clinicAL CARDIOLOGY Cardiology Journal 2021, Vol. 28, No. 4, 566–578 DOI: 10.5603/CJ.a2021.0054 Copyright © 2021 Via Medica original article ISSN 1897–5593 eISSN 1898–018X Long-term antibiotic therapy in patients with surgery-indicated not undergoing surgery infective endocarditis Nuria Vallejo Camazon1, 2 , Lourdes Mateu3, Germán Cediel1, Laura Escolà-Vergé4, Nuria Fernández-Hidalgo4, Mercedes Gurgui Ferrer5, Maria Teresa Perez Rodriguez6, Guillermo Cuervo7, Raquel Nuñez Aragón8, Cinta Llibre1, Nieves Sopena3, Maria Dolores Quesada9, Elisabeth Berastegui1, Albert Teis 1, Jorge Lopez Ayerbe1, Gladys Juncà1, Francisco Gual1, Elena Ferrer Sistach1, Ainhoa Vivero8, Esteban Reynaga3, María Hernández Pérez10, Christian Muñoz Guijosa1, Lluisa Pedro-Botet2, 3, Antoni Bayés-Genís1, 2 1 Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain; 2Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain; 3Unitat Malalties Infeccioses, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain; 4Servei de Malalties Infeccioses, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; 5 Unitat de Malalties Infeccioses, Hospital Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain; 6Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Complexo Hospitalario de Vigo, Vigo, Spain; 7Department of Infectious Diseases, Bellvitge University Hospital, L’Hospitalet de Llobregat, Barcelona, Spain; 8Internal Medicine Department, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain; 9Microbiology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain; 10Neurology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain Abstract Background: To date, there is little information regarding management of patients with infective endocarditis (IE) that did not undergo an indicated surgery. Therefore, we aimed to evaluate prognosis of these patients treated with a long-term antibiotic treatment strategy, including oral long term suppres- sive antibiotic treatment in five referral centres with a multidisciplinary endocarditis team. Methods: This retrospective, multicenter study retrieved individual patient-level data from five referral centres in Spain. Among a total of 1797, 32 consecutive patients with IE were examined (median age 72 years; 78% males) who had not undergone an indicated surgery, but received long-term antibiotic treatment (LTAT) and were followed by a multidisciplinary endocarditis team, between 2011 and 2019. Primary outcomes were infection relapse and mortality during follow-up. Results: Among 32 patients, 21 had IE associated with prostheses. Of the latter, 8 had an ascend- ing aorta prosthetic graft. In 24 patients, a switch to long-term oral suppressive antibiotic treatment (LOSAT) was considered. The median duration of LOSAT was 277 days. Four patients experienced a relapse during follow-up. One patient died within 60 days, and 12 patients died between 60 days and 3 years. However, only 4 deaths were related to IE. Conclusions: The present study results suggest that a LTAT strategy, including LOSAT, might be con- sidered for patients with IE that cannot undergo an indicated surgery. After hospitalization, they should be followed by a multidisciplinary endocarditis team. (Cardiol J 2021; 28, 4: 566–578) Key words: suppressive antibiotic treatment, infective endocarditis, surgery Address for correspondence: Nuria Vallejo Camazon, MD, Heart Institute, Hospital Universitari Germans Trias I Pujol, Carretera de Canyet s/n 08916, Badalona (Barcelona) Spain, tel: 934978915/934978863, e-mail: nvallejo73@hotmail.com Received: 15.02.2021 Accepted: 23.04.2021 This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially. 566 www.cardiologyjournal.org Nuria Vallejo Camazon et al., Long-term antibiotics in not operated surgical endocarditis Introduction ings to discuss and evaluate therapeutic strategies for patients with IE. Infective endocarditis (IE) is a severe, complex We included adult patients (age ≥ 18 years) entity with high morbidity, inhospital mortality with a definite diagnosis of IE (based on modified (20−30%) [1], and long-term mortality (~45%) [2], Duke criteria/European Society of Cardiology (ESC) despite recent advances in diagnostic and thera- criteria, modified in August 2015) and an indication peutic strategies [3–5]. The epidemiology of IE for surgery or device extraction, according to clinical has changed [6–8] towards patients with multiple guidelines [10]. None of these patients underwent comorbidities, prostheses, devices, congenital surgical procedures after an evaluation by the heart diseases, or transcatheter procedures [9]. MDET. All these patients survived the index hospi- Cardiac surgery and antibiotic treatment are talization with a plan established by the local MDET the cornerstones of IE treatment. According to for long-term intravenous treatment (> 8 weeks) or current recommendations [10], more than 70% of LOSAT. Patients with fungal IE were excluded. For patients with IE have an indication for surgery, but patients with relapses, only the episode in which less than 50% finally undergo operations, due to the local committee decided to treat with LTAT was surgical risk [11–13]. In-hospital mortality is high included. Patients that had been discharged with (~70%) among patients with surgery indicated a plan for LTAT during follow-up were also included. not undergoing surgery IE (SINUS-IE). How- Data were obtained on demographics, clinical ever, information is sparse regarding the clinical parameters, diagnostics (imaging, microbiological, characteristics and long-term outcomes for these and analytical parameters), and follow-up. A sim- patients [14]. plified, standard case-report form was designed. Clinical guidelines [10] do not specifically Data were recorded anonymously and sent to the mention antibiotic treatment or a recommended coordinating institution, where a database was treatment duration for patients with SINUS-IE. created specifically for this study. Oral antibiotics have shown to be effective for shortening intravenous treatment in selected Definitions cases of uncomplicated