QJM Advance Access published September 29, 2014 Q J Med doi:10.1093/qjmed/hcu188
Advance Access Publication 15 September 2014
Clinical features, microbiology and surgical outcomes of infective endocarditis: a 13-year study from a UK tertiary cardiothoracic referral centre D.J.B. MARKS1, C. HYAMS1, C.Y. KOO1, M. PAVLOU2, J. ROBBINS1, C.S. KOO1, G. RODGER3, J.F. HUGGETT3, J. YAP4, M.B. MACRAE5, R.H. SWANTON6, A.I. ZUMLA3,5,7 and R.F. MILLER2 From the 1Department of Medicine, 2Research Department of Infection and Population Health, Institute of Epidemiology and Healthcare, 3Research Department of Infection, Division of Infection and Immunity, University College London, London, UK, 4Department of Cardiothoracic Surgery, Heart Hospital, London, UK, 5Department of Clinical Microbiology, University College London Hospitals NHS Foundation Trust, London, UK, 6Department of Cardiology, The Heart Hospital, London, UK and 7National Institute of Health Research, Biomedical Research Centre, University College London Hospital, London, UK Address correspondence to Dr D.J.B. Marks, Centre for Molecular Medicine, Rayne Institute, 5 University Street, University College London, London WC1E 6JJ, UK. email: [email protected] Received 29 May 2014 and in revised form 26 August 2014
Summary Background: Infective endocarditis (IE) causes substantial morbidity and mortality. Patient and pathogen profiles, as well as microbiological and operative strategies, continue to evolve. The impact of these changes requires evaluation to inform optimum management and identify individuals at high risk of early mortality. Aim: Identification of clinical and microbiological features, and surgical outcomes, among patients presenting to a UK tertiary cardiothoracic centre for surgical management of IE between 1998 and 2010. Design: Retrospective observational cohort study. Methods: Clinical, biochemical, microbiological and echocardiographic data were identified from clinical records. Principal outcomes were all-cause 28-day mortality and duration of post-operative admission. Results: Patients (n = 336) were predominantly male (75.0%); median age 52 years (IQR = 41–67). Most cases involved the aortic (56.0%) or mitral (53.9%) valves. Microbiological diagnoses, obtained in 288 (85.7%) patients, included streptococci
(45.2%); staphylococci (34.5%); Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella (HACEK) organisms (3.0%); and fungi (1.8%); 11.3% had polymicrobial infection. Valve replacement in 308 (91.7%) patients included mechanical prostheses (69.8%), xenografts (24.0%) and homografts (6.2%). Early mortality was 12.2%, but fell progressively during the study (P = 0.02), as did median duration of post-operative admission (33.5 to 10.5 days; P = 0.0003). Multivariable analysis showed previous cardiothoracic surgery (OR = 3.85, P = 0.03), neutrophil count (OR = 2.27, P = 0.05), albumin (OR = 0.94, P = 0.04) and urea (OR = 2.63, P < 0.001) predicted early mortality. Conclusions: This study demonstrates reduced post-operative early mortality and duration of hospital admission for IE patients over the past 13 years. Biomarkers (previous cardiothoracic surgery, neutrophil count, albumin and urea), predictive of early post-operative mortality, require prospective evaluation to refine algorithms, further improve outcomes and reduce healthcare costs associated with IE.
! The Author 2014. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: [email protected] Page 1 of 11
D.J.B. Marks et al.
Introduction Infective endocarditis (IE) remains an important clinical challenge, with an incidence of 1.7–10/100,000 person years.1–3 Despite advances in antimicrobial strategies and surgical techniques, it still causes substantial morbidity and in-hospital mortality approaches 16%. This may reflect the evolving patient profile, as mean age has risen by 30–40 years since the pre-antibiotic era. Use of prosthetic valves, other implantable cardiac devices and haemodialysis have grown, and while cases attributable to rheumatic heart disease have declined those associated with intravenous drug misuse have increased.4,5 These factors potentially confer susceptibility to a different spectrum of pathogens. Staphylococci and oral streptococci account for most IE affecting native valves.1 Staphylococci are the pathogens predominantly encountered in early prosthetic valve IE,6 Streptococcus bovis is more prevalent in elderly patients (mirroring rates of lower gastrointestinal pathology) and enterococci (although principally associated with communityacquired IE) are increasingly described in nosocomial infections.7 Treatment of IE requires prolonged courses of antibiotics,8 sometimes accompanied by operative intervention.9 Surgery, ranging from vegetectomy with valve repair to radical valve replacement, is required in 25–30% of acute IE and in an additional 20–40% of cases long-term.10,11 Principal indications are refractory cardiac failure due to valvular insufficiency, persistent sepsis with a surgically removable focus and on-going life-threatening embolism. Surgical mortality rates are 8–16%,3,12,13 hence there is a need for prompt recognition of patients at high risk of early mortality or likely to require protracted hospital admission. Current prognostic scoring systems are not specifically designed for IE.14–16 Furthermore, increasing uptake of outpatient parenteral antibiotic services means that identification of variables characterising patients as safe for ambulatory management would prove valuable. We aimed to identify the clinical characteristics, risk factors, microbial aetiology, operative management and outcomes, and predictors of early mortality, of patients with IE referred for surgical management to a UK tertiary cardiothoracic centre, to guide improved management strategies and cost-effective service delivery.
Methods We performed a systematic retrospective observational study of all patients with IE referred for
cardiothoracic surgery to the Heart Hospital, London, over a 13-year period (1998–2010). The Heart Hospital is a 95-bedded tertiary cardiac hospital in central London, UK. Over 1000 cardiac operations are performed each year. Patients with IE who are being considered for surgery are referred from surrounding hospitals in North Central London and the Home Counties (Bedfordshire, Berkshire and Northamptonshire). Only patients >18 years old are treated at this centre. Patients were identified from a database, into which their data had been entered prospectively, and by screening the hospital electronic Clinical Data Repository. Case definition used the modified Duke criteria;17 for those not fulfilling these positive evidence of active endocarditis at operation or on histology of explanted valves was required. Patients were excluded if they were found to have an alternative diagnosis, or the database entry was a duplicate or readmission for the same episode of IE. Patient demographic data, clinical characteristics, laboratory investigations (haematological, biochemical, microbiological, virological and histopathological), echocardiography results and antibiotic use were recorded. Regarding risk factors, long-term intravascular access devices were defined as indwelling tunnelled or subcutaneous port central venous catheters, and presumed possible sources of infection if present at symptom onset. Microbiological data comprised results from blood cultures, cultures of heart valves, specific fungal cultures, serology for classically culture-negative organisms and nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA). Bacterial and fungal identifications were determined using the Vitek-1 (1998–2001; BioMe´rieux, France), Vitek 2 (2001–2010; BioMe´rieux, France) and API (2001– 2010; BioMe´rieux, France) automated systems, with occasional referrals to reference laboratories. All organisms were identified to species level. Antibiotic susceptibility testing of organisms identified on blood culture was initially by BSAC methods, followed by use of Vitek2 set to EUCAST breakpoints; organisms grown from valves were tested directly on Vitek2. In 50 patients between 2007 and 2009, heart valves (including vegetations and prosthetic valves) from operations were examined using 16S rRNA qPCR. This was performed as part of a research study, enrolling consecutive patients referred for surgical management of IE, if informed consent was provided. Tissue was sectioned under aseptic conditions into 10 mm2 pieces, and stored at 808C in RNAlater solution (Sigma, UK). Nucleic acids were extracted using the NucliSens Basic Kit (BioMe´rieux, The Netherlands). Extracts (0.05 ml) were analysed as Page 2 of 11
Outcomes of infective endocarditis previously described,26 using the PyroMark Q96 ID pyrosequencer (Biotage, Uppsala, Sweden; primer sequences in Supplementary Table S1). Organisms were identified by comparing sequences using the nucleotide BLAST database: ‘nucleotide collection (nr/nt),’ organism ‘bacteria (taxid: 2)’ (http://blast. ncbi.nlm.nih.gov). Surgical intervention used for management of IE was based on American Heart Association guidelines and included: haemodynamic instability, failed medical therapy, vegetation >1.5 cm or evidence of vegetation embolic event.9 Antibiotics administered for surgical prophylaxis in IE before valve repair or replacement were flucloxacillin and gentamicin, or teicoplanin and gentamicin in penicillin-allergic patients or those with MRSA. Patients routinely received antibiotics for a minimum of 4 weeks for native valve IE, and 6 weeks for prosthetic valve IE; extension of therapy beyond these times was considered for any patient with persistent fever or C-reactive protein (CRP) >10 mg/dl.
