Medicine

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OBSERVATIONAL STUDY

Polymicrobial Infective Endocarditis: Clinical Features and Prognosis Pablo Elpidio Garcı´a-Granja, MD, Javier Lo´pez, MD, PhD, Isidre Vilacosta, MD, PhD, Carlos Ortiz-Bautista, MD, Teresa Sevilla, MD, PhD, Carmen Olmos, MD, PhD, Cristina Sarria´, MD, PhD, Carlos Ferrera, MD, Itziar Go´mez, BS, and Jose´ Alberto San Roma´n, MD, PhD INTRODUCTION Abstract: To describe the profile of left-sided polymicrobial endocarditis (PE) and to compare it with monomicrobial endocarditis (ME). Among 1011 episodes of left-sided endocarditis consecutively diagnosed in 3 tertiary centers, between January 1, 1996 and December 31, 2014, 60 were polymicrobial (5.9%), 821 monomicrobial (81.7%), and in 123 no microorganism was detected (12.2%). Seven patients (0.7%) were excluded from the analysis because contamination of biologic tissue could not be discarded. The authors described the clinical, microbiologic, echocardiographic, and outcome of patients with PE and compared it with ME. Mean age was 64 years SD 16 years, 67% were men and 30% nosocomial. Diabetes mellitus (35%) were the most frequent comorbidities, fever (67%) and heart failure (43%) the most common symptoms at admission. Prosthetic valves (50%) were the most frequent infection location and coagulase-negative Staphylococci (48%) and enterococci (37%) the leading etiologies. The most repeated combination was coagulase-negative Staphylococci with enterococci (n ¼ 9). Polymicrobial endocarditis appeared more frequently in patients with underlying disease (70% versus 56%, P ¼ 0.036), mostly diabetics (35% versus 24%, P ¼ 0.044) with previous cardiac surgery (15% versus 8% P ¼ 0.049) and prosthetic valves (50% versus 37%, P ¼ 0.038). Coagulase-negative Staphylococci, enterococci, Gramnegative bacilli, anaerobes, and fungi were more frequent in PE. No differences on age, sex, symptoms, need of surgery, and in-hospital mortality were detected. Polymicrobial endocarditis represents 5.9% of episodes of left-sided endocarditis in our series. Despite relevant demographic and microbiologic differences between PE and ME, short-term outcome is similar. (Medicine 94(49):e2000) Abbreviations: HIV = human immunodeficiency virus, IE = infective endocarditis, ME = monomicrobial endocarditis, PE = polymicrobial endocarditis.

Editor: Steven Callens. Received: July 9, 2015; revised: October 13, 2015; accepted: October 15, 2015. From the Instituto de Ciencias del Corazo´n (ICICOR), Hospital Clı´nico Universitario, Valladolid (PEG-G, JL, CO-B, T S, IG, JASR); Hospital Clı´nico Universitario San Carlos (IV, CO, CF); and Hospital Clı´nico Universitario la Princesa, Madrid, Espan˜a (CS). Correspondence: Pablo Elpidio Garcı´a-Granja, MD, Instituto de Ciencias del Corazo´n (ICICOR), Hospital Clı´nico Universitario, C/ Ramo´n y Cajal 3, 47005 Valladolid, Espan˜a (e-mail: [email protected]). The authors have no conflicts of interest to disclose. Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved. This is an open access article distributed under the Creative Commons Attribution- NonCommercial License, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be used commercially. ISSN: 0025-7974 DOI: 10.1097/MD.0000000000002000

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owadays, the causative microorganism is identified in roughly 90% of the episodes of infectious endocarditis (IE).1 The isolation of more than one microorganism in patients with IE is quite uncommon, ranging from 1% to 6.8%.2,3 Theoretically, polymicrobial infective diseases are associated with a worse clinical course and prognosis than monomicrobial diseases.4–6 In the case of IE, this hypothesis remains unsettled, because scanty information is available in the literature. Besides, no comparison between polymicrobial endocarditis (PE) and monomicrobial endocarditis (ME) has been undertaken. Our purpose has been to analyze the clinical, microbiologic, and echocardiographic profile and the outcomes of patients with left-sided PE. We also aimed to compare them with that of patients with ME to establish whether the isolation of more than one pathogen is related to worse prognosis.

