Abbreviations used in this article: IE, infective endocarditis, IVDU, intravenous drug users, TEE, transesophageal echocardiography, TTE, transthoracic echocardiography.
Despite great medical progress, infective endocarditis (IE) remains a serious infection that affects a great number of patients each year (7,28,67). During the last 2 decades, profound changes have taken place in susceptible populations, distribution of responsible microorganisms, accuracy of diagnostic techniques, and procedures for medical management (54,58,62). Transesophageal echocardiography (TEE) has become the leading tool for the diagnosis of IE (5,52,59), and new diagnostic criteria were proposed in 1994 (16). Nowadays, intravenous drug users (IVDU) are the group at greatest risk of acquiring IE (57). Although often these patients are human immunodeficiency virus (HIV)-positive, to date there are few studies describing the role that HIV infection plays in the course of IE (50,66). Many series do not fully reflect these changes because they were either retrospective, collected over a long period of time, or both (22,23,46,49,55,68,69).
We conducted a prospective study with the aim of describing the incidence, place of acquisition, population involved, etiologic agents, diagnosis, and outcome of cases with IE in a large teaching institution. We focused particularly on those episodes that affected HIV-infected patients and nosocomially acquired cases in order to describe specific characteristics in these populations.
The size and characteristics of our institution (Hospital General Universitario “Gregorio Marañón,” Madrid, Spain) permitted the collection of a large, unselected series of IE in a short period of time, which in our view reflects the major changes in the features of IE at the beginning of the present century.
Our institution is a 1,750-bed tertiary teaching hospital serving an urban area of approximately 650,000 inhabitants. It has an active program of solid organ (renal, hepatic, and cardiac) transplantation and has specific units for infectious diseases, oncology, hematology, and intensive care medicine. The cardiology and cardiovascular services are closely related to the infectious diseases unit by a program of consulting service.
Study period: From March 1994 to October 1996 all cases of IE were prospectively followed by an infectious diseases consultant.
Inclusion criteria: Cases included in the study fulfilled 1 or more of the following criteria:
1) Clinical suspicion of IE. von Reyn (69), Steckelberg (59), and Durack (16) diagnostic criteria were employed. A case was included if it was accepted by 1 of the sets of criteria. (Steckelberg et al published a series of IE in 1991 in which they proposed a revised version of von Reyn’s criteria for IE. Steckelberg’s classification was simpler than von Reyn’s, but it is not the most commonly used in clinical practice today. Nevertheless we included it in our study in order to compare all available classifications.)
2) Echocardiographic evidence of IE. Cases that presented valvular vegetations, new prosthesis dehiscence, valve insufficiency, and perivalvular abscesses in an appropriate clinical setting were evaluated.
3) All patients with bloodstream infections caused by Streptococcus viridans, Streptococcus bovis, HACEK group micro-organisms, Staphylococcus aureus or Enterococcus spp. were prospectively screened. Special attention was paid to patients with primary bacteremia, mainly if they were IVDU or patients with prosthetic valves.
4) Histologic findings of IE.
Protocol: From each episode the following data were collected: Epidemiologic features (sex, age, underlying conditions, previous heart diseases, comorbidity according to the Charlson index  and invasive procedures during the previous 3 months); clinical characteristics (affected valve, signs and symptoms); laboratory and microbiologic results (isolates, susceptibility tests, and serology results if available); X-ray and echocardiographic findings; complications; treatment; and outcome.
Acute renal failure: an increase in the serum creatinine level to >2.0 mg/dL from a baseline level of <1.2 mg/dL or the need for hemodialysis.
Fever: 2 or more axillary temperatures >38 °C. (Axillary temperature is the most commonly used in clinical practice in Spain; it is simple and not invasive and avoids cross-contamination related to rectal or oral sampling.)
Right-sided involvement: tricuspid or pulmonary valves affected on echocardiography or the presence of a new murmur and pulmonary embolism.
Left-sided involvement: mitral or aortic valves affected on echocardiography or a new murmur in a patient with previous left-sided valve disease and/or systemic embolism (central nervous system, spleen, extremities).