logistic regression; in distributions demonstrating skewness, loge transformed values were used. Univariable and multivariable analyses were performed. In view of the low event frequency of mortality, a multivariable model was fitted, restricted to four factors selected based on clinical relevance and significance in univariable analyses.
Results Case identification and demographics Database screens initially identified 373 cases of IE. Of these, 37 met exclusion criteria, leaving 336 patients in the study. Table 1 shows demographic and microbiological characteristics of confirmed cases. Patients were predominantly male [75.0%, P < 0.0001, odds ratio (OR) = 3.00, 95% confidence interval (CI) = 2.16–4.16], with median age of 52 years (IQR = 41–67).
Site of infection IRB/Ethics statement Clinical data were analysed anonymously, using publically available secondary data and therefore no ethics statement was required for this work. The 16S rRNA PCR studies were approved by the Joint South London and Maudsley and the Institute of Psychiatry NHS Research Ethics Committee, project number 09/H0807/34; written informed consent was obtained from all participants included in this part of the study.
Statistical analysis Analyses were conducted using GraphPad Prism v4.01 (GraphPad Software Inc., San Diego, USA) and STATA Version 12 (StataCorp LP, TX, USA). All-cause 28-day mortality was the primary outcome. Duration of post-operative hospital admission (defined as length of stay from operation to discharge from the Heart Hospital) was the secondary outcome. Outcomes were ascertained using the hospital electronic database, which accurately records dates of death (both in the hospital and in the community) as well as dates of hospital admission; there were no missing data for these outcomes. Comparisons between survivors and non-survivors were assessed using the Mann–Whitney U-test or one-way analysis of variance with Bonferroni posttests for continuous data, and two-tailed Fisher’s exact test or 2 test for event frequencies, as appropriate. A P < 0.05 was considered significant. Probability of 28-day mortality was modelled using
Single valves were affected in 253 (75.3%) patients, 79 (23.5%) had multiple valve involvement, two had infection solely affecting the aortic root, and individual patients had IE involving atrial and ventricular septal defects, respectively. The aortic valve was involved in 188 (56.0%) patients, in whom 15 (8.0%) had aortic root complications. The mitral valve was affected in 181 (53.9%), tricuspid valve in 34 (10.1%) and pulmonary valve in 17 (5.1%) patients. Mechanical valves were infected in 44 (13.1%), and implanted tissue valves in 26 (7.7%), cases. The dominant haemodynamic abnormality was valvular regurgitation in 288 (93.5%) patients with valvular lesions; seven (2.3%) had stenotic and 15 (4.9%) mixed pathology.
Microbiology findings: diagnostics Positive cultures were obtained in 280 (83.3%) patients: from peripheral blood in 249 (74.1%) and explanted heart valves in 132 (39.3%). Specific fungal cultures, performed in 39 (11.6%) patients, were positive in three (in whom they contributed to diagnosis and management). Relevant serology, tested in 18 (5.4%) patients, was positive (Coxiella) in one. 16S rRNA qPCR was positive in 39 (78.0%) of 50 cases, and identified an organism not demonstrated by other means in 11 (22.0%). Organisms identified included: five streptococcal species, two S. aureus, and in individual cases Enterococcus, Bartonella, Cardiobacter and Aggregatibacter. Among the 11 culture-negative cases during the period of 16S rRNA testing, the latter detected a Page 3 of 11
D.J.B. Marks et al. Table 1 Microbiological characteristics of IE. IQR, interquartile range
Streptococci a-Haemolytic streptococci S. pneumoniae S. bovis Other streptococci Enterococci Staphylococci MSSA MRSA CNS Anaerobes Enterobacteriaceae HACEK Coxiella burnetii Other bacteria Fungi Polymicrobial No organism identified
n (%)
Age (years) (median, IQR)
Male (%)
152 77 12 10 21 32 116 62 2 52 8 3 10 1 32 6 38 49
55 57 45 66 44 60 48 46 42 49 40 41 43 80 47 61 44 53
121 62 11 8 15 25 83 49 2 37 6 2 5 1 22 3 25 30
(45.2%) (22.9%) (3.6%) (3.0%) (6.3%) (9.5%) (34.5%) (18.5%) (0.6%) (15.5%) (2.4%) (0.9%) (3.0%) (0.3%) (9.5%) (1.8%) (11.3%) (14.6%)
(43–69) (46–71) (33–60) (52–74) (36–54) (49–70) (37–63) (37–53) (37–47) (37–69) (40–57) (32–45) (36–56) (34–56) (43–70) (32–57) (35.25–63)
(79.6%) (80.5%) (91.7%) (80.0%) (71.4%) (78.1%) (71.6%) (79.0%) (100.0%) (71.2%) (75.0%) (66.7%) (50.0%) (100.0%) (68.8%) (50.0%) (65.8%) (61.2%)
pathogen in five (41.7%) patients. Nasal carriage of MRSA was detected in 20 (6.0%) patients. Overall, microbiological diagnosis was achieved in 288 (85.7%) patients. No differences in microbial aetiology were seen over the course of the study.
likely to be polymicrobial (P = 0.0005, OR = 7.58, 95% CI = 2.71–21.18).
Microbiology findings: relationship to demographics
Streptococcal infections were more common in patients with native valve IE (P < 0.0001, OR = 4.07, 95% CI = 2.22–7.47), and staphylococcal infections with mechanical valves (P = 0.01, OR = 2.23, 95% CI = 1.20–4.15). Bacteria other than streptococci and staphylococci were more prevalent in bioprosthetic valve IE (P = 0.0007, OR = 4.20, 95% CI = 1.92–9.19).
Patients with staphylococcal infections were younger than those with streptococci (P = 0.006), and among the latter those with ‘other’ streptococci were younger than patients with a-haemolytic organisms (P = 0.007), S. bovis (P = 0.004) and enterococci (P = 0.0006). Patients were more likely to be male with a-haemolytic streptococci (P < 0.0001, OR = 4.13, 95% CI = 2.01–8.50), enterococcus (P = 0.04, OR = 3.57, 95% CI = 1.20–10.60), methicillin-sensitive S. aureus (MSSA; P = 0.001, OR = 3.77, 95% CI = 1.71–8.29) and coagulasenegative staphylococci (CNS; P = 0.04, OR = 2.47, 95% CI = 1.09–5.58) infections.