METHODS Study Population Since January 1, 1996 to December 31, 2014, all patients with a final diagnosis of IE admitted in three tertiary centers were included in an ongoing multipurpose database. We used the Duke criteria until 20027 and the modified Duke criteria8 thereafter. All participant hospitals followed a standardized protocol, in which every patient underwent at least 1 physical examination, electrocardiogram, blood analysis, urine analysis, set of 3 blood cultures, and transthoracic and transesophageal echocardiography. We filled a standardized case report form with 26 epidemiological, 72 clinical, 26 laboratory, 6 electrocardiographic, 27 microbiologic, and 68 echocardiographic variables for every patient. The protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the local ethical committees. To establish the causative microorganism of each episode of IE, we combined both the information of the blood cultures and that obtained from the cultures of biologic infective tissues (ie, explanted valves or prosthesis, embolic material, etc). Patients were divided into 3 groups depending on the number of causative microorganims: PE (2 or more microorganims); ME (one); and unknown microorganism (zero). Patients in whom coagulase-negative Staphylococci or other common skin contaminants grew up in the cultures of a biologic infected tissue and not in the blood cultures were excluded from the analysis because contamination could not be ruled out. The main characteristics of PE were compared with those of ME.

Definition of Terms The episode of endocarditis was considered polymicrobial when 2 or more microorganims were cultured in at least 3 blood samples or isolated from infected tissues simultaneously or www.md-journal.com |

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consecutively within 7 days of the initial positive blood culture without evidence of other clinical infectious foci. Antibiotic treatment and indications of surgery followed the recommendations of the current European guidelines in every moment throughout the study period. Urgent surgery was defined as that performed before the finalization of the antibiotic treatment. If the signs and symptoms of the IE started after 48 hours from the hospital admission or in the first 3 days after discharge or up to 30 days after an operation, the episode was considered as nosocomial. We have analyzed possible predisposing events as situations with theoretical risk of bacteremia occurring within the previous 2 months of the beginning of the disease. Chronic renal disease was defined as a decrease of glomerular filtration rate below 60 ml/min/1.73 m2 for at least 3 months. Early prosthetic valve endocarditis was defined as occurring less than 1 year after surgery.9 Other definitions used in this study have been already described in previous works.10

Statistics Categorical variables are reported as frequency (n) and percentages. Continuous variables as mean  standard deviation or median and interquartile range (IQR). Normal distribution of quantitative variables was verified with the Kolmogorov– Smirnov test. Qualitative variables were compared with the x2 test and Fisher exact test. Continuous variables were compared with Student t test or its equivalent for nonparametric tests, Mann–Whitney U test, for variables that were not normally distributed. Data were analyzed using the SPSS V 15.0 software package (SPSS, Chicago, IL).

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(n ¼ 23; 41%). During hospitalization 60% developed heart failure, 45% renal failure, 28% persistent infection, 20% stroke, and 13% cardiogenic shock. Polymicrobial endocarditis affected native valves in 30 patients (19 mitral, 16 aortic) and prostheses in 30 (16 mechanical mitral prostheses, 8 mechanical aortic, 5 aortic bioprostheses, and 3 mitral bioprostheses). Early-onset prosthetic valve endocarditis occurred in 11 patients (37%) and late onset in 19 patients (63%). There were 12 multivalvular episodes. Transesophageal echocardiograms revealed valvular vegetations in 48 patients (80%) (diameter 18.4  35  7.3  4.1 mm; area 0.40  0.6 cm2), at least one periannular complication in 13 (22%) (5 abscesses, 8 pseudoaneurysms, and 2 fistulas), and moderate or severe valvular regurgitation in 40 (67%).