Nosocomial IE: the presence of IE more than 72 hours after admission linked to an invasive inhospital procedure or during the 8 weeks after discharge. (Most authors include as nosocomial endocarditis cases diagnosed 4–8 weeks after discharge if related to an invasive procedure during hospitalization. IE can remain silent for weeks, and the episode could be acquired during the hospitalization but not diagnosed then.) Cases related to cardiovascular surgery were excluded in the analysis of nosocomial IE.
Early prosthetic valve IE: Prosthetic valve IE occurring during the 60 days after valvular replacement.
Statistics: Data were entered and categorized using ACCESS software (Microsoft) and analyzed using the Winstat program (Kalmia Company, Inc.). Measures of significance were assessed by univariate and multivariate analysis. Qualitative variables were measured with the Fisher exact test or chi-square test (2-tailed). A p value of <0.05 was established as the level of significance for all tests. Descriptive univariate analysis of mortality-related factors was performed and a subset of significant variables was selected for multivariate analysis. The Epi Info program (Centers for Diseases Control and Prevention, Atlanta, GA) was used to calculate risk ratios (RR) with 95% confidence intervals (95% CI).
During the study period, 109 episodes of IE in 101 patients were attended at our hospital. The incidence was 6.4 cases per 100,000 inhabitants per year, 0.8 cases per 1,000 admissions and 3.5% of all episodes of significant bacteremia.
Eighty patients (73%) were male and 29 (27%) female. The male:female ratio was 2.76. Mean age was 50 years (range, 19–89 yr). Thirty-eight patients were older than 60 years (34.8%) and 16 (14.6%) older than 70 years.
All but 5 patients had underlying conditions before the episode (Table 1). By underlying conditions we mean any clinical condition that could be important to the patient’s outcome. Although some conditions, such as HIV, are not risk factors for IE, they are included here because they could change the outcome for the patient.
Thirty-six (33%) patients were HIV-positive and 17 (15.6%) had diabetes. A cardiac disease had been diagnosed in only 50 (45.8%) patients before the episode of IE: 18 (16.5%) had prosthetic valves, 17 (15.6%) a previous history of IE, 6 (5.5%) previous rheumatic valvulopathy, and 3 had a pacemaker. Mean comorbidity, estimated by the Charlson index, was 2.5 (range, 0–9).
An invasive procedure during the last 3 months was cited in 62% of cases, 39 (35.6%) patients were IVDU, 6 had undergone a valve replacement, and 4 had gastrointestinal surgery. There were 24 (22%) episodes of nosocomial IE; 6 of these were early prosthetic valve endocarditis, so 18 (16.5%) were nosocomial IE not related to cardiovascular surgery.
For analysis, the patients were divided according to the type of valve involved. Fifty-two (48%) episodes occurred on native valves, 39 (36%) were in IVDU, and 18 (16.5%) episodes were prosthetic valve IE: 6 cases early prosthetic valve endocarditis and 12 late prosthetic valve endocarditis.
Table 2 summarizes the diagnostic criteria of 109 episodes of IE comparing the classification of our patients according to the 3 different diagnostic criteria.
Ninety-four cases (86.2%) were classified as definite IE according to Durack criteria while only 15 (13.8%) fulfilled von Reyn’s or Steckelberg’s conditions for well-proven IE. Of 15 cases definitely proven at surgery or autopsy, 4 (26.6%), 6 (40%), and 0 cases had been previously rejected by von Reyn, Steckelberg and Durack criteria, respectively.
In 88 patients (80%) the symptoms appeared during the previous month. Only 6 patients had symptoms more than 3 months before diagnosis.
Fever was the most common finding and was present in 107 episodes (98%). Respiratory and neurologic manifestations were present in 54% and 32%, respectively. Nineteen (17.4%) patients had skin involvement and 17 (15.4%) had spleen enlargement. Although 17 patients (15.4%) had musculoskeletal manifestations, only 6 had frank arthritis, with a positive culture in 3 cases.
A new cardiac murmur was present in 65 (59%) patients (65.6% in left-sided versus 50% in right-sided IE) (Table 3).
Laboratory and X-ray data
Anemia was present in 72 (66%) cases, leukocytosis in 55 (50%), and thrombocytopenia in 20 (18%). Thirty-seven patients (34.6%) had renal dysfunction (47% in patients older than 60 years), and 9 (8%) had liver enzyme abnormalities. Forty (36.7%) patients had hematuria or pyuria in urinalysis. An abnormal cerebrospinal fluid was present in 5 patients (4.6%); 2 of them had meningitis.