left-sided IE [15]; however, Healthcare-associated endocarditis was there is a lack information regarding oral long- defined elsewhere [19]. -term antibiotic treatment (LTAT) in the context of The Charlson comorbidity index [20] (not SINUS-IE. Moreover, new imaging techniques [16], age adjusted) was used at admission to stratify such as positron emission tomography/computed overall co-morbidity. tomography (PET/CT) might play a role in moni- Moderate or severe renal disease was de- toring responses and establishing an appropriate fined as an estimated glomerular filtration rate (based duration for LTAT [17, 18] in SINUS-IE. on CKD-EPI method) below 60 mL/min/1.73 m2 at We hypothesized that an approach managed admission. by a multidisciplinary endocarditis team (MDET) Surgery was defined as the replacement or that included individualized LTAT, long-term oral repair of the affected heart valve during the index suppressive antibiotic treatment (LOSAT) when hospitalization. needed, and close follow-up might improve the Indications for surgery were adjudicated long-term prognosis in SINUS-IE. Accordingly, this prospectively during the index episode by the local study aimed to evaluate the clinical characteristics MDET, and they included: heart failure, embolic and outcome of patients with SINUS-IE treated event prevention, and uncontrolled infection [10]. with long-term antibiotic regimens in 5 Spanish The EuroSCORE [21, 22] (logistic Euroscore I referral centres. and Euroscore II) was calculated for all patients. For IEs related to a cardiovascular implantable Methods electronic device (CIED), percutaneous device extraction was considered an indication for surgery. Study design and data collection Follow-up was defined as the period from the For this multicenter, retrospective, observa- day antibiotic treatment for IE was started until tional study, patient-level data was collected from death for any reason or the last follow-up. Data local, prospective databases at 5 hospitals in Spain was collected at the end of intravenous antibiotic from January 2011 to January 2019. The 5 hospitals treatment, the beginning of oral antibiotic treat- were referral centres for IE with cardiac surgery ment, when administered, and at the end of an oral facilities. In addition, MDETs held regular meet- antibiotic prescription, after completion. www.cardiologyjournal.org 567 Cardiology Journal 2021, Vol. 28, No. 4 After discharge for IE, survivors were pro- Results spectively followed at regular intervals. Each local MDET established the periodicity of blood Baseline characteristics cultures, clinical evaluations, and imaging (PET/CT Between January 2011 and January 2019, 1797 and/or echocardiograms). patients with IE were identified in 5 participating Long-term antibiotic treatment (LTAT) centres. Among these, we identified 32 discharged was defined as an intravenous or oral antibiotic patients with SINUS-IE managed with a LTAT regimen that exceeded the standard duration (usu- strategy. The median follow-up time from diagnosis ally < 8 weeks) of the established treatment for was 487 days (IQR: 332−1210 days). The baseline an episode of native, device-related, or prosthetic- patient characteristics are detailed in Table 1. The related IE. When patients were switched to oral mean age was 72.1 ± 17 years and 78% were males. treatment, the term long-term oral suppres- Twenty-one (66%) patients had prosthetic valve en- sive antibiotic treatment (LOSAT) was used. docarditis (PVE). Of these, 20 were left-sided and The MDET determined, a priori, whether the one was right-sided PVE. Eight patients suffered duration of this treatment was time-defined or PVE before 1 year from valvular surgery (early life-long. However, the treatment durations were PVE) and the other 13 corresponded to late PVE. re-evaluated at follow-ups. Durations were based Seven patients had CIED-related IE (Table 2). In on patient status evolution and the response to these cases, the device was either not extracted treatment, according to analytical, clinical, and or incompletely extracted, which were counter- cardiac imaging parameters. When intravenous indications for surgery. Four patients had left-sided treatment was required, an outpatient parenteral native valve IE; 17 (53%) had healthcare-associated antibiotic therapy regimen was preferred. IE, and 14 (43.7%) had a history of previous IE. Of Relapse was defined as a documented, posi- note, 8 (25%) patients had ascending aorta pros- tive blood culture, caused by the same microorgan- thetic grafts (AAGs; Table 3). ism that caused the initial IE, and being observed Most patients had comorbidities. The mean within the first year after completing the standard Charlson index was 5 points (range: 3−7). The main established antimicrobial treatment. indication for surgery was uncontrolled infection Mortality was defined as death from any (75%), and 18 patients had local complications. The cause during follow-up. The causes of IE-related main reasons for not undergoing surgery, despite mortality were: heart failure, stroke, uncontrolled the indication, were: high surgical risk (75%), infection, sudden death, and other causes attribut- surgeon refusal, due to an unaffordable technical able to any IE complication. risk (15.6%), and patient refusal (6.2%). Outcomes Analysis of microbiological data, imaging Primary outcomes were: infection relapse and data, treatment, and outcomes mortality at the last follow-up. Twenty-four (75%) patients underwent transesophageal echocardiography (TEE) and 20 Ethics (63%) patients underwent a PET/CT. Remarkably, This study was performed in compliance with in 7 patients (5 with AAGs), the PET/CT estab- the Helsinki Declaration and was approved by the lished the IE diagnosis after a previous negative local Ethics Committee of Hospital Universitari or inconclusive TEE. Germans Trias i Pujol (Badalona, Barcelona, Spain). Blood cultures were positive in 94% of pa- tients. The most prevalent microorganisms were Statistical analysis coagulase-negative staphylococci (10/32, 31%) and