Microbiologic Profile of Polymicrobial Endocarditis The diagnosis of PE was performed according to the results of blood cultures or serology in 36 patients (60%), with cultures of biologic infected tissues in 7 (12%) and with the combination of both in 17 (28%). Three microorganisms were isolated in 6 patients and 2 in the rest. Coagulase-negative staphylococci, enterococci, Gram-negative bacilli and Staphylococcus aureus were the predominant pathogens. The microbiologic profile of PE is represented in Figure 1. The most frequent combinations of microorganims were: coagulase-negative Staphylococci plus enterococci (n ¼ 9, 15%), coagulase-negative Staphylococci plus Gram-negative bacilli (n ¼ 5, 8%) and coagulase-negative Staphylococci plus Streptococcus viridans (n ¼ 5, 8%). A total of 60% of staphylococcal strains were methicillin resistant and there were no streptocococcal strains resistant to penicillin.

Epidemiological Features of Polymicrobial Endocarditis

Treatment and Outcome of Polymicrobial Endocarditis

From January 1, 1996 to December 31, 2014, 1195 episodes of definite IE were diagnosed. Of them, 1011 were leftsided (85%) and formed our study group: 60 were polymicrobial (5.9%), 821 monomicrobial (81.2%), and in 123 patients no microorganism was detected (12.1%). Seven patients (0.7%) were excluded from the analysis because contamination of biologic tissue could not be discarded. Mean age was 64 years, SD 16 years (IQR: 57–75) and 40 were men (67%). The infection was nosocomial in 18 patients (30%). Of the remaining 42, 34 episodes were community acquired (57%) and 8 healthcare associated (13%). There were 53 patients with previous known cardiac abnormalities (90%): 30 (50%) had prosthetic valves, 12 (20%) degenerative, 5 (8%) rheumatic valvular heart disease, 2 (3%) congenital abnormalities, and 4 (7%) left-ventricular hypertrophy. Previous IE had occurred in 5 patients (8%). The spectrum of predisposing conditions was as follows: 10 (17%) indwelling intravenous catheters, 9 (15%) previous cardiac surgery, 7 (12%) local infections, 4 (7%) urogenital manipulations, and 3 (5%) dental manipulations. Only 1 patient was intravenous drug user. Finally, 42 patients (70%) had underlying conditions, being diabetes mellitus (35%), and chronic renal failure (17%) the most frequent. Just 1 patient was HIV positive.

Surgery was performed in 39 patients (65%): urgent in 19 (49%) and elective in 20 (51%). The main indications for urgent surgery were severe valvular dysfunction (45%), heart failure (42%) and persistent infection (42%). Patients received 3.1  0.8 antibiotics for a median of 10  5.7 weeks. Distribution of antibiotics was as follows: glycopeptides (65%), aminoglycosides (60%), penicillins (53%), cephalosporins (25%), carbapenems (10%), and fluoroquinolones (8%). Hospital stay was 49  30 days and total in-hospital mortality 33% (n ¼ 20). Principal causes of death were: uncontrolled infection (25%), heart failure (20%), and hemodynamic instability during extracorporeal circulation (20%).

Clinical and Echocardiographic Profile of Polymicrobial Endocarditis Time of evolution of symptoms to diagnosis was 46 days (IQR 7–61). The most frequent initial symptoms at admission were fever (n ¼ 40; 67%), dyspnea (n ¼ 27; 48%), and shivering

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En te CN r S Vi oco rid cc i an sG S G S. NB A ur A eus ae ro be s Fu n g S O . Bo i th v er i St s re H pt A CE K O th er s

60% 50% 40% 30% 20% 10% 0%

CNS = coagulase negative Staphylococci, GNB = Gram-negative bacilli, S. aureus = Staphylococus aureus, Viridans GS = Viridans group streptococci.