Microbiology findings: relationship to site of infection Microbiological subclasses varied according to valve involvement (2 = 27.74, P = 0.006; Table 2), with staphylococci more common in tricuspid valve IE (P = 0.04, OR = 2.39, 95% CI = 1.05–5.43); bacteria other than streptococci and staphylococci in pulmonary valve IE (P = 0.0004, OR = 4.89, 95% CI = 2.14–11.17); and pulmonary valve IE more
Microbiology findings: relationship to valve type
Predisposing risk factors The relationship between individual risk factors for IE and infection with various microbial subgroups was assessed. Overall, there was variation across microbial subgroups in patients who had undergone previous valve replacement (2 = 9.59, P = 0.008), valve repair (2 = 6.78, P = 0.03) or other cardiac surgery (2 = 6.16, P = 0.05). Individual categories achieving significance included under-representation of streptococci in patients with previous valve replacement (OR = 0.38, 95% CI = 0.19–0.78, P = 0.009) or previous IE (OR = 0.42, 95% CI = 0.19–0.93, P = 0.05); and over-representation of staphylococci in patients with cellulitis (OR = 3.60, 95% CI = 1.14–11.35, P = 0.05). No significant variation was observed in patients with congenital heart disease, previous rheumatic fever, Page 4 of 11
Outcomes of infective endocarditis Table 2 Valve involvement by microbiological subgroup Affected valve
Streptococci a-Haemolytic streptococci S. pneumoniae S. bovis Other streptococci Enterococci Staphylococci MSSA MRSA CNS Anaerobes Enterobacteriaceae HACEK Coxiella burnetii Other bacteria Fungi Polymicrobial No organism identified
Nature of affected valve
Aortic (n = 188)
Mitral (n = 181)
Tricuspid (n = 34)
Pulmonary (n = 17)
Native (n = 262)
92 (49.2%) 45 (24.1%)
84 (46.1%) 46 (25.4%)
10 (29.4%) 5 (14.7%)
9 (52.9%) 6 (35.3%)
132 (50.4%) 69 (26.3%)
8 6 12 21 65 34 1 30 5 1 3 1 20 3 21 21
5 6 8 19 54 26 1 27 1 2 5 0 17 4 16 30
2 0 1 2 16 10 0 6 1 1 0 0 4 0 4 6
1 0 1 1 5 2 0 3 2 1 3 0 5 0 7 1
(4.3%) (3.2%) (6.4%) (11.2%) (34.6%) (18.2%) (0.5%) (16.0%) (2.7%) (0.5%) (1.6%) (0.5%) (10.7%) (1.6%) (11.2%) (11.2%)
(2.8%) (3.3%) (4.4%) (10.5%) (29.8%) (14.4%) (0.6%) (14.9%) (0.6%) (1.1%) (2.8%) (0.0%) (9.4%) (2.2%) (8.8%) (16.6%)
(5.9%) (0.0%) (2.9%) (5.9%) (47.1%) (29.4%) (0.0%) (17.6%) (2.9%) (2.9%) (0.0%) (0.0%) (11.8%) (0.0%) (11.8%) (17.6%)
(5.9%) (0.0%) (5.9%) (5.9%) (29.4%) (11.8%) (0.0%) (17.6%) (11.8%) (5.9%) (17.6%) (0.0%) (29.4%) (0.0%) (41.2%) (5.9%)
11 9 17 26 78 47 1 30 2 1 8 1 21 1 24 36
(4.2%) (3.4%) (6.5%) (9.9%) (29.8%) (17.9%) (0.4%) (11.5%) (0.8%) (0.4%) (3.1%) (0.4%) (8.0%) (0.4%) (9.2%) (13.7%)
Bioprosthetic (n = 26)
Mechanical (n = 44)
8 (30.8%) 4 (15.4%)
9 (20.5%) 4 (9.1%)
1 1 1 1 10 2 0 8 3 1 2 0 7 2 8 3
(3.8%) (3.8%) (3.8%) (3.8%) (38.5%) (7.7%) (0.0%) (30.8%) (11.5%) (3.8%) (7.7%) (0.0%) (26.9%) (7.7%) (30.8%) (11.5%)
0 0 1 4 23 10 1 13 3 1 0 0 3 3 6 7
(0.0%) (0.0%) (2.3%) (9.1%) (52.3%) (22.7%) (2.3%) (29.5%) (6.8%) (2.3%) (0.0%) (0.0%) (6.8%) (6.8%) (13.6%) (15.9%)
intercurrent central venous access, permanent cardiac pacemaker, dialysis, diabetes mellitus, immunosuppression (HIV infection, medication-induced, or congenital), dental problems (defined as recent dental work, dental infection or documented poor dentition), intravenous drug misuse, homelessness, alcohol misuse, malnutrition or those who were current smokers. Congenital cardiac lesions included: bicuspid aortic valve (n = 36), atrial or ventricular septal defect (n = 9), tetralogy of Fallot (n = 5), congenital aortic stenosis (n = 3), patent ductus arteriosus (n = 2), other valve lesions (n = 2) or multiple complex lesions (n = 3). HIV infection was known in four individuals, with CD4 counts from 440 to 600/mm3; screening was not routinely performed. A single patient had received cytotoxic chemotherapy for acute myeloid leukaemia; blood cultures grew Corynebacterium macginleyi. Three patients were immunocompromised due to splenectomy (n = 2), or to combined cellular and humoral primary immunodeficiency (n = 1).
Heart Hospital for 151 (44.9%) patients, from either transthoracic (n = 107, 70.9%) or transoesophageal (n = 44, 29.1%) studies. The mean ( standard deviation) left ventricular ejection fraction was 60.1 12.9% and aortic root diameter was 3.29 0.49 cm. Abscesses were present in 17 (5.1%), aneurysms in three (1.0%), pseudoaneurysms in five (1.7%), valve perforations in 11 (3.7%) and fistulae in five (1.7%) patients.
Echocardiographic findings
Cumulative mortality was 3.0% within 24 h, 7.4% at 7 days and 12.2% at 28 days. The latter fell across the study (2 = 23.70, P = 0.02), being higher in the first 4 years (23.3%) compared with the second (7.9%, OR = 0.28, 95% CI = 0.12–0.68, P = 0.004) and third tertiles (8.8%, OR = 0.32, 95% CI = 0.15–
All patients underwent echocardiography for diagnosis of IE, although for most this was undertaken at the referring hospital. Indices were available from pre-operative echocardiograms performed at the
Surgical intervention Surgery included valve replacements in 308 (91.7%), and repair with vegetectomy in a further 25 (7.4%), patients. Three patients referred for surgery were ultimately treated with antibiotics alone. Of the valve replacements, 215 (69.8%) were mechanical, 74 (24.0%) xenografts and 19 (6.2%) homografts. There was no difference over time in the proportions of implant type used (Figure 1). Reoperation was required in 15 (4.9%) individuals.
Early post-operative mortality
Page 5 of 11
D.J.B. Marks et al. Homograft
100%
Xenograft
% Valve Implantations
Mechanical 80%
60%
40%
20%
0% 1998
1999
2000
2001
2002
2003
2004 Year
2005
2006
2007
2008
2009
2010
Figure 1. Valve implantation over the course of the study.
0.68, P = 0.003). Mortality did not vary with patient age, type of valve surgery, implant type, microbiological subclass or antimicrobial therapy.
