethoprim-sulfamethoxazole or fosfomycin, mostly with 302 vancomycin, daptomycin or dalvabancin have been studied in vitro and in vivo models, 303 frequently with good results.51 In fact, the results of a few retrospective cohort studies 304 suggested that combination of vancomycin with some beta-lactams might be associated 305 with improvement but only in “secondary” outcomes such as microbiologic or clinical 306 failure or persistent bacteremia, but reduction in mortality could not be shown.52, 53 A 307 pilot randomised trial also found shorter duration of MRSA bacteremia in patients treated 308 with vancomycin and flucloxacillin compared to vancomycin alone;54 however, this pilot 309 trial led to a bigger randomised study, in which vancomycin or daptomycin alone were 310 compared with combination with flucloxacillin or cefazolin.55 The vast majority of 311 patients received with vancomycin. Unfortunately, the trial had to be prematurely stopped 312 because of higher rate of acute renal injury in the combination arm, which was more 313 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 11 frequent among patients receiving vancomycin and flucloxacillin. It should be noted that 314 the combination of piperacillin-tazobactam with vancomycin has also been associated 315 with increased risk of acute renal injury compared to vancomycin monotherapy, which 316 reinforce the concept that penicillin derivatives particularly when combined with 317 vancomycin, may be nephrotoxic.56 Probably the combination of vancomycin and 318 cefazolin still merits to be clinically evaluated. 319 320 The combination of daptomycin and beta-lactams has also been found to be 321 synergistic in vitro and in animal studies. A retrospective cohort study found that patients 322 treated with daptomycin and a beta-lactam (mostly, cefepime and cefazoline) had a lower 323 adjusted probability of failure than patients treated with daptomycin in monotherapy.57 A 324 randomised trial comparing daptomycin and ceftaroline vs vancomycin or daptomycin in 325 monotherapy was prematurely stopped because there were 7 deaths among 23 patients 326 treated with monotherapy (all had intravascular infections, and 6 of them had been treated 327 with vancomycin) while no deaths occurred in the combination arm (17 patients).13 The 328 consequence is somehow paradoxical; despite being stopped because of a mortality 329 difference, the small sample size in this study may preclude a change clinical practice 330 since it is difficult to know which patients would benefit from this more expensive 331 regimen, or if any safety issue would arise if more patients are treated. At this point and 332 until more data are available, it seems reasonable to consider this combination for patients 333 with MRSA bacteraemia from endovascular sources. The combination should be 334 compared to daptomycin alone and/or daptomycin in combination with a beta-lactam in 335 patients with MRSA bacteraemia. 336 337 Combinations including intravenous fosfomycin are also being investigated. It 338 has the potential limitation of its high sodium content, which may be a problem for 339 patients with heart failure, mostly if used in infective endocarditis. Curiously, fosfomycin 340 and imipenem showed to be highly active in vitro against MRSA; a small randomised 341 trial in complicated MRSA bacteraemia or endocarditis compared 8 patients treated with 342 intravenous fosfomycin (2 g/6 hours) plus imipenem (1 g/6 hours) with 7 treated with 343 vancomycin.58 None of the cases receiving combination therapy presented persistent 344 bacteremia after 72 hours of therapy, and success rate was similar between the two arms. 345 A trial comparing daptomycin with daptomycin plus fosfomycin alone has completed 346 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 12 recruitment; a preliminary report of the results suggested a higher treatment success with 347 the combination.59 348 Therefore, while combination therapy in MSSA has not proved to be superior 349 to monotherapy so far, the results of several studies suggest that some combinations are 350 promising for MRSA and might improve the results of vancomycin monotherapy. 351 352 353 Switch to oral therapy 354 355 Because the duration of treatment of SAB must be at least 10-14 days in non- 356 complicated SAB and 4 weeks in complicated cases, patients with SAB have traditionally 357 needed prolonged hospitalisation in order to receive intravenous antibiotic treatment. 358 OPAT programmes allow a significant reduction in the hospital stay, but such 359 programmes are not available in all centres, and still the patients need a vascular catheter. 