Categorical variables are expressed as ab- Staphylococcus aureus (7/32, 22%). Blood cultures solute numbers and percentages. Continuous were negative in 2 patients that had previously variables are expressed as the mean and standard received antibiotic treatment. Of these, one had deviation (SD) or the median and 25–75 percentile previous cardiac surgery, and the surgery wound (interquartile range [IQR]), according to the data culture was positive for S. epidermidis; the other distribution (normal or non-normal). Survival had undergone surgery 2 months prior for native was evaluated with the Kaplan-Meier method aortic valve IE associated with S. sanguis; thus, and long-rank test. All analyses were performed this patient was treated for a relapse/early PVE. with STATA V.13.0 (College Station, Texas, United The median duration of parenteral antibiotic States). treatment was 8 weeks (IQR: 6−12 weeks). In 568 www.cardiologyjournal.org Nuria Vallejo Camazon et al., Long-term antibiotics in not operated surgical endocarditis Table 1. Baseline demographic, clinical, and Table 1 (cont.). Baseline demographic, clinical, microbiological characteristics of the study and microbiological characteristics of the study subjects. subjects. Parameters Overall Parameters Overall (n = 32) (n = 32) Age [years] 72 ± 17 Atrioventricular block 3 (9.4) Male sex 25 (78.1) Shock 1 (3.1) Healthcare-associated IE 17 (53.1) Indication for surgery Type of infection Hemodynamic 1 (3.1) Prosthetic valve IE 21 (65.6) Uncontrolled infection 24 (75) Early/late PVE 8/13 Local complication 18 Intracardiac device-related IE 7 (21.9) Embolic 1 (3.1) Native IE 4 (12.5) Device infection 6 (18.8) Clinical history-comorbidities EuroSCORE I (%), median (IQR) 32 (17-46) Previous cardiac surgery 19 (59.4) EuroSCORE II (%), median (IQR) 9.1 (6.7-14) Previous IE 14 (43.8) Reasons for no surgery Chronic renal failure 14 (43.8) Unaffordable surgical risk 24 (75) Hemodyalisis 3 (9.4) Patient refusal 2 (6.3) Diabetes mellitus 9 (28.1) Intra-surgery clinical complication* 1 (3.1) COPD 5 (15.6) Surgeon refusal (technical risk) 5 (15.6) Severe liver disease 4 (12.5) Outcome Cancer 4 (12.5) 0 to 60-day mortality 1 (3.1) HIV 1 (3.1) Cumulative 3-year mortality 12 (37) Charlson comordity index, 5 (3–7) median (IQR) Related to IE 4 (12.5) Laboratory tests Relapses 4 (12.5) Hemoglobin [g/dL] 10.2 ± 2.02 Data are presented as the number (%) and mean ± 1 standard deviation, unless otherwise indicated. *Neurological complication CRP [mg/L], median (IQR) 33 (12–124) during surgery without valve surgery attempted. COPD — chronic obstructive pulmonary disease; CRP — C-reactive protein; eGFR eGFR [mL/min/1.73 m2] 52.9 ± 24 — estimated glomerular filtration rate; HIV — human immunodefi- Echocardiography-PET/CT ciency virus; IE — infective endocarditis; IQR — interquartile range; PET/CT — positron emission tomography/computed tomography; TEE performed 24 (75) PVE — prosthetic valve endocarditis; TEE — transesophageal echocardiography PET/CT performed 20 (62.5) Control PET/CT performed 12 (37.5) Local complication 18 (56.3) Vegetation present 12 (37.5) 8 cases, only parenteral LTAT was administered, based on a decision by the local MDET. This Moderate or severe valve 8 (25) regurgitation treatment lasted 34 weeks (range: 8−34) and was Microbiology administered in an outpatient or day care setting (Table 4). Coagulase-negative staphylococci 10 (31.3) Twenty-four (75%) patients were switched to Staphylococcus aureus 7 (21.9) LOSAT after prolonged (12 patients) or adjusted Streptococcus spp 4 (12.5) to guidelines (12 patients) parenteral administra- Enterococcus faecalis 4 (12.5) tion. In 23 patients, the MDET initially established Non-HACEK Gram-negative bacili 2 (6.3) LOSAT as a life-long treatment, starting at dis- Negative blood cultures 2 (6.3) charge. The median duration of LOSAT was 277 Others 3 (9.4) days (IQR: 73−868). Complications Nine patients underwent PET/CTs to guide Embolization 8 (25) the duration and response to treatment. In these patients, the LOSAT was stopped, based on PET/ Stroke 6 (18.8) /CT information. None of these patients experi- Heart failure 5 (15.6) enced infection relapse. Æ www.cardiologyjournal.org 569 Cardiology Journal 2021, Vol. 28, No. 4 Table 2. Description of seven episodes of device infective endocarditis treated with oral long suppres- sive antibiotic treatment. Age Sex Underlying Etiology Percutaneous Antibiotic Final status [years] condition extraction treatment (follow-up, tried and duration years) 87 Male CRF, diabetes S. epidermidis Yes CMX 160/800 mg bid Relapse (0.2) Longlife Alive (3.2) 89 Male CRF S. aureus No CMX 160/800 mg bid Death (0.8) Longlife Not related 91 Male CRF S. aureus No CMX 160/800 mg bid Alive (1.6) Ø LVF 500 mg QD Longlife 88 Female Diabetes S. aureus Yes LVF 500 mg/2 days Alive (6.6) Longlife 82 Male CRF, COPD S. epidermidis No LVF 250 mg/2 days Death (3.5) (+ Rifampicine 300 mg Not related QD 4 months) 93 Female CRF, hepatopathy Enterococcus No Amoxicilin 1 g TD Death (0.4) faecalis Longlife Not related 69 Male COPD, hepatopathy S. epidermidis Yes Amoxicilin 1 g TD Alive (0.8) Longlife CMX — cotrimoxazole; COPD — chronic obstructive pulmonary disease; CRF — chronic renal failure; LVF — levofloxacine; bid — bis in die (twice a day); QD — quaque die (once a day); TD — ter in die (three times a day) Long-term oral suppressive antibiotic treat- doing well in follow-up. The second relapse was ment comprised a variety of oral antimicrobial a CIED-related IE, associated with coagulase-nega- classes. In initial treatments, 9 patients received tive Staphylococcus and incomplete extraction of the beta-lactams, 9 patients received trimethoprim- CIED lead. The patient was switched to oral TMP/ sulfamethoxazole (TMP/SMX), 2 patients received /SMX. After 2 months, positive blood cultures were clindamycin, and 4 patients received fluoroquinolo- detected, but without clinical repercussion, and nes (levofloxacin). Others agents were combined the same antibiotic regimen that was used in the with the initial