FIGURE 1. Microbiologic profile of the 60 episodes of polymicrobial left-sided infective endocarditis. Copyright

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2015 Wolters Kluwer Health, Inc. All rights reserved.

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Infective Endocarditis

TABLE 1. Demographic, Clinical, Echocardiographic and Outcome Differences Between Polymicrobial and Monomicrobial Endocarditis PE (n ¼ 60) Mean age, years; mean  SD Men, n (%) Origin Nosocomial, n (%) Not nosocomial Community acquired, n (%) Healthcare related, n (%) Previous Heart Disease Rheumatic valve disease, n (%) Pre-existing prosthetic valve, n (%) Degenerative valve disease, n (%) Previous endocarditis, n (%) Congenital heart disease, n (%) Predisposing Events Local infection, n (%) Intravenous catheters, n (%) Dental manipulation, n (%)  Urogenital manipulation, n (%) Previous cardiac surgery, n (%)y Previous noncardiac surgery, n (%) Intravenous drug use, n (%) Underlying disease Diabetes mellitus, n (%) Chronic renal insufficiency, n (%) Cancer, n (%) HIVz, n (%) Symptoms at Admission Time symptoms to diagnosis, days, median (IQR) New murmur, n (%) Shivering, n (%) Fever, n (%) Dyspnea, n (%) Heart failure, n (%) Renal insufficiency, n (%) Septic shock, n (%) Stroke, n (%) Cutaneous manifestations Symptoms During Hospitalization Fever, n (%) Heart failure, n (%) Renal insufficiency, n (%) Cardiogenic shock, n (%) Septic shock, n (%) Persistent infection, n (%) Stroke, n (%) Location Native, n (%) Mitral, n (%) Aortic, n (%) Prosthetic, n (%) Mechanic mitral, n (%) Mechanic aortic, n (%) Mitral bioprosthesis, n (%) Aortic bioprosthesis, n (%) Early onset, n (%) Late onset, n (%) Multivalvular Echo Findings

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2015 Wolters Kluwer Health, Inc. All rights reserved.

ME (n ¼ 821)

P

64  16 40 (67)

64  14 529 (64)

0.132 0.727

18 42 34 8

(30) (70) (81) (19)

215 606 554 52

(26) (74) (91) (9)

0.518

5 30 12 5 2

(8) (50) (20) (8) (3)

84 302 143 51 34

(10) (37) (17) (6) (4)

0.638 0.041 0.612 0.579 0.999

7 10 3 4 9 3 1 42 21 10 7 1

(12) (17) (5) (7) (15) (5) (2) (70) (35) (17) (12) (2)

97 110 47 27 62 49 25 461 192 112 86 16

(12) (13) (6) (3) (8) (6) (3) (56) (24) (14) (11) (2)

0.973 0.476 0.999 0.154 0.049 0.999 0.999 0.036 0.044 0.485 0.774 0.999

46 29 23 40 27 26 8 1 9 5

(7–61) (50) (41) (67) (48) (43) (14) (2) (15) (9)

37 371 325 591 331 324 157 58 93 82

(5–40) (46) (42) (73) (41) (40) (19) (7) (11) (10)

0.427 0.547 0.843 0.307 0.301 0.575 0.309 0.172 0.401 0.370

47 36 27 8 4 12 12

(78) (60) (45) (13) (9) (28) (20)

695 480 336 134 106 168 145

(85) (59) (41) (16) (19) (31) (18)

0.156 0.858 0.562 0.531 0.106 0.723 0.664

30 19 16 30 16 8 3 5 11 19 12

(50) (32) (27) (50) (27) (13) (5) (8) (37) (63) (20)

521 336 303 300 155 99 12 70 105 193 191

(64) (41) (37) (37) (19) (12) (2) (9) (35) (65) (23)