360 Therefore, the possibility of switching from intravenous to oral treatment in selected 361 patients with SAB, as is done in many other infections, is being investigated. Some 362 previous experience with oral therapy with ciprofloxacin and rifampin for patients with 363 right-sided S. aureus endocarditis was encouraging.60 An ongoing randomised trial will 364 try to demonstrate the non-inferiority of switching to oral vs continuing with intravenous 365 treatment in patients with non-complicated SAB after clinical stability is reached. Oral 366 treatment in the trial may be done with trimethoprim-sulfamethoxazole, clindamycin or 367 linezolid.61 Data from a recent propensity score-matched cohort study with limited 368 statistical power suggested that switching to oral linezolid may be a good alternative to 369 maintaining intravenous therapy in selected patients (90-day relapse rates, 2.2% vs 4.4%; 370 P=0.87).62 If oral therapy is demonstrated to be effective and safe, the best oral options 371 would need to be studied, depending on the susceptibility of the isolates and features of 372 the patients. Meanwhile, the role of infectious diseases specialists in these decisions is 373 also crucial. 374 375 Conclusions 376 377 SAB is still associated with a considerable mortality and morbidity, and 378 therefore there is room for improving the outcome of patients with SAB. Clinical 379 management of SAB is complex; the results of recent randomised, quasi-experimental 380 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 13 and observational studies have provided useful information, and the results of some 381 ongoing trials are awaited. In uncomplicated cases caused by MSSA, cloxacillin is the 382 drug of choice; however, in low-inoculum infections, cefazolin may provide some 383 advantages. For MRSA bacteraemia, vancomycin should be considered in uncomplicated 384 cases due to fully susceptible isolates; in other circumstances, daptomycin may be 385 preferred, except in pneumonia. In the case of clinical or microbiological failure, and in 386 severe or complex infections, different combination regimens should be considered. 387 Overall and so far, the newer drugs and combination regimens show some promising 388 results but must still consistently demonstrate their superiority over the traditional drugs, 389 and importantly, in which subgroups of patients they might be particularly beneficial. 390 Meanwhile, management based on quality-of-care indicators by infectious diseases 391 specialist is mandatory to guarantee the best results. 392 393 394 395 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 14 References: 396 1. Laupland KB, Lyytikäinen O, Søgaard M, Kennedy KJ, Knudsen JD, Ostergaard C, et 397 al; International Bacteremia Surveillance Collaborative. The changing epidemiology of 398 Staphylococcus aureus bloodstream infection: a multinational population-based 399 surveillance study. Clin Microbiol Infect. 2013;19(5):465-71. 400 2. Nambiar K, Seifert H, Rieg S, Kern WV, Scarborough M, Gordon NC, et al; 401 International Staphylococcus aureus collaboration (ISAC) study group and the ESCMID 402 Study Group for Bloodstream Infections and Sepsis (ESGBIS). Survival following 403 Staphylococcus aureus bloodstream infection: A prospective multinational cohort study 404 assessing the impact of place of care. J Infect. 2018;77(6):516-525. 405 3. Smit J, López-Cortés LE, Thomsen RW, Schønheyder HC, Nielsen H, Frøslev T, et al. 406 Statin Use and Risk of Community-Acquired Staphylococcus aureus Bacteremia: A 407 Population-Based Case-Control Study. Mayo Clin Proc. 2017;92(10):1469-1478. 408 4. Siméon S, Le Moing V, Tubiana S, Duval X, Fournier D, Lavigne JP, et al; 409 VIRSTA/AEPEI Study Group. Time to blood culture positivity: An independent 410 predictor of infective endocarditis and mortality in patients with Staphylococcus aureus 411 bacteraemia. Clin Microbiol Infect. 2019;25(4):481-488. 412 5. Kalil AC, Van Schooneveld TC, Fey PD, Rupp ME. Association between vancomycin 413 minimum inhibitory concentration and mortality among patients with Staphylococcus 414 aureus bloodstream infections: a systematic review and meta-analysis. JAMA. 415 2014;312(15):1552-64. 416 6. Van Hal SJ, Lodise TP, Paterson DL. The clinical significance of vancomycin 417 minimum inhibitory concentration in Staphylococcus aureus infections: a systematic 418 review and meta-analysis. Clin Infect Dis. 2012;54(6):755-71. 419 7. Aguado JM, San-Juan R, Lalueza A, Sanz F, Rodríguez-Otero J, Gómez-Gonzalez C, 420 Chaves F. High vancomycin MIC and complicated methicillin-susceptible 421 Staphylococcus aureus bacteremia. Emerg Infect Dis. 2011;17(6):1099-102. 422 8. Holmes NE, Turnidge JD, Munckhof WJ, Robinson JO, Korman TM, O'Sullivan MV, 423 Anderson TL, Roberts SA, Gao W, et al. Antibiotic choice may not explain poorer 424 outcomes in patients with Staphylococcus aureus bacteremia and high vancomycin 425 minimum inhibitory concentrations. J Infect Dis. 2011;204(3):340-7. 426 9. López-Cortés LE, Velasco C, Retamar P, del Toro MD, Gálvez-Acebal J, de Cueto M, 427 et al. Is reduced vancomycin susceptibility a factor associated with poor prognosis in 428 MSSA bacteraemia? J Antimicrob Chemother. 2015;70(9):2652-60. 