treatment or were used during follow-up. The third relapse was a prosthetic valve follow-up, including linezolid (n = 2) and rifampicin (Bentall surgery) IE, associated with coagulase- (combined with levofloxacin, n = 1). Four (17%) -negative Staphylococcus. The patient was treated patients experienced adverse drug-related events, with TMP/SMX LOSAT, but after 5 months, the including thrombocytopenia (n = 2), associated patient developed in vitro resistance to TMP/SMX. with linezolid, and digestive intolerance (n = 1) and After switching to oral clindamycin, the IE showed a skin disorder (n = 1), associated with TMP/SMX. a favourable evolution. The fourth relapse was an Only 1 of these patients required definitive LOSAT early PVE, associated with coagulase-negative discontinuation. In 2 cases, in vitro resistance was Staphylococcus. The patient was switched to oral resolved with another antibiotic treatment option. linezolid (600 mg bid). After 3 months, during Some antibiotic regimens and doses are described treatment, positive blood cultures were detected, in Tables 2 and 3. and the treatment was switched to intravenous Four patients experienced infection relapses vancomycin for 4 weeks. Subsequently, the patient during follow-up. All had positive blood cultures, was treated with oral TMP/SMX (160/800 mg bid), but no clinical repercussion. The median time to which was stopped after 1 year, due to stable infec- relapse was 144 days (IQR: 72−210). The first re- tion and clinical stability and disease improvement, lapse was a late PVE associated with Streptococcus based on PET/CT. viridans. An aortic abscess was treated with oral The estimated overall survival rates were amoxicillin (3 g/day), which was stopped after 78% at 1 year and 62% at 3 years (Fig. 1). Only 1 year, due to clinical stability; subsequently, positive 1 patient died within 60 days, due to an uncontrolled blood cultures were documented. Life-long amoxi- infection during treatment. Twelve patients died cillin was re-started, and the patient is currently between 60 days and 3 years, but only 4 deaths 570 www.cardiologyjournal.org Table 3. Description of eight cases of prosthetic endocarditis with previous ascending aortic surgery treated with long-term antibiotic treatment including oral long suppressive antibiotic treatment. Age Sex Underlying Type of Time Diagnosis Microbiology Length of Oral ATB and PET/CT Outcome status [years] condition surgery IV ATB duration Follow- up (follow-up, years) [week] 57 Male – Bentall Early TEE–PET/CT+ Moraxella 6 LVF Yes Alive (4) lacunata (500 mg bid) 3 months 85 Male – Dacron Late TEE–PET/CT+ S. epidermidis 9 CMX No Alive (1) Tube AA (160/800 mg bid) Longlife 56 Male COPD Bentall Late TEE–PET/CT+ Enterococcus faecalis 34 No Yes Alive (1) 32 Male – Bentall Early TEE–PET/CT+ Enterococcus faecalis 12 No Yes Alive (4) DA tube 57 Male – Bentall Early PET/CT+ TEE+ S. epidermidis 13 No Yes Alive (1) www.cardiologyjournal.org 44 Male – Bentall Early TEE+ S. aureus 8 LVF Yes Alive (5) (500 mg bid) Longlife 63 Male Diabetes Bentall Early TEE+ S. epidermidis 8 CMX No Recurrence (0.4) (160/800 mg bid) Death related (0.7) Longlife 71 Male – Bentall Early TEE–PET/CT+ Bovis group 8 Amoxicilin 1 g Yes Alive (1) Streptococcus TD 1 year AA — ascending aorta; ATB — antibiotherapy; CMX — cotrimoxazole; COPD — chronic obstructive pulmonary disease; DA — descending aorta; IV — intravenous; LVF — levofloxacine; PET/CT — positron emission tomography/computed tomography; TD — ter in die (three times a day); TEE — transesophageal echocardiography 571 Nuria Vallejo Camazon et al., Long-term antibiotics in not operated surgical endocarditis 572 Table 4. Description of eight cases of surgery indicated not undergoing surgery infective endocarditis treated with parenteral long term antibiotic treatment. Age Sex Underlying Type of IE Time Diagnosis Microbiology Length of ATB PET/CT Outcome status [years] condition complication IV ATB Follow up (follow-up, years) [week] 23 Male Congenital Pulmonar prothesis Late PET/CT Staphylococcus 12 Cloxaxilin Yes Alive (2.4) heart disease Pulmonar emboli aureus 43 Female NA Aortic prosthesis Late TEE (abscess) Cutibacterium 16 Ceftriaxone Yes Alive (2.8) Cardiology Journal 2021, Vol. 28, No. 4 acnes (12 weeks) Ertapenem (2 weeks) Daptomicin (2 weeks) 56 Male COPD Bentall Late PET/CT+ Enterococcus 34 Ampicilin + Yes Alive (0.9) (abscess) faecalis ceftriaxone 32 Male NA Bentall Early PET/CT+ Enterococcus 12 Ampicilin + Yes Alive(4) DA tube (abscess) faecalis ceftriaxone 57 Male NA Bentall Early PET/CT+ Staphylococcus 13 Daptomicin Yes Alive (1) TEE+ (abscess) epidermidis www.cardiologyjournal.org 86 Male CKD Aortic prosthesis Late TEE (abscess) Gemella 10 Ceftriaxone No Death (during haemolysans Ø treatment) Penicilin 78 Male Porcelain aorta Aortic prosthetic Late TEE (abcess) Viridans group 13 Ceftriaxone Yes Alive (1.7) Streptococcus 82 Male CKD Aortic prosthesis Late TEE (abscess) Aerococcus 9 Linezolid Yes Non related viridans Ø death (2) Ampicilin Ø Vancomicin Ø Daptomicin ATB — antibiotherapy; CKD — chronic kidney disease; COPD — chronic obstructive pulmonary disease; DA — descending aorta; IE — infective endocarditis; IV — intravenous; NA — not applicable; PET/CT — positron emission tomography/computed tomography; TEE — transesophageal echocardiography Nuria Vallejo Camazon et al., Long-term antibiotics in not operated surgical endocarditis 1.00 survive past the index hospitalization [14]. In the present study, among the patients with SINUS IE that were treated with LTAT and survived the acute 0.75 phase of IE, the main indication for surgery was Cumulative survival uncontrolled infection (75% of patients), including 18 (56%) patients with local complications (mainly 0.50 perianular abscesses) detected in imaging. Guideline recommendations concerning anti- 0.25 biotic treatments and durations are not sufficiently evidence-based for SINUS-IE, due to the lack of randomized controlled trials [9]. The standard 0.00 0 1 2 3 treatment for IE is 2–6 weeks of intravenous Years of follow-up