A 55-year-old heroin addict presented to the emergency department, complaining of shaking chills and fevers for 2 weeks. On examination, there was a loud holosystolic murmur, maximally audible in the epigastric space, and a pulsatile liver. Subcutaneous nodular lesions were noted on his palms. Blood cultures grew Pseudomonas aeruginosa. After nearly completing a prolonged course of intravenous antibiotic therapy, the patient died in his washroom from an overdose of heroin. This sad tale, often tragically repeated, represents a continuing challenge to the medical community. The patients’ palm lesions noted were
Osler’s nodes, originally described in 1908 by Sir William Osler, considered by many the father of internal medicine. Osler was born in 1849 and died in 1919. He was an astute clinician and educator, with professorships at McGill University, University of Pennsylvania, Johns Hopkins University, and Oxford University. Osler defined “chronic” infectious endocarditis as an illness lasting longer than 3 months and characterized by low grade fevers. This syndrome was distinct from a “malignant” form, which resulted in early death. Blood cultures usually grew streptococci or, occasionally, staphylococci. Osler made a practice of following his patients to the autopsy table. Vegetations on valves from patients who died of the chronic form looked more like “warts,” and were neither ”ulcerating or very large.” Osler thought anti-streptococcal vaccines might be of some benefit. There was little else to offer. Regardless of the form, nearly all patients died.
In this review, I discuss current methods for the diagnosis and management of infective endocarditis. Cases seen in recent years will illustrate key points.
Case 1 A 39-year-old computer programmer complained of occipital headaches, migratory muscle pains, afternoon fevers, and a 15-pound weight loss for 2 months. He had previously enjoyed excellent health. On examination his temperature was 38.0°C. An apical systolic heart murmur was noted. A transthoracic echocardiogram (TTE) showed mitral regurgitation, with a probable vegetation on the mitral valve. Blood cultures were drawn and the patient was admitted to the hospital. The next day, a transesophageal echocardiogram (TEE) showed perforation of the posterior mitral leaflet. That evening, the patient developed severe right flank pain. CT scan showed infarcts in the right kidney and spleen. The next day the patient underwent urgent mitral valve repair and was dismissed 5 days later to complete a course of intravenous ceftriaxone. All blood cultures grew viridans streptococci, exquisitely susceptible to penicillin.
Comment: This patient represents classic “subacute” bacterial endocarditis with fever, weight loss, and a heart murmur. In most cases, he would be cured with medical therapy alone. However, a TEE showed a lesion that was not appreciated on the initial TTE, and he required urgent surgery to restore a failing mitral valve.
Although the patient had no identified skin or mucosal lesions, when present these suggest the diagnosis. The subconjunctivial sacs and soft palate should be examined for petechiae, the nail beds for splinter hemorrhages, and digits for Janeway lesions.
Osler’s definition of endocarditis included remittent fever, history of valvular heart disease, embolic features, skin lesions, and heart failure. These remain useful bedside observations, and positive blood cultures usually clinch the diagnosis. Perhaps the most important technical advance in recent years for diagnosis is the echocardiogram. The major Duke criteria, published in 1994, include a predictable bacterial organism in blood culture, multiple positive blood cultures with the same organism, or an echocardiogram with definite vegetation, abscess, or valve dehiscence. Any two of the above suffice for diagnosis of probable endocarditis. Accepted minor criteria consist of predisposing lesions, history of intravenous drug abuse, temperature higher than 38°C, vasculitis, skin lesions, or “suggestive” echocardiographic or microbiologic findings. Five of these, or three with one major criterion, support the diagnosis. Transesophageal is superior to transthoracic echocardiography and should be performed if the TTE is equivocal or non-diagnostic.
Case 2 A 31-year-old warehouse manager with progressive dyspnea was transferred from an outside hospital. His illness began 8 months earlier with a dry cough and progressive fatigue. His past history was negative except for an asymptomatic heart murmur. On examination, he was pale and diaphoretic with a temperature of 36°C, pulse 110, and blood pressure of 108/56mm Hg. Neck veins were distended beats/min; loud heart murmurs and diffuse airway crackles were heard. The spleen was palpable. Blood cultures were drawn and antibiotics started.