429 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 15 10. Shallcross LJ, Fragaszy E, Johnson AM, Hayward AC. The role of the Panton- 430 Valentine leucocidin toxin in staphylococcal disease: a systematic review and meta- 431 analysis. Lancet Infect Dis. 2013;13(1):43-54. 432 11. Gallardo-García MM, Sánchez-Espín G, Ivanova-Georgieva R, Ruíz-Morales J, 433 Rodríguez-Bailón I, Viñuela González V, et al. Relationship between pathogenic, 434 clinical, and virulence factors of Staphylococcus aureus in infective endocarditis versus 435 uncomplicated bacteremia: a case-control study. Eur J Clin Microbiol Infect Dis. 436 2016;35(5):821-8. 437 12. Guimaraes AO, Cao Y, Hong K, Mayba O, Peck MC, Gutiérrez J, et al. A Prognostic 438 model of persistent bacteremia and mortality in complicated Staphylococcus aureus 439 bloodstream infection. Clin Infect Dis. 2019;68(9):1502-1511. 440 13. Geriak M, Haddad F, Rizvi K, Rose W, Kullar R, LaPlante K, et al. Clinical data on 441 daptomycin plus ceftaroline versus standard of care monotherapy in the treatment of 442 methicillin-resistant Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 443 2019;63(5). 444 14. Jensen AG, Wachmann CH, Espersen F, Scheibel J, Skinhøj P, Frimodt-Møller N. 445 Treatment and outcome of Staphylococcus aureus bacteremia: a prospective study of 278 446 cases. Arch Intern Med. 2002;162(1):25-32. 447 15. Lesens O, Hansmann Y, Storck D, Christmann D. Risk factors for metastatic infection 448 in patients with Staphylococcus aureus bacteremia with and without endocarditis. Eur J 449 Intern Med. 2003;14(4):227-231. 450 16. Yahav D, Yassin S, Shaked H, Goldberg E, Bishara J, Paul M, et al. Risk factors for 451 long-term mortality of Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect 452 Dis. 2016;35(5):785-90. 453 17. Smit J, López-Cortés LE, Kaasch AJ, Søgaard M, Thomsen RW, Schønheyder HC, 454 et al. Gender differences in the outcome of community-acquired Staphylococcus aureus 455 bacteraemia: a historical population-based cohort study. Clin Microbiol Infect. 456 2017;23(1):27-32. 457 18. Fowler VG Jr, Sanders LL, Sexton DJ, Kong L, Marr KA, Gopal AK, et al. Outcome 458 of Staphylococcus aureus bacteremia according to compliance with recommendations of 459 infectious diseases specialists: experience with 244 patients. Clin Infect Dis. 460 1998;27(3):478-86. 461 19. Jung N, Rieg S. Essentials in the management of S. aureus bloodstream infection. 462 Infection. 2018;46(4):441-442. 463 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 22 Table 1. Antimicrobials used for the treatment of S. aureus bacteremia. Drug EUCAST MIC breakpoint for S. aureus (mg/L) Parameter predictive of efficacy % Protein bound AEMPS approval for SAB therapy Recommended intravenous dosing for SAB Stable for OPAT use Cloxacillin * Time > MIC 95 Yes 2 g / 4-6 hours Caution with > 25ºC Cefazolin * Time > MIC 85-90 Yes 2 g / 8 hours Yes Vancomycin 2 AUC/MIC 50 Yes 15-20 mg/kg/8-12 h. Yes Teicoplanin 2 AUC/MIC 90 Yes 12 mg/kg followed by 6 mg/kg/day Yes Daptomycin 1 AUC/MIC 90 Yes 8-10 mg/kg/day Yes Linezolid 4 AUC/MIC 30 No 600 mg / 12 hours Yes Dalbavancin 0.125 AUC/MIC 90 No 1000 mg followed by 500 mg / week Yes Ceftaroline 1 Time > MIC 20 No 600 mg / 8 hours No Ceftobiprole 2 Time > MIC 16 No 500 mg / 8 hours Yes Fosfomycin 32 Time > MIC < 5 No 2g / 6 hours No TMP-SMX 2 Unknown 50-70 No 160/800 mg / 8 h. No Clindamycin 0.25 Time > MIC 60-90 No 600 mg /8 hours No SAB: S. aureus bacteremia; OPAT: outpatient antimicrobial therapy; TMP-SMX: trimethoprim sulfamethoxazole; AUC: area under the curve; MIC: minimum inhibitory concentration; AEMSP: Spanish Agency of Medicines and Health Products; (*): Susceptibility of staphylococci to cephalosporins is inferred from cefoxitin. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 23 Table 2. Summary of recommended drugs for the definitive treatment of S. aureus bacteraemia. Condition Susceptibility Options Uncomplicated bacteraemia Methicillinsusceptible Cloxacillin (preferred for infections with high bacterial load such as endocarditis or pneumonia) Cefazolin Penicillin allergy: consider cefazolin or daptomycin Association with aminoglycosides or rifampin is not recommended. Methicillinresistant Vancomycin Daptomycin (preferred if impaired renal function, high risk of nephrotoxicity, lower susceptibility to vancomycin and if achieving appropriate vancomycin levels is difficult). Teicoplanin Association with aminoglycosides or rifampin, or vancomycin plus cloxacillin are not recommended. Complicated bacteraemia Methicillinsusceptible As above; combinations have not been clearly shown to be superior but may be considered in case of failure or severe infections (cloxacillin or cefazolin plus daptomycin; cloxacillin plus fosfomycin). Methicillinresistant As above; consider daptomycin plus fosfomycin, and ceftaroline plus cefazoline or daptomycin for endovascular infections; imipenem plus fosfomycin may also be considered. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 24 Table 3. Summary of clinical studies on antimicrobial therapy for S. aureus bacteraemia included in this review. Author, year of publication, reference Antimicrobial agent(s) Study design Results Wilcox MH, 2009 [35] Linezolid versus vancomycin Randomised trial in suspected complicated skin and cSSTI and CRB Non-inferiority criteria were met for cSSSI and CRB; higher mortality was seen in patients treated with linezolid among those with negative cultures and in those with isolation of gram negative pathogens only. Fowler VG Jr, 2006 [37] Daptomycin (6 mg/Kg) versus either an antistaphylococcal penicillin or vancomycin plus gentamicin Randomised trial in bloodstream infections due to S. aureus including right-sided endocarditis Treatment success were 44.2% and 41.7% for daptomycin and standard therapy, respectively (95% CI, -10.2 to 15.1). The success rates were similar in subgroups of patients with complicated bacteremia, right-sided endocarditis, and MRSA Weston A, 2014 [38] Daptomycin versus vancomycin Retrospective cohort study of patients with MRSA bacteraemia. Use of propensity score and multivariable logistic regression. Impairment in renal function was not associated with treatment failure in patients treated with daptomycin in comparison with those treated with vancomycin. Murray ZP, 2013 [39] Daptomycin versus vancomycin Matched, retrospective cohort study of patients with MRSA bacteraemia due to isolates with vancomycin MIC >1 µg/mL 30-day mortality and persistent bacteremia were significantly lower in the daptomycin group (3.5% vs 12.9% [P = 0.047] and 18.8% vs 42.4% [P = 0.001], respectively). Logistic regression confirmed the association between vancomycin treatment and increased risk of clinical failure (adjusted OR, 4.5; 95% CI, 2.1-9.8) Paul M, 2015 [40] Trimethoprimsulfamethoxazole versus vancomycin Randomised trial of patients with severe MRSA infections (36% were bacteraemic) The risk ratio for treatment failure was 1.40 (0.91 to 2.16); in adjusted analysis, trimethoprim-sulfamethoxazole was significantly associated with treatment failure (adjusted OR 2.00, 1.09 to 3.65) Hidalgo- Tenorio C, 2019 [41] Dalbavancin (no comparator) Multicentre retrospective cohort study of patients with infective endocarditis and/or bacteraemia due to gram positive cocci after response to initial treatment (consolidation therapy) The effectiveness in endocarditis was 96.7%. The clinical cure rate in bacteraemia was 100% at 3 months; there were no recurrences or deaths during the follow-up Paladino JA, 2015 [42] Ceftaroline versus vancomycin Multicentre matched case-control study of patients with MRSA bactereamia and vancomycin MICs ≥2 μg/mL Clinical success at the end of treatment and recurrence at day 7 with ceftaroline and vancomycin were 81% vs 44% (P=0.06) and 6% vs. 38% (P=0.08), respectively. Vazquez JA, 2015 [43] Ceftaroline (no comparator) Multicentre registry of patients with S. aureus bacteraemia secondary to cSSSI and CABP treated with ceftaroline Clinical success was 58% (52% in SSSI, 67% in CABP). Clinical success rates of MRSA bacteraemia was 50% (8/16) for SSSI and 63% (10/16) for CAP Thwaites GE, 2018 [46] Standard therapy with or without adjunctive rifampicin Randomised, double-blind, placebocontrolled trial of patients with S. aureus bacteraemia By week 12, 17% of participants who received rifampicin versus 18% who received placebo experienced treatment failure, disease recurrence or died (absolute risk difference -1.4%, 95% CI 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 25 -7.0 to 4.3; hazard ratio 0.96, 0.68-1.35, p=0.81) Park GE, 2017 [47] Vancomycin monotherapy versus vancomycin/β-lactam combination Retrospective cohort study of patients with MRSA bacteraemia treated empirically with vancomycin alone or in combination with a β-lactam In comparison with vancomycin monotherapy, a difference in mortality could not be demonstrated in patients receiving vancomycin and a β-lactam (HR=0.579; 95% CI = 0.086-3.890, P = 0.574). Moise PA, 2013 [48] Daptomycin monotherapy versus daptomycin/β-lactam combination Multicentre registry of patients with S. aureus bacteraemia and mild to moderate renal impairment Success rate was 87% with daptomycin and a β-lactams and 78% with daptomycin alone (P = 0.336). In endocarditis, bone/joint infection or bacteremia from an unknown source, the figures were 90% and 57% (P = 0.061). Grillo S, 2019 [49] β-lactam monotherapy versus β-lactam/ daptomycin combination Retrospective cohort study in MSSA bacteraemia patients. Propensity score-matched analysis No significant differences between groups for all-cause mortality at 7 days (8.18% vs 7.74%; P = 1.00), and 30 days (17.3% vs 16.1%; P = .92), even in patients with high-risk source Casapao AM, 2017 [53] Vancomycin monotherapy versus vancomycin/β-lactam combination Retrospective cohort study of MRSA bacteraemia Combination was associated with lower rate of persistent