antibiotic treatment. This treatment is suitable for classical, uncomplicated, prosthetic-, native-, Figure 1. Survival in surgery indicated, but did not un- or device-related IE, but clinical guidelines do dergo surgery for infective endocarditis patients treated not mention antibiotic treatment or durations for with long term antibiotic treatment. patients with SINUS-IE. Consequently, patients with SINUS-IE are treated according to local ex- perience, in a heterogeneous manner. In the present study, 7 patients with local were related to IE (due to uncontrolled infection complications received prolonged LTAT. A recent in 1 patient, stroke in 2 patients, and heart failure study described treating IE with dalbavancin [26], in 1 patient). After 3 years of follow-up, 3 more a long-acting lipoglycopeptide antibiotic with ex- deaths occurred that were unrelated to IE. Of note, cellent anti-staphylococcal activity and a half-life in the group with SINUS-IE that had AAGs, only of 346 h. This treatment might be an attractive 1 IE-related death occurred after a previous relapse option for staphylococcal-associated endocarditis, (Table 3), and in the CIED device IE group, 3 deaths in patients with SINUS-IE that cannot tolerate oral occurred that were unrelated to IE (Table 2). antibiotic treatment. A recent case study showed a favourable outcome with dalvabancin [27]. In the Discussion present study, due to the retrospective design, no patients were treated with dalvabancin. According to available research, this study The role of oral antibiotic therapy in treating included the largest series (including left sided IE) IE remains controversial [28]. Oral antibiotics to date in describing the experiences and outcomes have high bioavailability and have been effective of patients with SINUS-IE treated with LTAT, in- in shortening intravenous treatment and treating cluding those that switched to LOSAT. All previous selected cases of uncomplicated IE caused by studies were small, retrospective studies or case susceptible organisms [15, 28−31]. Recently, an reports (Table 5). An overall survival of 62% at intervention study [32] demonstrated that a rapid 3 years, and only 4 relapses were observed. switch to oral TMP/SMX reduced the hospital stay Successful IE treatment requires prolonged and mortality in S. aureus-associated IE, including bactericidal antibiotic treatment and surgery to patients with cardiac abscesses or persistent bacte- remove infected material and drain abscesses. remia. Oral LOSAT for patients with SINUS-IE has Current indications for surgery in IE are well de- only been described in case reports [33], in case fined in the American Heart Association and ESC series for some specific situations (e.g., fungal IE guidelines [10, 23]. They include valve dysfunction [34], CIED--related IE [35, 36], aortic grafts [37]), that leads to heart failure, uncontrolled infection and briefly, in some contemporary series [25] and (defined as a paravalvular extension, abscess, or reviews [9]. persistent bacteremia), and recurrent/high risk of Prosthetic graft infection is a fatal complication embolism. More than 50% of patients with IE meet after thoracic aorta replacement; early mortality the surgical criteria, according to clinical guidelines was reported to be 25−42% [38]. In the present [24], but of those, 20–40% do not undergo surgery study, 8 patients with SINUS-IE that developed due to high perioperative risk [11, 14, 25]. In-hos- PVE after a previous surgery involving the aortic pital mortality is high in SINUS-IE, typically due to root and ascending aorta (Bentall procedure or shock and heart failure; only one third of patients ascending aorta graft replacement) were treated www.cardiologyjournal.org 573 574 Table 5. Review of literature regarding long suppressive antibiotic treatment (LSAT). Study N Sex Age Type of IE Etiology LSAT Follow-up, Relapses Mortality (male) (mean) years (mean) Vallejo et al. 2020 32 25 72 Prosthetic 21 CNS (10) CNS: 3 years 4 12 (4 IE (present study) Native 4 Staphylococcus — TMP/SMX related) Device related 7 aureus (7) — Clindamicin Enterococcus — Linezolid faecalis (4) — Levofloxacin Viridans-group S. aureus: Streptococci (3) — Levofloxacin Str. Gallolyticus ssp. — TMP/SMX pasterianus (1) Enterococcus: GNB (2)* — Amoxicilin Cardiology Journal 2021, Vol. 28, No. 4 Negative blood Streptococci cultures (2) — Amoxicilin Others (3)** GNB: — Cefuroxime — Levofloxacin Fernandez Hidalgo 2 (438) 1 70.9 Mitral prothesis S. epidermidis Unknown 0.4 years 0 0 et al. 2012 [25] 88.5 Aortic prothesis Enterococus faecalis Longlife 1.9 years Puerta Alcalde 1 1 78 Bentall Streptococcus gallolyticus Amoxicilin 1 year 0 0 et al. 2012 [18] Longlife Spaziante 1 1 78 Bioprothesis/ascending Staphylococcus epidermidis Dalvavancin 0.6 years 0 0 et al. 2019 [27] aortic graft www.cardiologyjournal.org Machelart 7 6 63 Bentall aortic prosthetic S. epidermidis (2) NA 2.6 years 1 1 (not et al. 2019 [44] Streptococcus agalactiae related) Bartonella quintana E. faecalis Coxiella burnetti Lechner et al., 1 1 58 Aortic prosthetic S. aureus TMP/SMX 1.5 years 0 0 2019 [37] +aortic graft Ramos et al. 2 (9) NA NA Aortic graft NA Unkown; 12 month/ 1 year 0 1 (not 2020 [39] /18 month related) Baddour et. al. 51 35 70 Device related Several Several NA 3 3 2001 [36] Tan et al. 2018 [35] 48 35 78 Device related Several Several 10 years 6 21 (1 year) Total patients 145 74 14 (9.6%) 38 (26%) *Escherichia coli, Moraxella lacunata; **Aerococcus viridans, Gemella haemolysans, Cultibacterium acnes; CNS — coagulase negative Staphylococci; GNB — Gram-negative bacilli; IE — infective endo- carditis; NA — not available TMP/SMX — trimetroprim-sulfamethoxazole Nuria Vallejo Camazon et al., Long-term antibiotics in not operated surgical endocarditis with LTAT. Five of these patients were treated experienced incomplete removal [45]. Currently, orally (two life-long treatments), and only one no comparable studies on LOSAT are available. death occurred during follow-up. The diagnosis and Therefore, the optimal choice, dose, or