Only 27 (24%) patients had a normal chest X-ray. Bilateral nodules or infiltrates were present in 43 episodes (40%). Fifteen patients had pleural effusion on chest X-ray;S. aureus was the etiologic agent in 13 of these patients.
Site of infection
Sixty-six (60.5%) patients had left-sided IE and 43 (39.5%) had right-sided IE (Table 4). Two patients had bilateral involvement. The tricuspid valve was the most common site of infection (41 cases); the mitral valve was affected in 28 (25.7%) patients, the aortic in 21 (19.2%), and 9 (8.2%) patients had aortic and mitral valves affected. While left-sided endocarditis predominated in native valve endocarditis and prosthetic valve endocarditis (80.8% and 100%, respectively), infection of the tricuspid valve was the most common in IVDU (79.5%).
Etiology of IE
Staphylococci were the most common microorganisms causing 64 (58.7%) episodes of IE (Table 5). S. aureus accounted for 49 cases and coagulase-negative Staphylococcus for 15. Of these 15 cases, 6 were prosthetic valve endocarditis, 3 were pacemaker IE, and 1 patient carried a defibrillator. The other 5 cases were nosocomially acquired. Five strains of S. aureus were methicillin-resistant (10%).
Streptococci were the second most common group (15.6%). Ten cases were caused by Str. viridans, 1 of which was resistant to penicillin (minimum inhibitory concentration [MIC] = 4). Enterococci caused 10 episodes (8 E. faecalis and 2 E. faecium); 1 isolate of E. faecium was resistant to ampicillin. High-level resistance to streptomycin or gentamicin was detected in 2 strains (1 E. faecalis and 1 E. faecium). (High-level resistance to streptomycin [MIC > 1, 000 μg/mL] means that synergistic effect of aminoglycosides with beta-lactams antibiotics cannot be expected.) One E. faecalis strain showed high-level resistance to all aminoglycosides.
There were 2 (1.8%) episodes of fungal endocarditis: 1 Candida albicans IE in an IVDU and 1 C. parapsilopsis IE in a patient with parenteral nutrition.
IE was polymicrobial in 3 (2.7%) cases. Blood cultures were negative in 15 cases (13.7%), but in 4 (3.7%), valve cultures yielded the etiologic agent. S. aureus was the main etiologic agent in native valve endocarditis and in IVDU, while in prosthetic valve endocarditis S. aureus and coagulase-negative Staph-ylococcus were equally frequent (33%).
All but 5 patients (95.4%) had an echocardiogram (Table 6). In 62 (57%) cases the results of both transthoracic echocardiography (TTE) and TEE studies could be compared. The results of echocardiography were consistent with IE in 54 of 105 TTE (51.4%) and in 57 of 62 TEE (92%). The diagnosis of IE was based on TTE in 54 (49.5%) cases, but in 38 (34.8%) cases TEE was necessary to confirm the diagnosis.
Perivalvular abscesses were present in 7 patients (6.4%) and a new valve dehiscence in 6 (5.5%). TTE detected only 1 perivalvular abscess (14.3%) while TEE detected all of them. TTE detected 1 (16.6%) valve dehiscence and TEE detected 5 (83%). In 12 (11%) cases with clinical criteria of IE the echocardiography was not diagnostic, but TEE had been performed in only 5 of these cases.
In patients older than 60 years, TTE was diagnostic in only 13 (34%) cases; in 20 (52.6%) cases, TEE detected IE not diagnosed with TTE.
Main complications are shown in Table 3. Embolic events were the most frequent complications (45%). Thirty (27.5%) patients had septic pulmonary emboli and 20 (18.3%) had systemic embolisms. The central nervous system was the most frequent site of embolization (13 cases). Patients with central nervous system embolisms were older (61% older than 60 years), the mitral valve was the most common site of infection (mitral valve, 7 cases; aortic valve, 4; both valves, 2), and they had a worse prognosis (mortality 46% versus 23%, p < 0.05). S. aureus was the etiologic agent of 65% of cases with embolic complications.