bacteremia (adjusted, 0.460; 95% CI, 0.229 - 0.923). Acute kidney injury was more common with combination (18.9% and 7.6%; P = 0.062) Davis JS, 2016 [54] Vancomycin versus vancomycin plus flucloxacillin Randomised pilot trial in patients with MRSA bacteraemia The mean time to resolution of bacteraemia in the combination group was 65% lower (95% CI, 41%-102%; P = 0.06). There were no differences in secondary endpoints (mortality, metastatic infection, nephrotoxicity, or hepatotoxicity) Jogersen SCJ, 2019 [57] Daptomycin monotherapy versus daptomycin/beta-lactam combination Retrospective cohort of patients with MRSA bacteraemia In inverse probability of treatment weighting-adjusted analyses, combination therapy was associated with significantly reduced odds of clinical failure (aOR 0.386, 95% CI 0.175- 0.853) Del Río A, 2014 [58] Fosfomycin plus imipenem (no comparator) Non comparative trial including 12 patients with complicated MRSA bacteremia or endocarditis requiring rescue therapy The success rate was 69% Heldman AW, 1996 [60] Oral ciprofloxacin plus rifampin versus intravenous oxacillin or vancomycin plus gentamicin Randomised trial in 44 drug users with right-sided staphylococcal endocarditis Three and one treatment failures occurred in the intravenous and oral arms, respectively. Drug toxicity was more common in the intravenous group (P < 0.0001) Willekens R, 2018 [62] Oral switch to linezolid versus standard parenteral therapy Prospective cohort study of low-risk patients with S. aureus bacteraemia No difference in 90-day relapse (2.2% vs 4.4%; P=0.87). No statistically significant difference in 30-day all-cause mortality (2.2% vs 13.3%; P=0.08) cSSSI: complicated skin and skin structure infection; CRB: Catheter-related bacteremia; OR: Odds ratio; CI: confidence interval; MRSA: methicillin resistant Staphylococcus aureus; CABP: community-acquired bacterial pneumonia. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 1 EIMC-D-19-00438 - CAMBIOS EFECTUADOS 1 2 Título: Tratamiento de la bacteriemia por Staphylococcus aureus: evidencias y retos 3 Title: Therapy of Staphylococcus aureus bacteremia: evidences and challenges 4 5 Resumen 6 7 La bacteriemia por Staphylococcus aureus continúa siendo un reto diario para los 8 clínicos. A pesar de todos los esfuerzos realizados, su mortalidad y morbilidad asociadas 9 no han descendido de forma significativa en los últimos 20 años. Existe evidencia de que 10 la adherencia a los indicadores de calidad para su manejo clínico es importante para 11 mejorar el pronóstico de los pacientes, aunque su cumplimiento sigue siendo menor de lo 12 deseado en muchos hospitales; en este sentido, la asistencia por especialistas en 13 Enfermedades Infecciosas ha demostrado contribuir a reducir la mortalidad de estos 14 pacientes. En este artículo se revisan los estudios clínicos más relevantes realizados en 15 los últimos años con objeto de evaluar la eficacia y seguridad de fármacos alternativos a 16 los clásicos. Sin embargo, éstos siguen siendo utilizados en un alto porcentaje de 17 pacientes, ya que los prometedores resultados obtenidos por esos fármacos alternativos y 18 determinadas combinaciones en estudios in vitro y modelos animales no se han traducido 19 en una evidente superioridad en los estudios clínicos con la frecuencia que se hubiera 20 esperado. Dicho esto, existen datos que sugieren que determinadas alternativas pueden 21 ofrecer ventajas en situaciones concretas. En general, es necesario un manejo 22 individualizado y experto de los pacientes para decidir la mejor terapia en base al foco, la 23 gravedad y complicaciones, las características de los pacientes y los datos 24 microbiológicos. 25 26 27 Manuscrito con cambios resaltados/manuscript with highlighted changes 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 Abstract 28 29 Staphylococcus aureus bacteremia (SAB) is still a challenge for clinicians. 30 Despite all efforts, the associated mortality and morbidity has not significantly improved 31 in the last 20 years. The available evidence suggests that adherence to some quality-of- 32 care indicators is important to improve the outcome of patients, but it is lower than desired 33 in many hospitals; in this sense, management of patients with SAB by infectious diseases 34 specialists has demonstrated to contribute in the reduction of their mortality. In this 35 article, the most relevant clinical studies published during last years and evaluating the 36 efficacy and safety of alternative drugs for the treatment of SAB are reviewed. However, 37 classic drugs are still used in a high proportion of patients because the promising results 38 obtained from in vivo and in vivo studies did not translate as frequently as expected into 39 evident superiority in clinical studies. Nevertheless, some data suggest that certain 40 alternatives may offer advantages in specific situations. Overall, an individualized and 41 expert approach is needed in order to decide the best treatment according to the source, 42 severity, complications, patients’ features and microbiological data. 43 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 Introduction 45 46 In the industrialized world, the population-based incidence of Staphylococcus 47 aureus bacteremia (SAB) ranges from 10 to 30 per 100,000 person-years and causes 2 to 48 10 deaths/100,000 population per year.1 SAB attracts the interest of medical scientists: it 49 generates more than 1,500 results in PubMed. 