duration management of PVE after aortic root or ascending of antibiotic treatment remain undefined; differ- aorta graft surgery are difficult and require long- ent outcomes have been reported in the few small -term, combined antibiotic treatment and surgery, observational studies that were published [35, 36]. when possible [39]. In patients with inconclusive The 5 hospitals included in the present study echocardiographic results, a combination of PET/ had a MDET that was comprised of cardiac imag- /CT and cardiac CT is recommended [40, 41] ing experts, cardiac surgeons, microbiologists, and (among our 8 patients, 5 were diagnosed with infectious disease specialists. Previous studies PET/CT after inconclusive or negative TEEs). showed that a team-based approach reduced the Consistent with some previous reports [37, 42−44], 1-year mortality in a mixed cohort of medically the present findings suggested that individualized and surgically managed patients with IE [46, 47]. LTAT might be effective (when there is no valvular Additionally, a recent study [48] showed improved dysfunction) in select patients with PVE compli- survival in patients that were managed medically. cated with AAG infections that are unfit to undergo The present study showed that close follow-up and surgery. Another option could be conservative individualized treatment, supported with cardiac surgery with valvular replacement and AAG pres- imaging, could improve the long-term prognosis in ervation. However, the risk of recurrence is high; patients with SINUS-IE treated with LTSAT includ- thus, chronic antibiotic suppressive treatment has ing LOSAT. Based on our experience, we propose been recommended, in some cases [38]. an algorithm (Fig. 2) for guiding the management of Positron emission tomography/computed patients with SINUS-IE and treatment with LOSAT. tomography is a functional molecular imaging technique that depicts metabolic activity. Several Limitations of the study studies [16, 17, 41] have shown its utility for di- This study had several limitations. First, agnosing PVE. Recently, ESC IE guidelines [10] antibiotic treatment was heterogeneous, because have included abnormal activity around a prosthetic administration was at the discretion of the physi- valve as a major criterion and embolic phenomena cian and the center, according to local protocols. as a minor criterion for diagnosing PVE. In the pre- Second, the definition of LOSAT was established ad sent study, PET/CT was performed as a diagnostic hoc. Third, patient-level data were retrospective, tool in 62.5% of patients. Additionally, PET/CT pooled, and prospectively analyzed. Proposed algo- has shown promise in monitoring responses to rithm is based on our own local experience without antimicrobial treatment in PVE, as suggested in previous supporting clinical evidence. small observational studies [18]. On the other hand, sometimes, false-negative findings have been at- Conclusions tributed to low inflammatory activity at the time of imaging, caused by prolonged antibiotic therapy. In Surgery indicated not undergoing surgery the present study, PET/CT was used to guide the IE remains a dreadful complication, and we lack cessation of LOSAT in 9 patients. Those patients evidence-driven management guidelines. Herein, had favourable outcomes, after antibiotic treatment it was shown that survivors could achieve a rea- was stopped, due to a reduction or termination of sonable long-term prognosis with an MDET-based, metabolic uptake detected with PET/CT. More managed approach, with close follow-up, individu- large-scale studies are warranted to investigate alized antibiotic treatment, including LOSAT, and this indication. guidance from new imaging techniques. More In the present study, 7 patients with CIED- multicenter prospective studies are needed to -related IE were treated with LOSAT. Of these, validate the proposed algorithm and to establish an 3 patients had incomplete percutaneous extractions, appropriate long-term strategy for treating patients and the other 4 had comorbidities that counter- with SINUS-IE. indicated percutaneous extraction, as judged by the MDET. Of these 7 patients, only one experi- Funding enced a relapse, and no IE-related deaths occurred. Antoni Bayes-Genis was supported by grants LOSAT was also given to select patients with de- from the Ministerio de Educación y Ciencia vice-related IE that were ineligible for device removal (SAF2014–59892), Fundació La MARATÓ de (either surgical or percutaneous) or patients that TV3 (201502, 201516), CIBER Cardiovascular www.cardiologyjournal.org 575 Cardiology Journal 2021, Vol. 28, No. 4 IE with surgery indication Evaluation by MDET Suitable for surgery or device extraction? YES Surgery or extraction NO SINUS-IE Complet aortic surgery* or device extraction? NO YES Native IE Prosthetic IE Device related IE HF/Valve Embolic Uncontrolled disfunction phenomena infection 4/6 week IV conventional ATB treatment Treatment HF by GP/Valve Heart 4/6 week IV conventional Team and MDET Consider LTAT (IV or LOSAT) ATB treatment PET/CT available? YES NO Guided duration Consider longlife by PET LOSAT Figure 2. Proposed algorithm for treating surgery indicated, but did not undergo surgery for infective endocarditis (SINUS-IE) with long term antibiotic treatment (LTAT); MDET — multidisciplinary endocarditis team; IE — infective endocarditis; IV — intravenous; HF — heart failure; GP — general practitioner; LOSAT — long-term oral suppres- sive antibiotic treatment; PET/CT — positron emission tomography/computed tomography; ATB — antibiotherapy; *In cases of ascending aortic graft preservation. (CB16/11/00403), and AdvanceCat 2014. María a nationwide population-based study. Eur J Cardiothorac Surg. 2018; 54(5): 860–866, doi: 10.1093/ejcts/ezy156, indexed in Hernández Pérez is supported by a Juan Rodes Pubmed: 29648662. research contract (JR17/00006) from Instituto de 3. Thuny F, Grisoli D, Collart F, et al. Management of infective en- Salud Carlos III. docarditis: challenges and perspectives. Lancet. 