As the patient was being wheeled for urgent heart surgery, he suffered a huge left-sided stroke. Contrast studies showed a leaking basilar artery aneurysm with subarachnoid hemorrhage. Once his neurologic problem stabilized, urgent mitral and aortic valve replacement was performed. Both valves were severely damaged and rife with vegetations. Admission blood cultures grew viridans streptococci, susceptible to penicillin. After prolonged hospitalization, the patient was transferred for continued care to a rehabilitation unit closer to home.
Comment: Neurologic complications of endocarditis are more common than generally appreciated, and occur in at least one third of patients at the time of diagnosis. Stroke is the most frequent finding, but encephalopathy, retinal embolic lesions, mycotic aneurysm, brain abscess, and meningitis can also occur. Fortunately, most neurologic problems resolve with medical management, but as seen in this patient, some are devastating and have permanent sequelae.
Organisms responsible for the majority of cases of native valve endocarditis are streptococci, as was true in Osler’s time. Staphylococcus aureus is next in frequency, followed by gram-negative bacilli, fungi, coagulase-negative staphylococci, and a poorly-defined category of “culture negative” cases. Therapy for infection caused by penicillin-susceptible streptococci is straightforward. The preferred agent is intravenous penicillin or ampicillin, with ceftraxione or vancomycin as alternatives. Streptococci less susceptible to penicillin, including nutritionally variant organisms, are treated more vigorously with a penicillin and low-dose aminoglycoside.
The HACEK group of gram-negative bacteria (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella species) often produce large vegetations. Embolic lesions to major organs or extremities are a fairly common presenting feature. Treatment with ceftriaxone or ampicillin plus gentamicin is usually successful.
“Culture negative” endocarditis includes infections due to microorganisms difficult to culture on standard media. These uncommon pathogens include Bartonella, Brucella, Chlamydia, Coxiella, Francisella, Legionella, and Tropheryma whippeli.
Bartonella endocarditis has been reported in the homeless population. Blood cultures are usually negative. Serology is helpful. More recently, polymerase drain reactions (PCR) from resected valve tissue have proven useful. Treatment of choice is ampicillin plus gentamicin, but mortality remains approximately 25%.
Patients with endocarditis due to Coxiella burnetii (Q fever) are likewise difficult to diagnose. They may not have fever. However, there is generally underlying valvular heart disease, and frequently patients are immunosuppressed. Vegetations are rarely detected on echocardiogram. Routine blood cultures are negative. Fortunately, serology is quite specific for the diagnosis. A combination of doxycycline and chloroquine is the current treatment of choice.
PCR and special immunohistochemical techniques may be useful in the diagnosis of these unusual etiologies. Unfortunately, the methodology is not currently available at most hospitals. Broad-range PCR on surgical tissue help to identify more typical organisms (staphylococci and streptococci), whose growth may be suppressed by conventional antibiotic therapy. Although promising, PCR technology may lack specificity in these cases.
Case 3 A 61-year-old executive was admitted with a 4 week history of fevers and fatigue. Three months earlier he had undergone a bovine aortic valve replacement with mitral valve repair. Blood cultures drawn by a local physician grew methicillin-resistant Staphylococcus epidermidis (MRSE). Despite antibiotics, the patient’s fatigue persisted and he returned for further evaluation. On examination, he was afebrile, with a resting pulse of 71 beats/min and a blood pressure of 135/63mm Hg. However, he was very pale. Loud systolic and diastolic murmurs were heard throughout the precordium. His spleen was enlarged and very soft.
The patient underwent urgent reoperation. At surgery, partial aortic valve dehiscence as a result of a large subprosthetic abscess was discovered. Both aortic and mitral valve were replaced. Admission and operative cultures were negative on antibiotic therapy.