Congestive heart failure developed in 35 (31%) cases and acute renal failure in 19 (17.4%). Nine patients suffered an atrioventricular blockage. Seven valvular abscesses were found (4 in native mitral valve and 3 in aortic prosthetic valves).
Treatment and outcome
All patients received medical treatment with a mean duration of 31 days (range, 2–90 d). Surgical treatment was indicated in 46 (42%) cases. In 17 episodes surgery could not be carried out due to the critical condition of the patients. Indications for surgery were valvular dysfunction (28 cases), treatment failure (11 cases), and perivalvular abscess (7 cases). Twenty-five (23%) patients underwent valve replacement during admission or in the following 6 months. The 3 patients with IE who carried a pacemaker and the patient with a defibrillator required surgical removal to control the infection.
Related mortality was 25.7%. All patients with early prosthetic valve endocarditis died, but only 3 (25%) with late prosthetic valve endocarditis died (Table 7). Mortality did not increase with age (24% in younger versus 29% in older than 60 years). In univariate analysis, bad prognosis factors were left-sided IE (RR 5.43 95% CI 1.75–16.8), mitral IE (RR 2.89, 95% CI 1.58–5.29), early prosthetic valve endocarditis (RR 4.68, 95% CI 3.23–6.78), S. aureus left-sided IE (RR 2.56, 95% CI 1.30–14.52), central nervous system involvement (RR 2.11, 95% CI 1.13–3.94), congestive heart failure (RR 5.29, 95% CI 2.59–10.8), and acute renal failure (RR 3.55, 95% CI 2.03–6.23). When multivariate analysis was performed, early prosthetic valve endocarditis, the presence of congestive heart failure, and acute renal impairment were the only factors significantly related to mortality.
During the study period, there were 24 episodes (22%) of nosocomial IE. We excluded the 6 cases related to cardiovascular surgery so we analyzed the remaining 18 patients. Although only 4 of our patients with nosocomial IE had underlying conditions that predisposed to IE, in the other cases there was a previous invasive procedure that could explain this complication. Nine patients had the same microorganisms in blood and in line cultures, 1 patient with a urine catheter had the same microorganism isolated in blood and urine, and the remaining 4 patients had IV lines, but these were not sent to the laboratory for culture.
Eleven patients were male (61%) and 7 female. Mean age was 57.2 years, 8 (44.4%) were older than 60 years. All but 1 patient had been hospitalized because of a serious underlying condition. Four patients had cardiac diseases that predispose to IE (1 had a valvular prosthesis, 1 a defibrillator, and 2 rheumatic valvulopathies). Fifteen patients had intravenous catheters and 4 underwent complicated abdominal surgery during hospitalization.
Left-sided involvement predominated (67%), the mitral valve was infected in 6 (33.3%), aortic valve in 5 (28%), and both valves in 1 case. Six (33.3%) patients had tricuspid IE. In 8 (44%) episodes TEE was necessary to confirm the diagnosis.
Staphylococci were the main etiologic agents (7 coagulase-negative Staphylococcus and 4 S. aureus). All S. aureus isolates were methicillin-resistant. Enterococci caused 5 episodes; the E. faecium strain was resistant to ampicillin, and 2 of 4 isolates of E. faecalis showed high-level resistance to aminoglycosides. In 11 cases the culture of removed catheters or intravascular devices showed the same microorganism as blood cultures.
In 8 (44.4%) patients surgical treatment was indicated but surgery was carried out in only 3 cases due to the critical clinical status of the remaining 5 cases. The overall mortality was 44.4%; in 6 (33.3%) patients death was directly related to the episode of IE.
Infective endocarditis in HIV-positive patients
During the study period, we followed 36 episodes of IE in 30 HIV-positive patients (33% of the total and 84.6% of IE in IVDU). Thirty-one were male, mean age was 32 years, and 33 (91.6%) cases were IVDU patients.
Fifteen patients (41%) had a CD4 cell count of 200–500/mm 3 and 17 (47%) ≤200/mm 3 . In 4 patients CD4 cell count was not available. According to the Centers for Disease Control (CDC) classification, 18 (50%) patients fulfilled AIDS criteria.
Thirty-one (86%) episodes were right-sided IE. The tricuspid valve was the most common (25 cases), in 2 cases the mitral was the valve affected, and in 2 the aortic. All but 2 patients had a TTE that was diagnostic in 28 (77.7%). TEE was performed in 4 cases but it was diagnostic in only 1 case.