2012; 379(9819): 965–975, doi: 10.1016/S0140-6736(11)60755-1, indexed in Pub- Conflict of interest: None declared med: 22317840. 4. Cahill TJ, Baddour LM, Habib G, et al. Challenges in Infec- tive Endocarditis. J Am Coll Cardiol. 2017; 69(3): 325–344, doi: References 10.1016/j.jacc.2016.10.066, indexed in Pubmed: 28104075. 5. San Román JA, Vilacosta I, López J, et al. Critical questions about 1. Hoen B, Duval X. Infective endocarditis. N Engl J Med. 2013; left-sided infective endocarditis. J Am Coll Cardiol. 2015; 66(9): 368(15): 1425–1433, doi: 10.1056/nejmcp1206782. 1068–1076, doi: 10.1016/j.jacc.2015.07.016, indexed in Pubmed: 2. Østergaard L, Oestergaard LB, Lauridsen TK, et al. Long- 26314535. -term causes of death in patients with infective endocarditis 6. Olmos C, Vilacosta I, Fernández-Pérez C, et al. The evolving who undergo medical therapy only or surgical treatment: nature of infective endocarditis in spain: a population-based study 576 www.cardiologyjournal.org Nuria Vallejo Camazon et al., Long-term antibiotics in not operated surgical endocarditis (2003 to 2014). J Am Coll Cardiol. 2017; 70(22): 2795–2804, doi: 21. Nashef S, Roques F, Michel P, et al. European system for cardiac 10.1016/j.jacc.2017.10.005, indexed in Pubmed: 29191329. operative risk evaluation (EuroSCORE). Eur J Cardio-Thoracic 7. Delahaye F, Duclos A. Is infective endocarditis changing Surg. 1999; 16(1): 9–13, doi: 10.1016/s1010-7940(99)00134-7. over time? J Am Coll Cardiol. 2017; 70(22): 2805–2807, doi: 22. Nashef SAM, Roques F, Sharples LD, et al. EuroSCORE II. Eur 10.1016/j.jacc.2017.10.016, indexed in Pubmed: 29191330. J Cardiothorac Surg. 2012; 41(4): 734–44; discussion 744, doi: 8. Murdoch DR, Corey GR, Hoen B, et al. Clinical presentation, 10.1093/ejcts/ezs043, indexed in Pubmed: 22378855. etiology, and outcome of infective endocarditis in the 21st centu- 23. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis ry: the International Collaboration on Endocarditis-Prospective in adults: diagnosis, antimicrobial therapy, and management of Cohort Study. Arch Intern Med. 2009; 169(5): 463–473, doi: complications: a scientific statement for healthcare professionals 10.1001/archinternmed.2008.603, indexed in Pubmed: 19273776. from the american heart association. Circulation. 2015; 132(15): 9. Fernández-Hidalgo N, Almirante B. Current status of infectious en- 1435–1486, doi: 10.1161/CIR.0000000000000296, indexed in docarditis: New populations at risk, new diagnostic and therapeutic Pubmed: 26373316. challenges. Enferm Infecc Microbiol Clin. 2018; 36(2): 69–71, doi: 24. Prendergast BD, Tornos P. Surgery for infective endocarditis: who 10.1016/j.eimc.2017.11.020, indexed in Pubmed: 29325999. and when? Circulation. 2010; 121(9): 1141–1152, doi: 10.1161/ 10. Habib G, Lancellotti P, Antunes M, et al. 2015 ESC Guidelines /CIRCULATIONAHA.108.773598, indexed in Pubmed: 20212293. for the management of infective endocarditis. Eur Heart J. 2015; 25. Fernández-Hidalgo N, Almirante B, Tornos P, et al. Immediate 36(44): 3075–3128, doi: 10.1093/eurheartj/ehv319. and long-term outcome of left-sided infective endocarditis. A 12- 11. Chu VH, Park LP, Athan E, et al. Association between surgical -year prospective study from a contemporary cohort in a referral indications, operative risk, and clinical outcome in infective endo- hospital. Clin Microbiol Infect. 2012; 18(12): E522–E530, doi: carditis: a prospective study from the International Collaboration 10.1111/1469-0691.12033, indexed in Pubmed: 23077981. on Endocarditis. Circulation. 2015; 131(2): 131–140, doi: 10.1161/ 26. Hidalgo-Tenorio C, Vinuesa D, Plata A, et al. DALBACEN co- CIRCULATIONAHA.114.012461, indexed in Pubmed: 25480814. hort: dalbavancin as consolidation therapy in patients with 12. Iung B, Doco-Lecompte T, Chocron S, et al. AEPEI Study Group. endocarditis and/or bloodstream infection produced by gram- Cardiac surgery during the acute phase of infective endocarditis: positive cocci. Ann Clin Microbiol Antimicrob. 2019; 18(1): discrepancies between European Society of Cardiology guide- 30, doi: 10.1186/s12941-019-0329-6, indexed in Pubmed: lines and practices. Eur Heart J. 2016; 37(10): 840–848, doi: 31629409. 10.1093/eurheartj/ehv650, indexed in Pubmed: 26685134. 27. Spaziante M, Franchi C, Taliani G, et al. Serum bactericidal activ- 13. Habib G, Erba PA, Iung B. et el. Clinical presentation, aetiology ity levels monitor to guide intravenous dalbavancin chronic sup- and outcome of infective endocarditis. Results of the ESC-EORP pressive therapy of inoperable staphylococcal prosthetic valve EURO-ENDO (European infective endocarditis) registry: a pro- endocarditis: a case report. Open Forum Infect Dis. 2019; 6(11): spective cohort study. Eur Heart J. 2019; 40(39): 3222–3232, doi: ofz427, doi: 10.1093/ofid/ofz427, indexed in Pubmed: 31737736. 10.1093/eurheartj/ehz620, indexed in Pubmed: 31504413. 28. Al-Omari A, Cameron DW, Lee C, et al. Oral antibiotic therapy 14. Vallejo Camazón N, Cediel G, Núñez Aragón R, et al. Short- and for the treatment of infective endocarditis: a systematic review. long-term mortality in patients with left-sided infective endocar- BMC Infect Dis. 2014; 14: 140, doi: 10.1186/1471-2334-14-140, ditis not undergoing surgery despite indication. Rev Esp Cardiol indexed in Pubmed: 24624933. (Engl Ed). 2020; 73(9): 734–740, doi: 10.1016/j.rec.2019.09.011, 29. Mzabi A, Kernéis S, Richaud C, et al. Switch to oral antibiotics in indexed in Pubmed: 31767290. the treatment of infective endocarditis is not associated with in- 15. Iversen K, Ihlemann N, Gill SU, et al. Partial oral versus in- creased risk of mortality in non-severely ill patients. Clin Micro- travenous antibiotic treatment of endocarditis. N Engl J Med. biol Infect. 2016; 22(7): 607–612, doi: 10.1016/j.cmi.2016.04.003, 2019; 380(5): 415–424, doi: 10.1056/NEJMoa1808312, indexed indexed in Pubmed: 27091094. in Pubmed: 30152252. 30. Heldman AW, Hartert TV, Ray SC, et al. Oral antibiotic treatment 16. Millar BC, Habib G, Moore JE. New diagnostic approaches of right-sided staphylococcal endocarditis in injection drug users: in infective endocarditis. Heart. 