50 51 S. aureus infections that lead to bacteremia are frequently acquired in the context 52 of healthcare, and preventive measures may reduce S. aureus bacteremia rates, but the 53 population at risk continues to increase. In addition, it must be recognized that we have 54 not been able to significantly and universally improve its prognosis in the last 20 years.2 55 Beyond mortality, the morbidity and economical costs of SAB continues to be very high, 56 as surgical procedures (sometimes with loss of prosthetic or vascular implants), and 57 additional admission days are frequently needed, and finally patient's quality of life may 58 be severely impaired. Preventive measures for healthcare-associated SAB includes 59 typical infection control actions and decolonisation of patients undergoing high-risk 60 procedures. Curiously, statin use was associated with a dose-dependent lower risk of 61 developing community-acquired SAB in a large Danish population-based study, with 62 adjusted odds ratios (OR) of 0.84 (95% confidence interval [CI], 0.68-1.04) for current 63 users using <20 mg/day, 0.71 (95% CI, 0.58-0.87) for 20-39 mg/day, and 0.63 (95% CI, 64 0.49-0.81) for ≥40 mg/day.3 The pathophysiological bases of this association are not 65 clear, so these results should be reproduced before any recommendation can be done. 66 67 Outcome predictors and potential targets for better clinical management 68 69 The outcome of SAB depends on three aspects: the bacteria, the patient, and the 70 clinical management. Regarding the bacteria, methicillin-resistance have been repeatedly 71 associated with worse outcomes even after controlling for confounders. While some 72 methicillin-resistant S. aureus (MRSA) may be more virulent, the main reason for this 73 increased mortality is probably related to the fact that MRSA are resistant to classic first 74 line anti-staphylococcal drugs and increases the risk of inappropriate empirical therapy. 75 Infections with high bacterial load as shown by shorter time to blood cultures positivity 76 have also been associated with worse outcomes.4 The impact of vancomycin minimum 77 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 4 inhibitory concentration (MIC) on the outcome of patients with MRSA bacteraemia 78 attracted considerable attention a few years ago, curiously at the time when some new 79 drugs active against MRSA were commercialised. However, the results from different 80 systematic reviews and meta-analysis are contradictory, probably due to differences in 81 the methodology used in the individual studies and their limitations, because an adequate 82 control of the many host-dependent and treatment-related confounders is complex.5,6 83 Unexpectedly, vancomycin MIC was also associated to worse prognosis in patients with 84 methicillin-susceptible S. aureus (MSSA) not treated with this antibiotic in some studies, 85 suggesting that reduced vancomycin susceptibility could itself be a marker for some other 86 intrinsic property of these isolates that would cause a poorer outcome.7,8 However, some 87 later studies did not find any association between reduced vancomycin susceptibility and 88 higher mortality, rate of complicated SAB or severity at presentation.9 Therefore, whether 89 this should be considered for therapeutic decisions is controversial. In addition, the impact 90 of several bacterial factors that might serve as therapeutic targets has been studied. So far, 91 clonality, different virulence factors (alpha-toxin, TSST-1, PVL, etc.) or agr type and its 92 dysfunction have not been consistently associated with worse outcomes.10,11 Therefore, 93 more studies are needed to identify potential therapeutic bacterial targets. 94 95 Regarding the host, different putative outcome biomarkers have also been studied. 96 Again, many of the studies performed are flawed by an inadequate control of confounders. 97 Interleukin IL-8 (a neutrophil-recruiting chemokine) and CCL2 (a myeloid cell-recruiting 98 chemokine) showed the strongest association with mortality among 13 studied proteins, 99 and baseline IL-17A levels were higher in patients with persistent SAB or those with 100 endovascular and metastatic tissue infections in a study.12 Data from a recent trial failed 101 to demonstrate an association of IL-10 serum levels and outcome.13 Again, the numerous 102 circumstances that determine the prognosis of SAB makes it difficult to assess the real 103 relevance of each of these biomarkers individually. Regarding phenotypic features of the 104 patients, worse outcomes are consistently associated with older age, a higher Charlson 105 comorbidity index or Pitt score, community acquisition (probably as a marker for 106 endocarditis) or liver cirrhosis.14-15 Male gender might be associated with increased risk 107 of SAB, with male-to-female ratios of 1.5 and a adjusted hazard ratio for 30-day mortality 108 of 1.30 (95% CI, 1.11-1.53).16,17 The basis for this increased risk is not well understood. 