S. aureus was the main etiologic agent (78%). In 2 patients the episode was polymicrobial, and in 2 blood cultures were negative.
All patients were febrile at diagnosis; respiratory symptoms, anemia and pulmonary embolism were present in 92%, 83%, and 70% of cases, respectively. Chest X-ray was normal in only 2 patients; 61% had bilateral nodules and 14% a bilateral infiltrate.
Overall mortality was 19.5%. Two patients died of opportunistic infections (1 untreatable Cryptosporidium diarrhea and 1 disseminated M.tuberculosis infection); mortality related to IE was 14%. An increased mortality rate was observed in patients with left-sided involvement (60% versus 6%, p < 0.01).
Comparing patients with and without AIDS criteria, patients with advanced HIV infection were older (30 versus 37 years) and had an increased risk of unrelated mortality during the episode (11.7% versus 0%), but we did not find any differences in clinical presentation or outcome due to endocarditis.
To our knowledge, the present study is among the largest series of IE collected over a short period of time. During the last years, there have been only a few prospectively collected series of IE (28,32,54,57,67). In this study we describe the most relevant changes that have taken place recently in IE. We summarize in Table 8 the main characteristics of the most relevant published series of IE, and we add our results to the table. We can appreciate a significant increase in the proportion of IE related to IVDU, the increased relevance of S. aureus as etiologic agent, and a frank reduction of mortality, but only in series with a high proportion of IVDU (57).
The real incidence of IE is difficult to know because most series are retrospective or collected over a long period of time (see Table 8). Recent studies have shown an increasing number of cases especially in the elderly (28,63,67). Our incidence is similar to that reported by Hogevik et al (28), Watanakunakorn et al (70), and Benn et al (4) and slightly greater than that reported by Carton et al in Spain (7). These findings probably reflect an improvement in diagnostic methods and in clinical surveillance more than a real rise in the incidence.
More than 50% of cases of IE in non-IVDU patients were in the elderly. As in our series, these patients frequently have severe underlying conditions and heart disorders that require hospital admission and invasive procedures that could predispose to bacteremia and nosocomial IE (61,67). In accordance with recent studies, our data confirm that age is not a risk factor for mortality, but special attention should be paid to renal function (21,61). Most of these cases are misdiagnosed with TTE, so TEE should be performed in older patients with clinical suspicion of IE (72).
The main underlying condition in our series was HIV infection (33%), probably due to the high proportion of IVDU (35.7%). Most of our IVDU patients with IE were HIV-positive as in other Spanish studies (17,51,65). Clinical and microbiologic characteristics of the episode of IE in HIV-positive patients did not differ from those previously described in HIV-negative IVDU (24,43,44,66). In contrast to Pulvirenti et al (50), in our series a worse prognosis was not found in patients in advanced stages of HIV infection. In our experience, mortality due to IE in HIV-positive patients, as in the general population, was related to affected valve and hemodynamic status more than to immunosuppression.
Less than half of our patients had previously recognized heart disease. Only 5.5% had rheumatic valvulopathies reflecting the decline of this condition as a risk factor predisposing to IE, although it is still the most important factor in undeveloped countries. In series like ours, with a large number of IVDU, there is frequently a lack of cardiac disorders apart from a previous history of IE (57,70). Prosthetic valves have been the most common cardiac disease; the high mortality observed in this group obliges us to use prophylactic measures (13,18,42).
Our results confirm once again the sensitivity of the new Durack criteria when compared with classic von Reyn and Steckelberg criteria (16,59,69). Of pathologically proven cases, none has been rejected by the Duke criteria, contrasting with 26.6% and 40% by the von Reyn and Steckelberg classifications, respectively. The Durack criteria have repeatedly proven their sensitivity and specificity; they are especially useful to select definite cases when surgery or necropsy are not performed (2,10,15,25,27). Their sensitivity is significantly greater in every group of IE: pediatric IE (60), IE in the elderly (21), and prosthetic valve endocarditis (45). Nevertheless, many authors have communicated their doubts about the “possible” category of these criteria and have proposed a more precise definition of possible cases to improve their specificity (3,37,47,56).