2016; 102(10): 796–807, doi: prospective randomized comparison with parenteral therapy. Am 10.1136/heartjnl-2014-307021, indexed in Pubmed: 26908095. J Med. 1996; 101(1): 68–76, doi: 10.1016/s0002-9343(96)00070-8, 17. Millar BC, de Camargo RA, Alavi A, et al. PET/Computed tomog- indexed in Pubmed: 8686718. raphy evaluation of infection of the heart. PET Clin. 2019; 14(2): 31. Stamboulian D, Bonvehi P, Arevalo C, et al. Antibiotic manage- 251–269, doi: 10.1016/j.cpet.2018.12.006, indexed in Pubmed: ment of outpatients with endocarditis due to penicillin-suscepti- 30826023. ble streptococci. Rev Infect Dis. 1991; 13 Suppl 2: S160–S163, 18. Puerta-Alcalde P, Cuervo G, Simonetti AF, et al. PET/CT added doi: 10.1093/clinids/13.supplement_2.s160, indexed in Pubmed: to Duke criteria facilitates diagnosis and monitoring of long-term 2017645. suppressive therapy of prosthetic endocarditis. Infect Dis (Lond). 32. Tissot-Dupont H, Gouriet F, Oliver L, et al. High-dose trimeth- 2017; 49(9): 698–701, doi: 10.1080/23744235.2017.1300683, in- oprim-sulfamethoxazole and clindamycin for Staphylococcus au- dexed in Pubmed: 28298163. reus endocarditis. Int J Antimicrob Agents. 2019; 54(2): 143–148, 19. Núñez Aragón R, Pedro-Botet Montoya ML, Mateu Pruñonosa L, doi: 10.1016/j.ijantimicag.2019.06.006, indexed in Pubmed: et al. Factores asociados y análisis descriptivo de la endocarditis 31181351. infecciosa adquirida en el entorno hospitalario de un centro ter- 33. Cunha BA, Brahmbhatt K, Raza M. Haemophilus parainfluenzae ciario de referencia. Enferm Infecc Microbiol Clin. 2013; 31(1): aortic prosthetic valve endocarditis (PVE) successfully treated 15–22, doi: 10.1016/j.eimc.2012.03.014. with oral levofloxacin. Heart Lung. 2015; 44(4): 317–320, doi: 20. Charlson ME, Pompei P, Ales KL, et al. A new method of clas- 10.1016/j.hrtlng.2015.04.006, indexed in Pubmed: 25998992. sifying prognostic comorbidity in longitudinal studies: develop- 34. Baddour LM. Long-term suppressive therapy for fungal endo- ment and validation. J Chronic Dis. 1987; 40(5): 373–383, doi: carditis. Clin Infect Dis. 1996; 23(6): 1338–1340, doi: 10.1093/ 10.1016/0021-9681(87)90171-8, indexed in Pubmed: 3558716. clinids/23.6.1338-a, indexed in Pubmed: 8953098. www.cardiologyjournal.org 577 Cardiology Journal 2021, Vol. 28, No. 4 35. Tan EM, DeSimone DC, Sohail MR, et al. Outcomes in patients 42. Heuzé C, Lepage L, Loubet P, et al. Infective endocarditis with cardiovascular implantable electronic device infection managed after bentall surgery: usefulness of new imaging modalities with chronic antibiotic suppression. Clin Infect Dis. 2017; 64(11): and outcomes. JACC Cardiovasc Imaging. 2018; 11(10): 1535– 1516–1521, doi: 10.1093/cid/cix181, indexed in Pubmed: 28329125. –1537, doi: 10.1016/j.jcmg.2017.12.007, indexed in Pubmed: 36. Baddour LM. Long-term suppressive antimicrobial therapy for 29454780. intravascular device-related infections. Am J Med Sci. 2001; 43. Saitto G, Russo M, Pugliese M, et al. Infectious aortic root 322(4): 209–212, doi: 10.1097/00000441-200110000-00011, in- pseudoaneurysm after bentall procedure: to treat or not to treat dexed in Pubmed: 11678518. by redo operation? Aorta (Stamford). 2019; 7(3): 90–92, doi: 37. Lechner AM, Pretsch I, Hoppe U, et al. Successful long-term 10.1055/s-0039-1694013, indexed in Pubmed: 31614379. antibiotic suppressive therapy in a case of prosthetic valve en- 44. Machelart I, Greib C, Wirth G, et al. Graft infection after docarditis and a case of extensive aortic and subclavian graft a Bentall procedure: A case series and systematic review of the infection. Infection. 2020; 48(1): 133–136, doi: 10.1007/s15010- literature. Diagn Microbiol Infect Dis. 2017; 88(2): 158–162, 019-01321-6, indexed in Pubmed: 31123929. doi: 10.1016/j.diagmicrobio.2017.03.002, indexed in Pubmed: 38. Takano T, Terasaki T, Wada Y, et al. Treatment of prosthetic graft 28330738. infection after thoracic aorta replacement. Ann Thorac Cardio- 45. Baddour LM, Cha YM, Wilson WR. Clinical practice. Infections vasc Surg. 2014; 20(4): 304–309, doi: 10.5761/atcs.oa.13-00059, of cardiovascular implantable electronic devices. N Engl J Med. indexed in Pubmed: 23801180. 2012; 367(9): 842–849, doi: 10.1056/NEJMcp1107675, indexed 39. Ramos-Martínez A, Blanco-Alonso S, Calderón-Parra J, et al. in Pubmed: 22931318. Endocarditis in patients with ascending aortic prosthetic graft: 46. Botelho-Nevers E, Thuny F, Casalta JP, et al. Dramatic reduction a series from a national referral hospital. J Am Coll Cardiol. 2020; in infective endocarditis-related mortality with a management- 75(18): 2380–2382, doi: 10.1016/j.jacc.2020.03.035, indexed in -based approach. Arch Intern Med. 2009; 169(14): 1290–1298, doi: Pubmed: 32381170. 10.1001/archinternmed.2009.192, indexed in Pubmed: 19636030. 40. Swart LE, Gomes A, Scholtens AM, et al. Improving the diag- 47. Chirillo F, Scotton P, Rocco F, et al. Impact of a multidisciplinary nostic performance of f-fluorodeoxyglucose positron-emission management strategy on the outcome of patients with native tomography/computed tomography in prosthetic heart valve en- valve infective endocarditis. Am J Cardiol. 2013; 112(8): 1171– docarditis. Circulation. 2018; 138(14): 1412–1427, doi: 10.1161/ –1176, doi: 10.1016/j.amjcard.2013.05.060, indexed in Pubmed: CIRCULATIONAHA.118.035032, indexed in Pubmed: 30018167. 23831163. 41. Pizzi M, Roque A, Fernández-Hidalgo N, et al. Improving the 48. Kaura A, Byrne J, Fife A, et al. Inception of the ‚endocarditis diagnosis of infective endocarditis in prosthetic valves and intra- team’ is associated with improved survival in patients with in- cardiac devices with 18 f-fluordeoxyglucose positron emission to- fective endocarditis who are managed medically: findings from mography/computed tomography angiography. Circulation. 2015; a before-and-after study. Open Heart. 2017; 4(2): e000699, doi: 132(12): 1113–1126, doi: 10.1161/circulationaha.115.015316. 10.1136/openhrt-2017-000699, indexed in Pubmed: 29344368. 578 www.cardiologyjournal.org