109 110 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 5 Regarding the clinical management, a key aspect is the concept of “complicated 111 bacteraemia”. Since its definition in 1998,18 some consensus has been reached for its 112 criteria, including the presence of a foreign indwelling implant or intravascular device, 113 positive follow-up blood cultures or fever lasting more than 72 hours while on active 114 treatment, evidence of metastatic sites of infection or deep-seated focus, and infectious 115 endocarditis. At present, the duration of antimicrobial treatment in uncomplicated cases 116 is 10-14 days, while it is at least 28 days since the first negative follow-up blood culture 117 in case of complicated SAB; also, echocardiography must be done in these cases (see 118 Figure 1). Transoesophagic echocardiography (TOE) may be reserved for some patients, 119 such as those at high-risk of endocarditis (particularly, in case of predisposing valve 120 diseases, prosthetic valves and intracardiac devices) or with a high clinical suspicion and 121 poor echocardiographic window. A scoring system to guide the indications for TEE has 122 been developed based on a cohort of 678 patients from a single hospital.20 The score 123 included community acquisition, presence of a cardiac device and persistent bacteremia 124 for at least 72 hours, and showed a high specificity (96%) but low sensitivity (21%) for 125 the day-1 model, with a high sensitivity (98.8%) and negative predictive value (98.5%) 126 for the day-5 model. Another score for day 2 of the bacteremia included similar variables 127 and showed a negative predictive value of 98.8% (95% CI 98.4 - 99.4) and a sensitivity 128 of 95.8% (95% CI 94.3 - 97.8) for a score value ≤ 2. Unfortunately, none of these scores 129 have been so far validated in external cohorts. Anyhow, the best moment to perform an 130 echocardiography is not well stablished, probably because it is essential to individualize 131 the decision on the bases of the type of clinical presentation and characteristics of the 132 patients, once the follow-up cultures results are available. 133 Consultation or direct management by infectious diseases specialists has been 134 associated with better prognosis in different studies and meta-analysis.22 However, 135 standardisation of management is still a problem. Some quality-of-care indicators for the 136 management of SAB have been identified; unfortunately, adherence to these indicators in 137 clinical practice is lower than desirable as shown by the results of two recent published 138 surveys carried out in United States and Canada.23 The application of a bundle including 139 six of these evidence-based indicators (early treatment with cloxacillin for MSSA, early 140 source control, follow-up blood cultures in all cases, echocardiography if indicated, 141 vancomycin dose based on trough levels if this drug is used, and duration of treatment of 142 at least 14 days in uncomplicated SAB and 4 weeks in complicated cases) using a 143 structured intervention was shown to increase the adherence to the indicators and was 144 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 6 associated with lower mortality in a quasi-experimental multicentre study;24 this approach 145 has been validated in later studies.25, 26 A proposal for the clinical management of S. 146 aureus bacteremia is included in Figure 1. 147 148 Antimicrobial therapy 149 150 Until recently, the preferred options for the treatment of SAB had remained 151 unchanged for decades. The fact that SAB-associated morbidity and mortality continue 152 to be high had triggered the search for new alternatives; in fact, there are many published 153 studies with in vitro and in vivo evaluation of the activity of new drugs and new 154 combinations. However, the promising results of these models did not always translate to 155 improved outcomes in clinical studies. Therefore, in this review we will mainly discuss 156 the results of clinical studies. The different drugs used for SAB are specified in Table 1, 157 and a summary of the recommended regimens in Table 2. The published studies 158 included in this review are included in Table 3. 