Post-operative hospital admission and readmissions The median duration of post-operative hospital admission was 21 days (IQR = 10–35), and did not differ between valve replacements and repairs. This fell over the course of the study (P = 0.01), with a median of 33.5 (IQR = 21–43.25) days in the first year and 10.5 (IQR = 8–13) in the final year (P = 0.0003). There was variation across microbiological subgroups (P = 0.002), with longer admissions being associated with staphylococcal infections (median 31 days, IQR = 18–42, P = 0.01; compared to non-staphylococcal infections), and trends towards longer admission not achieving significance in anaerobic and other bacterial, fungal and polymicrobial infections (Figure 2). Data on duration of post-operative Intensive Care admissions were not systematically available. Readmission rates to the Heart Hospital were 0.6% (two patients) at 28 days, and 13.7% (46 patients) at 1 year; of these 7 (2.1%) required reoperation for IE.
Intravenous drug users Of particular interest were patients with IE secondary to intravenous drug misuse. Long-term outcomes of this group are described (Table 3); follow-up was to the end of the study. Among these 26 patients, median age was 33 years (IQR 29.25–41.75), and 24 (92.3%) were male. The 28-day mortality was comparable to the rest of the cohort as was mortality over the course of the study (34.6% among
intravenous drug users compared with 24.5% in other IE patients; P = 0.25); nine individuals died during longer term follow-up. Of the 17 survivors, nine had chronic infection with hepatitis C, three had recurrent IE, two continued to misuse intravenous drugs, and two defaulted long-term outpatient surveillance. Only one individual was HIV-infected at presentation with IE.
Biomarkers of early post-operative mortality Univariable predictors of mortality are shown in Table 4. Of the echocardiographic parameters recorded, only peak velocity across the aortic valve was significantly different in patients with early post-operative death compared to survivors (3.15 and 2.02 ms 1, respectively; P = 0.03). A multivariable model was subsequently developed for ascertaining associations with mortality. Final parameters included neutrophil count (OR = 2.27 per 1 unit increase in log10 value, 95% CI = 1.01–5.00, P = 0.05), albumin (OR = 0.94, 95% CI = 0.88–1.00, P = 0.04), urea (OR = 2.63, 95% CI = 1.35–5.00, P < 0.001) and previous cardiothoracic surgery (OR = 3.85, 95% CI = 1.15–12.50, P = 0.03).
Discussion This large single centre case series from a tertiary cardiothoracic referral hospital demonstrates that IE remains an important cause of morbidity, mortality and hospital admission. It builds upon a previous study from our centre published a decade ago.18 The results highlight a number of clinically important observations. First, there has been no Page 6 of 11
UQR = 126
45
**
40 35 30 25 20 15 10 5
No Organism Identified
Polymicrobial
Fungi
Other
HACEK
Enterobacteriaceae
Anaerobes
Staphylococci
0 Streptococci
Duration of Hospital Admission (Days)
Outcomes of infective endocarditis
Microbiological Category
Figure 2. Duration of post-operative hospital admission across microbiological subgroups. **P < 0.01.
perceptible shift in the distribution of causative organisms in our cohort since radical changes to guidelines for antibiotic prophylaxis, consistent with findings from Europe19 and the USA.20 Second, despite advances in sampling and culture techniques, microbiological diagnosis was not achieved in 14.3% of patients; use of 16S rRNA testing in a subset of cases did, however, identify organisms not detected by other means in 22%. Third, early mortality and duration of post-operative hospital admission fell over the study. These improvements are likely to be multifactorial. While there have been differences in case mix,18 increased surgical experience operating in IE, and changes in two members of senior surgical staff at our centre over the course of the study, the most important development occurred in 2002 when there was significant restructuring of service delivery. This resulted in consolidation of cardiothoracic services (including a dedicated specialist intensive care unit) on a single site, improved pre-operative evaluation with introduction of regular multidisciplinary meetings, and daily ward rounds by a dedicated microbiologist. The timing of this reorganisation correlates with the major improvement we observed in mortality. These factors are also likely to have impacted positively on the durations of post-operative admissions, alongside utilisation of outpatient parenteral antibiotic therapy and enhanced community rehabilitation programmes. These trends are mirrored in
the outcomes in our centre for patients managed for thoracic empyema.21 Fourth, we delineated a series of simple clinical and blood test biomarkers for early post-operative mortality, confirming and extending those from previous series.18,22–24 Finally, we report long-term outcomes from surgical intervention in intravenous drug users. Key findings included that, contrary to general perception,25 84.6% underwent operation for left-sided, and less than one-third for rightsided, IE; long-term mortality was 34.6%; and survivors had high rates of ongoing drug misuse and chronic co-morbid disease (particularly hepatitis C infection). The demographic and microbiological characteristics of our cohort are similar to those from other centres in Europe3,5,26–28 and the USA,29 supporting generalisation of our data. Most demonstrate a rise in S. aureus infections, related to increasing healthcare contacts, invasive procedures and intravenous drug use.5 In our patients, there remained a small excess of a-haemolytic streptococci over S. aureus, which may relate to differences in predisposing factors including the greater prevalence of previous IE and congenital heart disease. We detected a lower rate of aortic root complications (associated with increased surgical mortality and need for re-operation) than in our cohort reported 20 years previously.30 There was also an excess of polymicrobial infections in patients with Page 7 of 11
D.J.B. Marks et al. Table 3 Characteristics and outcomes from surgical intervention for IE among 26 injection drug users Patients
Organism
Affected valve
Implant
Outcome
1 2 3 4 5 6 7 8 9 10 11 12
MSSA MSSA MSSA MSSA MSSA MSSA CNS a-Haemolytic streptococcus Other streptococcus Other streptococcus Other streptococcus Polymicrobial (CNS, MSSA, other streptococcus) No organism isolated a-Haemolytic streptococcus CNS Other streptococcus MSSA a-Haemolytic streptococcus No organism isolated No organism isolated MSSA MSSA MSSA MSSA No organism isolated No organism isolated
AV AV AV AV AV AV AV AV AV AV AV AV
Biological Mechanical Mechanical Homograft Biological Biological Mechanical Biological Biological Mechanical Biological Biological
Died (day 14) Died (20 months) Alive Died (2 months) Alive Alive Alive Died (day 6) Died (4 years) Alive Alive Died (3 months)
AV AV, MV AV, MV, TV AV, MV, TV MV MV MV MV MV, TV MV, TV TV TV TV TV
Biological Biological Mechanical Mechanical Mechanical Biological Mechanical Mechanical Mechanical Repair Repair Repair Repair Biological
Alive Alive Alive Died (6 months) Alive Died (4 months) Alive Alive Died (day 9) Alive Alive Alive Alive Alive
13 14 15 16 17 18 19 20 21 22 23 24 25 26
AV, aortic valve; MV, mitral valve; TV, tricuspid valve.