Comment: This is a classic presentation of early-onset prosthetic valve endocarditis. Usual organisms are S. epidermidis and S. aureus Streptococci, vancomycin-resistant enterococci (VRE), diphtheroids, gram-negative bacilli, and fungi (yeast and molds) are all seen in this setting, albeit less frequently.
S. epidermidis is of special interest because it produces hemolysins, grows very slowly on cell surfaces, and binds to host and foreign proteins. This biofilm creates a barrier to host defenses and appears to neutralize certain antibiotics. In addition there is clonal variability, with some isolates fully susceptible to oxacillin, while other clones are resistant.
Standard therapy for staphylococcal prosthetic valve endocarditis is oxacillin with gentamicin and rifampin. For oxacillin-resistant species, vancomycin is substituted. Prosthetic valve enterococcal endocarditis resistant to both penicillin and vancomycin is a growing concern. Some medical centers report VRE colonization rates as high as 30%. Therapy is daunting. For strains with a minimum inhibitory concentrations (MIC) less than 128 gr/mL to ampicillin, ampicillin/sulbactam plus an aminoglycoside has been recommended. For strains totally resistant to ampicillin, quinupristin/dalfopristin, linezolid, or daptomycin may be tried, but the overall success rate is probably no better than 50%.
Case 4 A 31-year-old automobile mechanic underwent aortic valve and graft replacement for severe aortic regurgitation with a large aneurysm of the ascending aorta. His post-operative course was complicated by massive bleeding at the distal graft anastomosis, and respiratory failure. After prolonged hospitalization, the patient was discharged improved, but 2 days later he complained of blurred vision and fevers. His wife noted a green hue from his right pupil. The patient was readmitted and started on intravenous acyclovir for presumed acute retinal necrosis. However, several days later, vitrectomy fluid grew Pseudoallescheria boydii.
Therapy was switched to intravenous miconazole but, shortly afterward, the patient suffered a cardiac arrest. Although his pulse and blood pressure were restored, he remained comatose and support was withdrawn. At autopsy, invasive prosthetic aortic valve and graft endocarditis was noted. Blood and tissue cultures also grew P. boydii.
Comment: Fungal prosthetic valve endocarditis is a devastating disease. Predisposing factors are prolonged use of central vascular catheters, often for antibiotic therapy or parenteral nutrition, and immunosuppression. Most success has been reported combining surgery with intravenous antifungal therapy. Patients should be continued on oral suppressive therapy afterward to prevent relapse later in life.
“Pacemaker endocarditis,” seen with increasing frequency, applies to pacemakers, defibrillators, or combinations thereof. Usual causes are skin flora microbes (staphylococci and Propionibacterium species) that gain access through a generator pocket wound. An echocardiogram may not show vegetations unless they extend to the tricuspid valve. Removal of all hardware, combined with intravenous antibiotic therapy, is necessary for cure. Some impacted leads require open heart surgery for removal.
Hospital-associated bacteremia from another source may spread to a heart valve or pacemaker lead, causing endocarditis. S. aureus bacteremia from intravenous catheters, hemodialysis fistula, and surgical wounds is most likely to do this. Patients on hemodialysis may be colonized with methicillin-resistant S. aureus (MRSA), a risk factor for infection. While intra-nasal mupirocin ointment may reduce MRSA colonization transiently, it is probably not effective for long-term prophylaxis.
Case 5 A 54-year-old accountant was admitted with chills and palpitations for several days. A bovine aortic valve prosthesis had been implanted 2 years earlier. The patient had complained of intermittent fevers for 6 months. A single blood culture had grown Propionibacterium acnes. Although a TEE was interpreted as normal, he was treated with intravenous vancomycin. Follow-up blood cultures were negative and a TTE was read as normal.
On examination, the patient was acutely ill with distended neck veins. His pulse was 50 beats/min and blood pressure 110/50mm Hg. Systolic and diastolic murmurs were present. Blood cultures were drawn, and antibiotics started.
An electrocardiogram showed heart block. A temporary pacemaker was placed. A TEE revealed a huge atrial septal abscess with a fistula from the right atrium to the aorta. The patient was taken emergently to surgery, where the prosthesis was found to have nearly completely dehisced. The fistula was resected and the aortic valve replaced with a homograft. Postoperatively the patient remained in cardiogenic shock and died. Admission blood and valve cultures subsequently grew P. acnes.