159 160 Monotherapy 161 162 Penicillinase-resistant penicillins (cloxacillin, oxacillin) are usually considered 163 the drugs of choice for MSSA bacteremia. However, cefazolin, a first generation 164 cephalosporin, has several potential advantages: available data suggest it may have lower 165 liver and renal toxicity, lower rate of phlebitis, and better stability at room temperature, 166 making it more convenient for outpatient parenteral antimicrobial therapy (OPAT).27 In 167 case of patients under hemodialysis, the longer half-life of cefazolin (1 g/day or 2 gr after 168 the dialysis session) allows to reduce the manipulation of the dialysis catheter. Despite it 169 was traditionally considered a less efficacious drug because of showing lower in vitro 170 activity when exposed to higher bacterial concentrations (the so-called inoculum effect), 171 the results of several recent meta-analysis have challenged that idea by showing similar 172 efficacy and lower renal toxicity.28-30 The inoculum effect seems to be related to the 173 inactivation of the drug by a type A beta-lactamase codified by blaZ gene. An 174 observational study including 185 isolates from 5 centres in USA found the blaZ gene in 175 77% of them; 27% had a >4-fold increase in the cefazolin MIC when exposed to a high 176 inoculum, and 4% were not-susceptible to cefazolin, all of which harboured blaZ genes.31 177 Some data support a clinical impact of the inoculum effect;30 if this is confirmed in future 178 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 13 and observational studies have provided useful information, and the results of some 381 ongoing trials are awaited. In uncomplicated cases caused by MSSA, cloxacillin is the 382 drug of choice; however, in low-inoculum infections, cefazolin may provide some 383 advantages. For MRSA bacteraemia, vancomycin should be considered in 384 uncomplicated cases due to fully susceptible isolates; in other circumstances, 385 daptomycin may be preferred, except in pneumonia. In the case of clinical or 386 microbiological failure, and in severe or complex infections, different combination 387 regimens should be considered. Overall and so far, the newer drugs and combination 388 regimens show some promising results but must still consistently demonstrate their 389 superiority over the traditional drugs, and importantly, in which subgroups of patients 390 they might be particularly beneficial. Meanwhile, management based on quality-of-care 391 indicators by infectious diseases specialist is mandatory to guarantee the best results. 392 393 394 395 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 14 References: 396 1. 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Heldman AW, Hartert TV, Ray SC, Daoud EG, Kowalski TE, Pompili VJ, et al. Oral 615 antibiotic treatment of right-sided staphylococcal endocarditis in injection drug users: 616 prospective randomized comparison with parenteral therapy. Am J Med. 1996;101:68- 617 76. 618 61. Kaasch AJ, Fätkenheuer G, Prinz-Langenohl R, Paulus U, Hellmich M, Weiß V, et 619 al; SABATO trial group (with linked authorship to the individuals in the 620 Acknowledgements section). Early oral switch therapy in low-risk Staphylococcus aureus 621 bloodstream infection (SABATO): study protocol for a randomized controlled trial. 622 Trials. 2015;16:450. 623 62. Willekens R, Puig-Asensio M, Ruiz-Camps I, Larrosa MN, González-López JJ, 624 Rodríguez-Pardo D, et al. Early oral switch to linezolid for low-risk patients with 625 Staphylococcus aureus bloodstream infections: a propensity-matched cohort study. Clin 626 Infect Dis. 2018. doi: 10.1093/cid/ciy916. 627 628 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 21 Figure legend 629 630 Figure. Proposed management of S. aureus bacteremia. 631 MSSA: methicillin-resistant S. aureus. MRSA: methicillin-resistant S. aureus. 632 633 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 22 Table 1. Antimicrobials used for the treatment of S. aureus bacteremia. Drug EUCAST MIC breakpoint for S. aureus (mg/L) Parameter predictive of efficacy % Protein bound AEMPS approval for SAB therapy Recommended intravenous dosing for SAB Stable for OPAT use Cloxacillin * Time > MIC 95 Yes 2 g / 4-6 hours Caution with > 25ºC Cefazolin * Time > MIC 85-90 Yes 2 g / 8 hours Yes Vancomycin 2 AUC/MIC 50 Yes 15-20 mg/kg/8-12 h. Yes Teicoplanin 2 AUC/MIC 90 Yes 12 mg/kg followed by 6 mg/kg/day Yes Daptomycin 1 AUC/MIC 90 Yes 8-10 mg/kg/day Yes Linezolid 4 AUC/MIC 30 No 600 mg / 12 hours Yes Dalbavancin 0.125 AUC/MIC 90 No 1000 mg followed by 500 mg / week Yes Ceftaroline 1 Time > MIC 20 No 600 mg / 8 hours No Ceftobiprole 2 Time > MIC 16 No 500 mg / 8 hours Yes Fosfomycin 32 Time > MIC < 5 No 2g / 6 hours No TMP-SMX 2 Unknown 50-70 No 160/800 mg / 8 h. No Clindamycin 0.25 Time > MIC 60-90 No 600 mg /8 hours No SAB: S. aureus bacteremia; OPAT: outpatient antimicrobial therapy; TMP-SMX: trimethoprim sulfamethoxazole; AUC: area under the curve; MIC: minimum inhibitory concentration; AEMSP: Spanish Agency of Medicines and Health Products; (*): Susceptibility of staphylococci to cephalosporins is inferred from cefoxitin. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65