bioprosthetic valves; this might infer a greater susceptibility to colonisation or that culture is easier from such explants. Rates of culture-negative IE were comparable to other series.31,32 16S rRNA PCR has an important role in such cases as it increases diagnostic yield for typical organisms,33 can detect nucleic acid in tissue samples (including explanted valves and peripheral emboli), and identify non-cultivable bacteria. Even when cultures are positive, the technique is still valuable to highlight true pathogens where multiple organisms are isolated from separate cultures by confirming which are detectable on explanted valves. Nonetheless, although its use during a subset of years in our study identified bacteria in a proportion of patients with culturenegative IE, the sensitivity remained limited (
Advance Access Publication 15 September 2014
Clinical features, microbiology and surgical outcomes of infective endocarditis: a 13-year study from a UK tertiary cardiothoracic referral centre D.J.B. MARKS1, C. HYAMS1, C.Y. KOO1, M. PAVLOU2, J. ROBBINS1, C.S. KOO1, G. RODGER3, J.F. HUGGETT3, J. YAP4, M.B. MACRAE5, R.H. SWANTON6, A.I. ZUMLA3,5,7 and R.F. MILLER2 From the 1Department of Medicine, 2Research Department of Infection and Population Health, Institute of Epidemiology and Healthcare, 3Research Department of Infection, Division of Infection and Immunity, University College London, London, UK, 4Department of Cardiothoracic Surgery, Heart Hospital, London, UK, 5Department of Clinical Microbiology, University College London Hospitals NHS Foundation Trust, London, UK, 6Department of Cardiology, The Heart Hospital, London, UK and 7National Institute of Health Research, Biomedical Research Centre, University College London Hospital, London, UK Address correspondence to Dr D.J.B. Marks, Centre for Molecular Medicine, Rayne Institute, 5 University Street, University College London, London WC1E 6JJ, UK. email: [email protected] Received 29 May 2014 and in revised form 26 August 2014
Summary Background: Infective endocarditis (IE) causes substantial morbidity and mortality. Patient and pathogen profiles, as well as microbiological and operative strategies, continue to evolve. The impact of these changes requires evaluation to inform optimum management and identify individuals at high risk of early mortality. Aim: Identification of clinical and microbiological features, and surgical outcomes, among patients presenting to a UK tertiary cardiothoracic centre for surgical management of IE between 1998 and 2010. Design: Retrospective observational cohort study. Methods: Clinical, biochemical, microbiological and echocardiographic data were identified from clinical records. Principal outcomes were all-cause 28-day mortality and duration of post-operative admission. Results: Patients (n = 336) were predominantly male (75.0%); median age 52 years (IQR = 41–67). Most cases involved the aortic (56.0%) or mitral (53.9%) valves. Microbiological diagnoses, obtained in 288 (85.7%) patients, included streptococci
(45.2%); staphylococci (34.5%); Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella (HACEK) organisms (3.0%); and fungi (1.8%); 11.3% had polymicrobial infection. Valve replacement in 308 (91.7%) patients included mechanical prostheses (69.8%), xenografts (24.0%) and homografts (6.2%). Early mortality was 12.2%, but fell progressively during the study (P = 0.02), as did median duration of post-operative admission (33.5 to 10.5 days; P = 0.0003). Multivariable analysis showed previous cardiothoracic surgery (OR = 3.85, P = 0.03), neutrophil count (OR = 2.27, P = 0.05), albumin (OR = 0.94, P = 0.04) and urea (OR = 2.63, P < 0.001) predicted early mortality. Conclusions: This study demonstrates reduced post-operative early mortality and duration of hospital admission for IE patients over the past 13 years. Biomarkers (previous cardiothoracic surgery, neutrophil count, albumin and urea), predictive of early post-operative mortality, require prospective evaluation to refine algorithms, further improve outcomes and reduce healthcare costs associated with IE.
! The Author 2014. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: [email protected] Page 1 of 11
D.J.B. Marks et al.
Introduction Infective endocarditis (IE) remains an important clinical challenge, with an incidence of 1.7–10/100,000 person years.1–3 Despite advances in antimicrobial strategies and surgical techniques, it still causes substantial morbidity and in-hospital mortality approaches 16%. This may reflect the evolving patient profile, as mean age has risen by 30–40 years since the pre-antibiotic era. Use of prosthetic valves, other implantable cardiac devices and haemodialysis have grown, and while cases attributable to rheumatic heart disease have declined those associated with intravenous drug misuse have increased.4,5 These factors potentially confer susceptibility to a different spectrum of pathogens. Staphylococci and oral streptococci account for most IE affecting native valves.1 Staphylococci are the pathogens predominantly encountered in early prosthetic valve IE,6 Streptococcus bovis is more prevalent in elderly patients (mirroring rates of lower gastrointestinal pathology) and enterococci (although principally associated with communityacquired IE) are increasingly described in nosocomial infections.7 Treatment of IE requires prolonged courses of antibiotics,8 sometimes accompanied by operative intervention.9 Surgery, ranging from vegetectomy with valve repair to radical valve replacement, is required in 25–30% of acute IE and in an additional 20–40% of cases long-term.10,11 Principal indications are refractory cardiac failure due to valvular insufficiency, persistent sepsis with a surgically removable focus and on-going life-threatening embolism. Surgical mortality rates are 8–16%,3,12,13 hence there is a need for prompt recognition of patients at high risk of early mortality or likely to require protracted hospital admission. Current prognostic scoring systems are not specifically designed for IE.14–16 Furthermore, increasing uptake of outpatient parenteral antibiotic services means that identification of variables characterising patients as safe for ambulatory management would prove valuable. We aimed to identify the clinical characteristics, risk factors, microbial aetiology, operative management and outcomes, and predictors of early mortality, of patients with IE referred for surgical management to a UK tertiary cardiothoracic centre, to guide improved management strategies and cost-effective service delivery.
Methods We performed a systematic retrospective observational study of all patients with IE referred for
cardiothoracic surgery to the Heart Hospital, London, over a 13-year period (1998–2010). The Heart Hospital is a 95-bedded tertiary cardiac hospital in central London, UK. Over 1000 cardiac operations are performed each year. Patients with IE who are being considered for surgery are referred from surrounding hospitals in North Central London and the Home Counties (Bedfordshire, Berkshire and Northamptonshire). Only patients >18 years old are treated at this centre. Patients were identified from a database, into which their data had been entered prospectively, and by screening the hospital electronic Clinical Data Repository. Case definition used the modified Duke criteria;17 for those not fulfilling these positive evidence of active endocarditis at operation or on histology of explanted valves was required. Patients were excluded if they were found to have an alternative diagnosis, or the database entry was a duplicate or readmission for the same episode of IE. Patient demographic data, clinical characteristics, laboratory investigations (haematological, biochemical, microbiological, virological and histopathological), echocardiography results and antibiotic use were recorded. Regarding risk factors, long-term intravascular access devices were defined as indwelling tunnelled or subcutaneous port central venous catheters, and presumed possible sources of infection if present at symptom onset. Microbiological data comprised results from blood cultures, cultures of heart valves, specific fungal cultures, serology for classically culture-negative organisms and nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA). Bacterial and fungal identifications were determined using the Vitek-1 (1998–2001; BioMe´rieux, France), Vitek 2 (2001–2010; BioMe´rieux, France) and API (2001– 2010; BioMe´rieux, France) automated systems, with occasional referrals to reference laboratories. All organisms were identified to species level. Antibiotic susceptibility testing of organisms identified on blood culture was initially by BSAC methods, followed by use of Vitek2 set to EUCAST breakpoints; organisms grown from valves were tested directly on Vitek2. In 50 patients between 2007 and 2009, heart valves (including vegetations and prosthetic valves) from operations were examined using 16S rRNA qPCR. This was performed as part of a research study, enrolling consecutive patients referred for surgical management of IE, if informed consent was provided. Tissue was sectioned under aseptic conditions into 10 mm2 pieces, and stored at 808C in RNAlater solution (Sigma, UK). Nucleic acids were extracted using the NucliSens Basic Kit (BioMe´rieux, The Netherlands). Extracts (0.05 ml) were analysed as Page 2 of 11
Outcomes of infective endocarditis previously described,26 using the PyroMark Q96 ID pyrosequencer (Biotage, Uppsala, Sweden; primer sequences in Supplementary Table S1). Organisms were identified by comparing sequences using the nucleotide BLAST database: ‘nucleotide collection (nr/nt),’ organism ‘bacteria (taxid: 2)’ (http://blast. ncbi.nlm.nih.gov). Surgical intervention used for management of IE was based on American Heart Association guidelines and included: haemodynamic instability, failed medical therapy, vegetation >1.5 cm or evidence of vegetation embolic event.9 Antibiotics administered for surgical prophylaxis in IE before valve repair or replacement were flucloxacillin and gentamicin, or teicoplanin and gentamicin in penicillin-allergic patients or those with MRSA. Patients routinely received antibiotics for a minimum of 4 weeks for native valve IE, and 6 weeks for prosthetic valve IE; extension of therapy beyond these times was considered for any patient with persistent fever or C-reactive protein (CRP) >10 mg/dl.