Comment and Conclusions
Continued fevers despite appropriate antibiotic and medical management are cause for alarm. Ring abscesses may develop. This is a clear indication for surgical intervention. Fevers may also be caused by embolic events (arterial or venous), drug reactions, and intravascular catheter-related infections. Close monitoring is necessary to avoid major events. Vigilance should be maintained for widening pulse pressures and rhythm disturbances as these are ominous signs of progressive infection.
Indications for urgent surgery include progressive valvular dysfunction; aortic root, ring or septal abscesses; large vegetations (greater than l cm in diameter); and organisms such as VRE, MRSA, Pseudomonas species, and fungi refractive to antimicrobial therapy. It is important to note that, even with appropriate therapy and a bacteriologic “cure,” about one half of patients will have enough valve damage to require surgery later in life.
Despite our best efforts, the death rate from infective endocarditis remains in the range of 10–20%. Death is more likely with prosthetic valve endocarditis and when the organism is S. aureus. Patients still succumb from congestive heart failure, embolic phenomenon, and ruptured mycotic aneurysms, just as they did during Osler’s time.
It is clear there is room for improvement in the diagnosis and management of endocarditis. First, we must continue to refine microbiologic techniques, to allow diagnosis more quickly and accurately. Second, we must develop more effective antimicrobial therapy, especially for pathogens resistant to conventional antimicrobials. Third, we must learn how to combat biofilms. Perhaps in the future we can avoid removal of foreign materials. Finally, we must follow our patients closely and pursue timely surgical intervention when indicated. In recent years this has become more difficult, because patients, once stabilized, are often discharged home or to a skilled nursing facility to complete antibiotic therapy.
While we have learned more about infective endocarditis over the past quarter century, the challenges we face today are greater than ever before.
- Osler W. Chronic infectious endocarditis. Q J Med. 1909;2: 219-30.
- Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345:1318-30.
- Durack DT, Lukes AS, Bright KD, et al: New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Am J Med. 1994;96:200-9.
- Salgado AV, Furlan AJ, Keys TF. Neurologic complications of endocarditis: a 12 year experience. Neurology. 1989;39:173-8.
- Wilson WR, Karchmer AW, Dajani AS, et al: Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci and HACEK micro organisms. JAMA. 1995;274:1706-13.
- Lepidi H, Houpikian P, Liang Z, Raoult D. Cardiac valves in patients with Q-fever endocarditis. J Infect Dis. 2003;187: 1097-106.
- Bosshard PP, Kronenberg A, Zbinden R, et al. Etiologic diagnosis of infective endocarditis by broad-range PCR. Clin Infect Dis. 2003;37:167-72.
- Keys TF. Early-onset prosthetic valve endocarditis. Cleve Clin J Med. 1993;60:455-9.
- Proctor RA. Coagulase-negative staphylococcal infection: a diagnostic and therapeutic challenge. Clin Infect Dis. 2000;31:31-3.
- Melgar GR, Nasser RM, Gordon SM, et al. Fungal prosthetic-valve endocarditis in 16 patients: an 11-year experience in a tertiary care hospital. Medicine. 1997;76:94-103.
- Fowler VG, Sanders LL, Kong LK, et al. Infective endocarditis due to Staphylococcus aureus. Clin Infect Dis. 1999;28:106-14.
- Douglas A, Moore-Gillon J, Eykyn S. Fever during treatment of infective endocarditis. Lancet. 1986;1:1341-3.
- Tornos MP, Permanyer-Miralda G, Olona J, et al. Long term complications of native valve endocarditis in non-addicts: a 15 year follow up study. Ann Intern Med. 1992;117:567-72.
- Andrews MM, Von Reyn CF. Patients election criteria and management guidelines for outpatient parenteral antibiotic therapy for native valve infective endocarditis. Clin Infect Dis. 2001;32:203-9.