Bacterial endocarditis is a life-threatening infectious disease. In recent years, significant changes have occurred in risk factors, prophylaxis, common causal microorganisms, antibiotic resistance patterns of these organisms, diagnostic criteria and antibiotic treatment of bacterial endocarditis. This review focuses on antibiotic treatment of the most frequently encountered forms of bacterial endocarditis in adults.

Part of the management of bacterial endocarditis is prevention. Updated recommendations by the American Heart Association for the prevention of bacterial endocarditis have recently been published.^1,2

Epidemiology

Patients with most congenital heart malformations, acquired valvular defects (e.g., rheumatic heart disease), prosthetic valves and previous bacterial endocarditis are at increased risk for bacterial endocarditis.¹ High risk is conferred by certain complex cyanotic congenital heart diseases, such as transposition of the great arteries and tetralogy of Fallot. Except for isolated secundum atrial septal defects, other congenital defects are associated with moderately increased risk. Hypertrophic cardiomyopathy and mitral valve prolapse with valvular regurgitation are associated with moderately increased risk. Injection drug users have a high risk of bacterial endocarditis, particularly involving the right side of the heart (tricuspid or pulmonic valve).³ Persons who developed significant valvular regurgitation after exposure to appetite suppressant drugs (in particular, fenfluramine and dexfenfluramine) are also at higher risk.⁴

While virtually any bacterial organism can cause bacterial endocarditis, the vast majority of infections are caused by gram-positive cocci. The viridans group of streptococci is the most common cause of endocarditis involving native heart valves in patients with congenital heart disease and in patients who are not injection drug users.⁵ Coagulase-positive staphylococci (Staphylococcus aureus) commonly cause bacterial endocarditis in patients with prosthetic valves and in injection drug users.⁶ Presence of these organisms is also a common cause of acute bacterial endocarditis in persons whose heart valves were previously normal.⁷

Infection with coagulase-negative staphylococci (Staphylococcus epidermidis) is a relatively common cause of bacterial endocarditis in patients with valvular prostheses.⁸ Enterococci are causative agents in approximately 5 to 10 percent of bacterial endocarditis cases reported in several series.⁵ Streptococcus bovis occasionally causes bacterial endocarditis in patients with an underlying colon malignancy or other intestinal disorder. Approximately 5 to 10 percent of patients who are not injection drug users and who have native valve endocarditis are infected with a slow-growing gram-negative bacillus of the HACEK group⁹ (Haemophilus parainfluenzae, Haemophilus aphrophilus, Actinobacillus actinomycetem-comitans, Cardiobacterium hominis, Eikenella corrodens and Kingella kingae).

Diagnosis

Diagnostic criteria¹⁰ for bacterial endocarditis are provided in Tables 1 and 2.¹¹

The definite diagnosis of bacterial endocarditis can be based on pathologic criteria or clinical criteria. A diagnosis of definite bacterial endocarditis is made if the patient meets one of the following conditions: two major criteria; one major criteria and three minor criteria; or five minor criteria (Table 2).

Bacterial endocarditis is considered possible if some clinical manifestations of endocarditis are present but are not sufficient to meet the criteria for definite bacterial endocarditis. Because of the serious consequences of untreated bacterial endocarditis, many patients are treated initially as if they have bacterial endocarditis until additional information is obtained that might resolve the diagnostic dilemma.

Clinical manifestations of bacterial endocarditis are highly variable and frequently non-specific. Some degree of fever is common. Patients may present acutely ill with high fever and marked systemic toxicity (acute bacterial endocarditis), or they may present with vague, nonspecific symptoms (fatigue, weakness, malaise, anorexia, arthralgias, low-grade fever) lasting weeks to months (subacute bacterial endocarditis). Some patients present with congestive heart failure, stroke or a severe localized infection such as pneumonia, cellulitis or septic arthritis. Manifestations that are thought to represent immunologic phenomena (glomerulonephritis, Osler's nodes, Roth spots and positive rheumatoid factor) are more common in patients with a subacute course than in patients with an acute presentation.⁷

Physicians must have a high index of suspicion for bacterial endocarditis, particularly in patients with predisposing conditions or high-risk behaviors. Findings on physical examination include signs of congestive heart failure, heart murmur consistent with valvular regurgitation, petechiae, splenomegaly and conjunctival or retinal hemorrhages. Laboratory findings include anemia, leukocytosis, elevated erythrocyte sedimentation rate and microscopic hematuria. However, bacterial endocarditis may be present in the absence of many of these findings.⁷

If bacterial endocarditis is considered a possibility based on history, physical findings and preliminary laboratory findings, at least two sets of blood cultures, preferably 12 hours apart, should be obtained and an echocardiogram should be performed. Most typical cardiac lesions are evident on transthoracic echocardiography. Transesophageal echocardiography is more sensitive for lesions of endocarditis and should be performed if the results of transthoracic echocardiogram are negative or equivocal⁷ and bacterial endocarditis is considered likely.