logistic regression; in distributions demonstrating skewness, loge transformed values were used. Univariable and multivariable analyses were performed. In view of the low event frequency of mortality, a multivariable model was fitted, restricted to four factors selected based on clinical relevance and significance in univariable analyses.
Results Case identification and demographics Database screens initially identified 373 cases of IE. Of these, 37 met exclusion criteria, leaving 336 patients in the study. Table 1 shows demographic and microbiological characteristics of confirmed cases. Patients were predominantly male [75.0%, P < 0.0001, odds ratio (OR) = 3.00, 95% confidence interval (CI) = 2.16–4.16], with median age of 52 years (IQR = 41–67).
Site of infection IRB/Ethics statement Clinical data were analysed anonymously, using publically available secondary data and therefore no ethics statement was required for this work. The 16S rRNA PCR studies were approved by the Joint South London and Maudsley and the Institute of Psychiatry NHS Research Ethics Committee, project number 09/H0807/34; written informed consent was obtained from all participants included in this part of the study.
Statistical analysis Analyses were conducted using GraphPad Prism v4.01 (GraphPad Software Inc., San Diego, USA) and STATA Version 12 (StataCorp LP, TX, USA). All-cause 28-day mortality was the primary outcome. Duration of post-operative hospital admission (defined as length of stay from operation to discharge from the Heart Hospital) was the secondary outcome. Outcomes were ascertained using the hospital electronic database, which accurately records dates of death (both in the hospital and in the community) as well as dates of hospital admission; there were no missing data for these outcomes. Comparisons between survivors and non-survivors were assessed using the Mann–Whitney U-test or one-way analysis of variance with Bonferroni posttests for continuous data, and two-tailed Fisher’s exact test or 2 test for event frequencies, as appropriate. A P < 0.05 was considered significant. Probability of 28-day mortality was modelled using
Single valves were affected in 253 (75.3%) patients, 79 (23.5%) had multiple valve involvement, two had infection solely affecting the aortic root, and individual patients had IE involving atrial and ventricular septal defects, respectively. The aortic valve was involved in 188 (56.0%) patients, in whom 15 (8.0%) had aortic root complications. The mitral valve was affected in 181 (53.9%), tricuspid valve in 34 (10.1%) and pulmonary valve in 17 (5.1%) patients. Mechanical valves were infected in 44 (13.1%), and implanted tissue valves in 26 (7.7%), cases. The dominant haemodynamic abnormality was valvular regurgitation in 288 (93.5%) patients with valvular lesions; seven (2.3%) had stenotic and 15 (4.9%) mixed pathology.
Microbiology findings: diagnostics Positive cultures were obtained in 280 (83.3%) patients: from peripheral blood in 249 (74.1%) and explanted heart valves in 132 (39.3%). Specific fungal cultures, performed in 39 (11.6%) patients, were positive in three (in whom they contributed to diagnosis and management). Relevant serology, tested in 18 (5.4%) patients, was positive (Coxiella) in one. 16S rRNA qPCR was positive in 39 (78.0%) of 50 cases, and identified an organism not demonstrated by other means in 11 (22.0%). Organisms identified included: five streptococcal species, two S. aureus, and in individual cases Enterococcus, Bartonella, Cardiobacter and Aggregatibacter. Among the 11 culture-negative cases during the period of 16S rRNA testing, the latter detected a Page 3 of 11
D.J.B. Marks et al. Table 1 Microbiological characteristics of IE. IQR, interquartile range
Streptococci a-Haemolytic streptococci S. pneumoniae S. bovis Other streptococci Enterococci Staphylococci MSSA MRSA CNS Anaerobes Enterobacteriaceae HACEK Coxiella burnetii Other bacteria Fungi Polymicrobial No organism identified
n (%)
Age (years) (median, IQR)
Male (%)
152 77 12 10 21 32 116 62 2 52 8 3 10 1 32 6 38 49
55 57 45 66 44 60 48 46 42 49 40 41 43 80 47 61 44 53
121 62 11 8 15 25 83 49 2 37 6 2 5 1 22 3 25 30
(45.2%) (22.9%) (3.6%) (3.0%) (6.3%) (9.5%) (34.5%) (18.5%) (0.6%) (15.5%) (2.4%) (0.9%) (3.0%) (0.3%) (9.5%) (1.8%) (11.3%) (14.6%)
(43–69) (46–71) (33–60) (52–74) (36–54) (49–70) (37–63) (37–53) (37–47) (37–69) (40–57) (32–45) (36–56) (34–56) (43–70) (32–57) (35.25–63)
(79.6%) (80.5%) (91.7%) (80.0%) (71.4%) (78.1%) (71.6%) (79.0%) (100.0%) (71.2%) (75.0%) (66.7%) (50.0%) (100.0%) (68.8%) (50.0%) (65.8%) (61.2%)
pathogen in five (41.7%) patients. Nasal carriage of MRSA was detected in 20 (6.0%) patients. Overall, microbiological diagnosis was achieved in 288 (85.7%) patients. No differences in microbial aetiology were seen over the course of the study.
likely to be polymicrobial (P = 0.0005, OR = 7.58, 95% CI = 2.71–21.18).
Microbiology findings: relationship to demographics
Streptococcal infections were more common in patients with native valve IE (P < 0.0001, OR = 4.07, 95% CI = 2.22–7.47), and staphylococcal infections with mechanical valves (P = 0.01, OR = 2.23, 95% CI = 1.20–4.15). Bacteria other than streptococci and staphylococci were more prevalent in bioprosthetic valve IE (P = 0.0007, OR = 4.20, 95% CI = 1.92–9.19).
Patients with staphylococcal infections were younger than those with streptococci (P = 0.006), and among the latter those with ‘other’ streptococci were younger than patients with a-haemolytic organisms (P = 0.007), S. bovis (P = 0.004) and enterococci (P = 0.0006). Patients were more likely to be male with a-haemolytic streptococci (P < 0.0001, OR = 4.13, 95% CI = 2.01–8.50), enterococcus (P = 0.04, OR = 3.57, 95% CI = 1.20–10.60), methicillin-sensitive S. aureus (MSSA; P = 0.001, OR = 3.77, 95% CI = 1.71–8.29) and coagulasenegative staphylococci (CNS; P = 0.04, OR = 2.47, 95% CI = 1.09–5.58) infections.