The tricuspid valve was the most commonly affected (32%). This fact is not surprising given the high proportion of patients that were IVDU. In non-IVDU patients the mitral valve predominated. In 4 patients an intracardiac device was the focus of infection. Now, more and more patients carry pacemakers, which means that a follow-up of these patients is necessary when fever and bacteremia are present to rule out IE. These infections are usually difficult to cure with only antibiotic therapy, and they frequently require surgery (1,6,31).
In our institution, Staphylococci are the most important etiologic agents of IE in every type of patient, so empirical treatment should include drugs with antistaphylococcal activity. In the last few decades, the number of cases of IE caused by Staphylococci, especially S. aureus, has increased (54,70,71). Hospital-acquired strains and those obtained from IVDU frequently show resistance to methicillin, thereby complicating treatment (26,36,51). Group viridans Streptococci have declined in importance and in our study were responsible for only 10% of cases. Enterococci accounted for 10% of episodes; the main problem of enterococcal IE is to choose the best treatment when the microorganisms show a decreased susceptibility to the usual drugs (9,10). Reports of resistance to aminoglycosides, glycopeptides, and beta-lactams have led to the search for new combinations (20,41).
Transesophageal echocardiography played an important role in our study; it provided an accurate diagnosis of IE in 38 cases in which TTE was negative. Only 1 case of perivalvular abscess and 1 new valve dehiscence were detected with TTE, while TEE detected 100% and 83%, respectively. Like other authors, we reaffirm that TEE is an essential tool when there is clinical suspicion of prosthetic valve endocarditis, IE in the elderly, nosocomially acquired IE, and for the early detection of complications especially in left-sided IE (14,30,34,35,38,39,52,53,72).
Nosocomial IE represents a significant percentage of IE (19,33), and these episodes are often caused by microorganisms resistant to many available treatments (19). In our series, the most common source of infection was vascular access sites, so many cases could be prevented by improving catheter care. Nosocomial IE is difficult to diagnose because often these patients are severely ill, and symptoms of IE are attributed to underlying conditions.
Many studies have shown that the prognosis of patients with IE has improved, probably due to earlier diagnosis and better timed surgery (29,40,48,55,64,68,73). The mortality of IE is largely dependent on the underlying conditions of the population represented and has been estimated at 20% in recent series (7,28,63,67). Besides early prosthetic valve endocarditis, congestive heart failure and acute renal failure were the only factors significantly linked to mortality in our multivariate analysis. In patients with heart failure, surgical therapy is usually the only choice, although timing of surgery continues to be a matter of debate. Acute renal failure is another factor that worsens the prognosis of IE; advanced age is among the main conditions that predispose to renal dysfunction, so it is very important to survey these patients (12,21).
From March 1994 to October 1996 we prospectively collected 109 episodes of infective endocarditis (IE) with an incidence of 6.4 cases/100,000 inhabitants per year. Mean age was 50 years, and 58 (35%) cases were in patients older than 60 years. Fifty-two (48%) episodes occurred on native valves, 39 (36%) were in intravenous drug users, and 18 (16.5%) were cases of prosthetic valve endocarditis. Eighteen cases (16.5%) were nosocomially acquired, and 36 cases were in human immunodeficiency virus (HIV)-positive patients.
Durack classification did not reject any definitely proven cases, while the von Reyn and Steckelberg classifications rejected 26.6% and 40%, respectively. The tricuspid valve was the most common (37.6%) site of infection. Mitral valve was affected in 28 cases, aortic in 21, and both in 9.
Staphylococci were the main etiologic agent in every group of patients. Staphylococcus aureus caused 49 (45%) cases. Only 9% of all episodes of IE are now caused by group viridans Streptococci. Transthoracic echocardiography diagnosed only 54 (49.5%) cases. Transesophageal echocardiography confirmed the diagnosis in another 38 cases. Related mortality was 26%. Bad prognosis factors in multivariate analysis were early prosthetic valve endocarditis, congestive heart failure during the episode, and acute renal dysfunction.
With this study we have observed many changes in IE: new predisposing conditions, new populations at risk, new etiologic agents, and new diagnostic criteria and procedures, but in our experience IE is still a serious infection with a fearsome mortality, especially in seriously compromised populations like those patients with early prosthetic valve endocarditis.
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