0.038 0.158 0.111 0.038 0.141 0.770 0.076 0.959 0.876

0.046

0.562

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PE (n ¼ 60) Vegetations, n (%) Periannular extension, n (%) Abscesses, n (%) Pseudoaneurysms, n (%) Fistulas, n (%) Moderate-severe valvular regurgitation, n (%) Antibiotic Treatment Number of antibiotics, mean  SD Duration of treatment, weeks, mean  SD Penicillins, n (%) Cephalosporins, n (%) Carbapenems, n (%) Glycopeptides, n (%) Macrolides, n (%) Aminoglycosides, n (%) Fluoroquinolones, n (%) Outcome Need of surgery, n (%) Urgent, n (%) Elective, n (%) In hospital mortality, n (%)

48 13 5 8 2 40



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ME (n ¼ 821)

(80) (22) (8) (13) (3) (67)

723 231 130 129 30 573

P

(88) (28) (16) (16) (4) (70)

0.055 0.273 0.117 0.616 0.999 0.582

3.1  0.8 10  6 32 (53) 15 (25) 6 (10) 39 (65) 0 (0) 48 (60) 5 (8)

2.7  1 97 428 (52) 218 (27) 69 (8) 378 (46) 8 (1) 590 (72) 33 (4)

0.002 0.178 0.857 0.792 0.669 0.005 0.999 0.581 0.174

39 19 20 20

487 270 217 244

0.392 0.417

(65) (49) (51) (33)

(59) (55) (45) (30)

0.611



Urogenital manipulation: transurethral prostate resections (n ¼ 2), endoscopic lithotripsy (n ¼ 1), cystoscopy (n ¼ 1). Local infections: chronic infections of the sternotomy (n ¼ 4), infections of the pacemaker?s bag (n ¼ 2), persistent cutaneous infection after removing a chemotherapy catheter (n ¼ 1). z HIV ¼ human immunodeficiency virus. y

Comparison Between Polymicrobial and Monomicrobial Endocarditis

Demographic, clinical, echocardiographic, and outcome differences between PE and ME are depicted in Table 1. Polymicrobial endocarditis appeared more frequently in patients with underlying diseases (70% versus 56%, P ¼ 0.04), more often in diabetics (35% versus 24%, P ¼ 0.04). It was more frequently prosthetic (50% versus 37%, P ¼ 0.04), and healthcare related

(19% versus 9%, P ¼ 0.046). No differences in other echocardiographic findings were found. Coagulase-negative Staphylococci, enterococci, Gram-negative bacilli, anaerobes, and fungi were more frequent in PE (Table 2). Among Staphylococcal species, methicillin resistance was more frequent (60% versus 39%, P ¼ 0.028) in PE. The number of antibiotics prescribed (3.1  0.8 versus 2.7  1, P ¼ 0.002) and the use of glycopeptides (65% versus 46%, P ¼ 0.005) were also higher in PE, but the

TABLE 2. Comparison of the Microbiologic Profile Between Polymicrobial and Monomicrobial Endocarditis

Number of microorganisms Coagulase-negative Staphylococci, n (%) Enterococci, n (%)  Gram-negative bacilli, n (%) Viridans group streptococci, n (%) Staphylococcus aureus, n (%) y Anaerobes, n (%) Fungi, n (%) Other Streptococci, n (%) Streptococcus bovis, n (%) HACEK, n (%) z Others, n (%) Methicillin resistant Staphylococcal spp, n (%) Penicillin resistant Streptococcal spp, n (%)

PE

ME

P

126 29 (48) 22 (37) 15 (25) 16 (27) 14 (23) 11 (18) 5 (8) 3 (5) 3 (5) 2 (3) 6 (10) 18 (60) 0 (0)

821 166 (20) 109 (13) 35 (4) 131 (16) 187 (23) 19 (2) 16 (2) 67 (8) 49 (6) 5 (1) 37 (5) 131 (39) 2 (3)

Polymicrobial Infective Endocarditis: Clinical Features and Prognosis.

To describe the profile of left-sided polymicrobial endocarditis (PE) and to compare it with monomicrobial endocarditis (ME).Among 1011 episodes of le...
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