Microbiology findings: relationship to site of infection Microbiological subclasses varied according to valve involvement (2 = 27.74, P = 0.006; Table 2), with staphylococci more common in tricuspid valve IE (P = 0.04, OR = 2.39, 95% CI = 1.05–5.43); bacteria other than streptococci and staphylococci in pulmonary valve IE (P = 0.0004, OR = 4.89, 95% CI = 2.14–11.17); and pulmonary valve IE more
Microbiology findings: relationship to valve type
Predisposing risk factors The relationship between individual risk factors for IE and infection with various microbial subgroups was assessed. Overall, there was variation across microbial subgroups in patients who had undergone previous valve replacement (2 = 9.59, P = 0.008), valve repair (2 = 6.78, P = 0.03) or other cardiac surgery (2 = 6.16, P = 0.05). Individual categories achieving significance included under-representation of streptococci in patients with previous valve replacement (OR = 0.38, 95% CI = 0.19–0.78, P = 0.009) or previous IE (OR = 0.42, 95% CI = 0.19–0.93, P = 0.05); and over-representation of staphylococci in patients with cellulitis (OR = 3.60, 95% CI = 1.14–11.35, P = 0.05). No significant variation was observed in patients with congenital heart disease, previous rheumatic fever, Page 4 of 11
Outcomes of infective endocarditis Table 2 Valve involvement by microbiological subgroup Affected valve
Streptococci a-Haemolytic streptococci S. pneumoniae S. bovis Other streptococci Enterococci Staphylococci MSSA MRSA CNS Anaerobes Enterobacteriaceae HACEK Coxiella burnetii Other bacteria Fungi Polymicrobial No organism identified
Nature of affected valve
Aortic (n = 188)
Mitral (n = 181)
Tricuspid (n = 34)
Pulmonary (n = 17)
Native (n = 262)
92 (49.2%) 45 (24.1%)
84 (46.1%) 46 (25.4%)
10 (29.4%) 5 (14.7%)
9 (52.9%) 6 (35.3%)
132 (50.4%) 69 (26.3%)
8 6 12 21 65 34 1 30 5 1 3 1 20 3 21 21
5 6 8 19 54 26 1 27 1 2 5 0 17 4 16 30
2 0 1 2 16 10 0 6 1 1 0 0 4 0 4 6
1 0 1 1 5 2 0 3 2 1 3 0 5 0 7 1
(4.3%) (3.2%) (6.4%) (11.2%) (34.6%) (18.2%) (0.5%) (16.0%) (2.7%) (0.5%) (1.6%) (0.5%) (10.7%) (1.6%) (11.2%) (11.2%)
(2.8%) (3.3%) (4.4%) (10.5%) (29.8%) (14.4%) (0.6%) (14.9%) (0.6%) (1.1%) (2.8%) (0.0%) (9.4%) (2.2%) (8.8%) (16.6%)
(5.9%) (0.0%) (2.9%) (5.9%) (47.1%) (29.4%) (0.0%) (17.6%) (2.9%) (2.9%) (0.0%) (0.0%) (11.8%) (0.0%) (11.8%) (17.6%)
(5.9%) (0.0%) (5.9%) (5.9%) (29.4%) (11.8%) (0.0%) (17.6%) (11.8%) (5.9%) (17.6%) (0.0%) (29.4%) (0.0%) (41.2%) (5.9%)
11 9 17 26 78 47 1 30 2 1 8 1 21 1 24 36
(4.2%) (3.4%) (6.5%) (9.9%) (29.8%) (17.9%) (0.4%) (11.5%) (0.8%) (0.4%) (3.1%) (0.4%) (8.0%) (0.4%) (9.2%) (13.7%)
Bioprosthetic (n = 26)
Mechanical (n = 44)
8 (30.8%) 4 (15.4%)
9 (20.5%) 4 (9.1%)
1 1 1 1 10 2 0 8 3 1 2 0 7 2 8 3
(3.8%) (3.8%) (3.8%) (3.8%) (38.5%) (7.7%) (0.0%) (30.8%) (11.5%) (3.8%) (7.7%) (0.0%) (26.9%) (7.7%) (30.8%) (11.5%)
0 0 1 4 23 10 1 13 3 1 0 0 3 3 6 7
(0.0%) (0.0%) (2.3%) (9.1%) (52.3%) (22.7%) (2.3%) (29.5%) (6.8%) (2.3%) (0.0%) (0.0%) (6.8%) (6.8%) (13.6%) (15.9%)
intercurrent central venous access, permanent cardiac pacemaker, dialysis, diabetes mellitus, immunosuppression (HIV infection, medication-induced, or congenital), dental problems (defined as recent dental work, dental infection or documented poor dentition), intravenous drug misuse, homelessness, alcohol misuse, malnutrition or those who were current smokers. Congenital cardiac lesions included: bicuspid aortic valve (n = 36), atrial or ventricular septal defect (n = 9), tetralogy of Fallot (n = 5), congenital aortic stenosis (n = 3), patent ductus arteriosus (n = 2), other valve lesions (n = 2) or multiple complex lesions (n = 3). HIV infection was known in four individuals, with CD4 counts from 440 to 600/mm3; screening was not routinely performed. A single patient had received cytotoxic chemotherapy for acute myeloid leukaemia; blood cultures grew Corynebacterium macginleyi. Three patients were immunocompromised due to splenectomy (n = 2), or to combined cellular and humoral primary immunodeficiency (n = 1).
Heart Hospital for 151 (44.9%) patients, from either transthoracic (n = 107, 70.9%) or transoesophageal (n = 44, 29.1%) studies. The mean ( standard deviation) left ventricular ejection fraction was 60.1 12.9% and aortic root diameter was 3.29 0.49 cm. Abscesses were present in 17 (5.1%), aneurysms in three (1.0%), pseudoaneurysms in five (1.7%), valve perforations in 11 (3.7%) and fistulae in five (1.7%) patients.
Echocardiographic findings
Cumulative mortality was 3.0% within 24 h, 7.4% at 7 days and 12.2% at 28 days. The latter fell across the study (2 = 23.70, P = 0.02), being higher in the first 4 years (23.3%) compared with the second (7.9%, OR = 0.28, 95% CI = 0.12–0.68, P = 0.004) and third tertiles (8.8%, OR = 0.32, 95% CI = 0.15–
All patients underwent echocardiography for diagnosis of IE, although for most this was undertaken at the referring hospital. Indices were available from pre-operative echocardiograms performed at the
Surgical intervention Surgery included valve replacements in 308 (91.7%), and repair with vegetectomy in a further 25 (7.4%), patients. Three patients referred for surgery were ultimately treated with antibiotics alone. Of the valve replacements, 215 (69.8%) were mechanical, 74 (24.0%) xenografts and 19 (6.2%) homografts. There was no difference over time in the proportions of implant type used (Figure 1). Reoperation was required in 15 (4.9%) individuals.
Early post-operative mortality
Page 5 of 11
D.J.B. Marks et al. Homograft
100%
Xenograft
% Valve Implantations
Mechanical 80%
60%
40%
20%
0% 1998
1999
2000
2001
2002
2003
2004 Year
2005
2006
2007
2008
2009
2010
Figure 1. Valve implantation over the course of the study.
0.68, P = 0.003). Mortality did not vary with patient age, type of valve surgery, implant type, microbiological subclass or antimicrobial therapy.
Post-operative hospital admission and readmissions The median duration of post-operative hospital admission was 21 days (IQR = 10–35), and did not differ between valve replacements and repairs. This fell over the course of the study (P = 0.01), with a median of 33.5 (IQR = 21–43.25) days in the first year and 10.5 (IQR = 8–13) in the final year (P = 0.0003). There was variation across microbiological subgroups (P = 0.002), with longer admissions being associated with staphylococcal infections (median 31 days, IQR = 18–42, P = 0.01; compared to non-staphylococcal infections), and trends towards longer admission not achieving significance in anaerobic and other bacterial, fungal and polymicrobial infections (Figure 2). Data on duration of post-operative Intensive Care admissions were not systematically available. Readmission rates to the Heart Hospital were 0.6% (two patients) at 28 days, and 13.7% (46 patients) at 1 year; of these 7 (2.1%) required reoperation for IE.
Intravenous drug users Of particular interest were patients with IE secondary to intravenous drug misuse. Long-term outcomes of this group are described (Table 3); follow-up was to the end of the study. Among these 26 patients, median age was 33 years (IQR 29.25–41.75), and 24 (92.3%) were male. The 28-day mortality was comparable to the rest of the cohort as was mortality over the course of the study (34.6% among
intravenous drug users compared with 24.5% in other IE patients; P = 0.25); nine individuals died during longer term follow-up. Of the 17 survivors, nine had chronic infection with hepatitis C, three had recurrent IE, two continued to misuse intravenous drugs, and two defaulted long-term outpatient surveillance. Only one individual was HIV-infected at presentation with IE.
Biomarkers of early post-operative mortality Univariable predictors of mortality are shown in Table 4. Of the echocardiographic parameters recorded, only peak velocity across the aortic valve was significantly different in patients with early post-operative death compared to survivors (3.15 and 2.02 ms 1, respectively; P = 0.03). A multivariable model was subsequently developed for ascertaining associations with mortality. Final parameters included neutrophil count (OR = 2.27 per 1 unit increase in log10 value, 95% CI = 1.01–5.00, P = 0.05), albumin (OR = 0.94, 95% CI = 0.88–1.00, P = 0.04), urea (OR = 2.63, 95% CI = 1.35–5.00, P < 0.001) and previous cardiothoracic surgery (OR = 3.85, 95% CI = 1.15–12.50, P = 0.03).
Discussion This large single centre case series from a tertiary cardiothoracic referral hospital demonstrates that IE remains an important cause of morbidity, mortality and hospital admission. It builds upon a previous study from our centre published a decade ago.18 The results highlight a number of clinically important observations. First, there has been no Page 6 of 11
UQR = 126
45
**
40 35 30 25 20 15 10 5
No Organism Identified
Polymicrobial
Fungi
Other
HACEK
Enterobacteriaceae
Anaerobes
Staphylococci
0 Streptococci
Duration of Hospital Admission (Days)
Outcomes of infective endocarditis
Microbiological Category
Figure 2. Duration of post-operative hospital admission across microbiological subgroups. **P < 0.01.
perceptible shift in the distribution of causative organisms in our cohort since radical changes to guidelines for antibiotic prophylaxis, consistent with findings from Europe19 and the USA.20 Second, despite advances in sampling and culture techniques, microbiological diagnosis was not achieved in 14.3% of patients; use of 16S rRNA testing in a subset of cases did, however, identify organisms not detected by other means in 22%. Third, early mortality and duration of post-operative hospital admission fell over the study. These improvements are likely to be multifactorial. While there have been differences in case mix,18 increased surgical experience operating in IE, and changes in two members of senior surgical staff at our centre over the course of the study, the most important development occurred in 2002 when there was significant restructuring of service delivery. This resulted in consolidation of cardiothoracic services (including a dedicated specialist intensive care unit) on a single site, improved pre-operative evaluation with introduction of regular multidisciplinary meetings, and daily ward rounds by a dedicated microbiologist. The timing of this reorganisation correlates with the major improvement we observed in mortality. These factors are also likely to have impacted positively on the durations of post-operative admissions, alongside utilisation of outpatient parenteral antibiotic therapy and enhanced community rehabilitation programmes. These trends are mirrored in
the outcomes in our centre for patients managed for thoracic empyema.21 Fourth, we delineated a series of simple clinical and blood test biomarkers for early post-operative mortality, confirming and extending those from previous series.18,22–24 Finally, we report long-term outcomes from surgical intervention in intravenous drug users. Key findings included that, contrary to general perception,25 84.6% underwent operation for left-sided, and less than one-third for rightsided, IE; long-term mortality was 34.6%; and survivors had high rates of ongoing drug misuse and chronic co-morbid disease (particularly hepatitis C infection). The demographic and microbiological characteristics of our cohort are similar to those from other centres in Europe3,5,26–28 and the USA,29 supporting generalisation of our data. Most demonstrate a rise in S. aureus infections, related to increasing healthcare contacts, invasive procedures and intravenous drug use.5 In our patients, there remained a small excess of a-haemolytic streptococci over S. aureus, which may relate to differences in predisposing factors including the greater prevalence of previous IE and congenital heart disease. We detected a lower rate of aortic root complications (associated with increased surgical mortality and need for re-operation) than in our cohort reported 20 years previously.30 There was also an excess of polymicrobial infections in patients with Page 7 of 11
D.J.B. Marks et al. Table 3 Characteristics and outcomes from surgical intervention for IE among 26 injection drug users Patients
Organism
Affected valve
Implant
Outcome
1 2 3 4 5 6 7 8 9 10 11 12
MSSA MSSA MSSA MSSA MSSA MSSA CNS a-Haemolytic streptococcus Other streptococcus Other streptococcus Other streptococcus Polymicrobial (CNS, MSSA, other streptococcus) No organism isolated a-Haemolytic streptococcus CNS Other streptococcus MSSA a-Haemolytic streptococcus No organism isolated No organism isolated MSSA MSSA MSSA MSSA No organism isolated No organism isolated
AV AV AV AV AV AV AV AV AV AV AV AV
Biological Mechanical Mechanical Homograft Biological Biological Mechanical Biological Biological Mechanical Biological Biological
Died (day 14) Died (20 months) Alive Died (2 months) Alive Alive Alive Died (day 6) Died (4 years) Alive Alive Died (3 months)
AV AV, MV AV, MV, TV AV, MV, TV MV MV MV MV MV, TV MV, TV TV TV TV TV
Biological Biological Mechanical Mechanical Mechanical Biological Mechanical Mechanical Mechanical Repair Repair Repair Repair Biological
Alive Alive Alive Died (6 months) Alive Died (4 months) Alive Alive Died (day 9) Alive Alive Alive Alive Alive
13 14 15 16 17 18 19 20 21 22 23 24 25 26
AV, aortic valve; MV, mitral valve; TV, tricuspid valve.
bioprosthetic valves; this might infer a greater susceptibility to colonisation or that culture is easier from such explants. Rates of culture-negative IE were comparable to other series.31,32 16S rRNA PCR has an important role in such cases as it increases diagnostic yield for typical organisms,33 can detect nucleic acid in tissue samples (including explanted valves and peripheral emboli), and identify non-cultivable bacteria. Even when cultures are positive, the technique is still valuable to highlight true pathogens where multiple organisms are isolated from separate cultures by confirming which are detectable on explanted valves. Nonetheless, although its use during a subset of years in our study identified bacteria in a proportion of patients with culturenegative IE, the sensitivity remained limited (