Treatment

An appropriate antibiotic regimen is essential for the successful treatment of bacterial endocarditis. Bacterial endocarditis is characterized by a high concentration of infecting organisms within endocardial vegetation; the use of high levels of antibiotics over an extended time is necessary to eradicate these organisms, even when there is good in vitro sensitivity to the antibiotic. The challenge is greater when the infecting organism has reduced sensitivity to antibiotics. The choice of antibiotic therapy is based on several factors, including the identity of the infecting organism, the profile of antibiotic sensitivity of the organism, the pharmacokinetics of antibiotic agents, and the individual characteristics of the patient (i.e., drug allergies, renal function). A more extensive discussion of treatment recommendations for bacterial endocarditis is available from the American Heart Association.¹²

VIRIDANS STREPTOCOCCI

Infection with viridans streptococci is a common cause of endocarditis involving native valves with preexisting congenital or acquired defects. S. bovis is another streptococcal species that causes bacterial endocarditis. Most of these organisms are highly sensitive to penicillin. Patients infected with one of these organisms should be treated for four weeks with intravenous penicillin in doses of 12 million to 18 million units every 24 hours or 2 g of ceftriaxone (Rocephin) in a single daily dose given intravenously or intramuscularly. The penicillin can be administered continuously or in six divided doses. The bacteriologic cure rate with such treatment is approximately 98 percent.

Accumulating evidence has shown that an equivalent cure rate can be achieved with a two-week combination of penicillin or ceftriaxone and gentamicin (Garamycin) administered intramuscularly or intravenously.¹³ This alternative two-week regimen is appropriate for uncomplicated bacterial endocarditis in patients with a low risk of complications from gentamicin.

When infection with viridans streptococci involves a prosthetic valve, penicillin should be administered for six weeks with concomitant gentamicin during at least the first two weeks. Patients with viridans streptococci infection who have a documented allergy to penicillin should be treated with vancomycin (Vancocin), 30 mg per kg every 24 hours intravenously in two divided doses. If the dosage exceeds 2 g in 24 hours, serum levels should be monitored. Vancomycin and gentamicin dosages and intervals should be adjusted in patients with impaired renal function. Patients with an equivocal history of penicillin allergy should be challenged with a test dose.¹⁴

Occasionally, bacterial endocarditis is caused by viridans streptococci that are moderately susceptible to penicillin. These patients should be treated with intravenous penicillin at a dosage of 18 million units every 24 hours for four weeks and with gentamicin for the first two weeks. The unusual patient with bacterial endocarditis due to viridans streptococci with low susceptibility to penicillin should be treated with a combination of intravenous penicillin and gentamicin for four to six weeks. Generally, a four-week course of therapy is indicated for patients with symptoms of less than three months' duration and a six-week course of therapy is appropriate for patients with symptoms lasting longer than three months. Patients with documented penicillin allergy should receive vancomycin for four to six weeks (Table 3).

In recent years, hemodynamically stable patients with viridans streptococcal bacterial endocarditis have been treated as outpatients after an initial course of inpatient therapy.⁸ Ceftriaxone therapy in a single daily dose is particularly amenable to this treatment strategy.

ENTEROCOCCI

Medical treatment of enterococcal endocarditis is challenging and difficult because of the increasing resistance of enterococci to multiple antibiotics.^15,16 Enterococcal organisms are uniformly resistant to a concentration of penicillin G of 0.1 μg per mL. A combination of high-dose penicillin or ampicillin and an aminoglycoside (streptomycin or gentamicin) has a synergistic bactericidal effect on enterococci and usually produces cure. However, enterococcal resistance to aminoglycosides has become a problem. Testing the isolated organism is crucial to determine the pattern of antibiotic susceptibility/resistance; an organism resistant to gentamicin may be sensitive to streptomycin and vice versa.¹²

Patients with an infecting organism that is relatively sensitive to gentamicin should be treated with a combination of high-dose penicillin (18 million to 30 million units every 24 hours, intravenously) and gentamicin at standard dosage for four to six weeks. Streptomycin at a dosage of 7.5 mg per kg every 12 hours may be substituted for gentamicin if the susceptibility pattern favors streptomycin. Other amino-glycosides are not as effective as these agents.¹² Ampicillin in a dosage of 12 g every 24 hours intravenously can be substituted for penicillin in these regimens. Cephalosporins are not effective in the treatment of enterococcal bacterial endocarditis. Vancomycin in a dosage of 30 mg per kg every 24 hours should be used in patients with penicillin allergy.

High-level resistance of enterococci to penicillin (minimal inhibitory concentration greater than 16 μg per mL) may be on the basis of intrinsic resistance or caused by production of β-lactamase. When intrinsic resistance of this magnitude is present, vancomycin should be substituted for penicillin. When resistance is due to β-lactamase production, ampicillin-sulbactam (12 g of ampicillin per 24 hours) or vancomycin should be substituted for penicillin. Table 4 summarizes treatment regimens for enterococcal bacterial endocarditis.

Unfortunately, enterococcal resistance to vancomycin is becoming an increasing problem.¹⁵ Several combinations of agents are being tested for effectiveness in the treatment of vancomycin-resistant enterococci.¹⁵

STAPHYLOCOCCI

S. aureus is a common cause of bacterial endocarditis in patients with prosthetic valves and in injection drug users. This organism is also the most common cause of acute bacterial endocarditis in patients with previously normal cardiac valves. In this situation, the organisms frequently seed the blood stream from localized staphylococcal infections such as abscesses, cellulitis and osteomyelitis. The vast majority of S. aureus isolates from patients with bacterial endocarditis are resistant to penicillin. The unusual patient with bacterial endocarditis caused by a penicillin-susceptible S. aureus can be treated with penicillin as described in the treatment for endocarditis caused by viridans streptococci.

For S. aureus organisms that are resistant to penicillin, a factor in determining antibiotic treatment is whether the organism is sensitive to methicillin. Nafcillin (Unipen) or oxacillin (Bactocill) should be administered (2 g intravenously every four hours) for four to six weeks to patients with bacterial endocarditis due to methicillin-susceptible S. aureus (MSSA). Adding gentamicin for the first three to five days of treatment may protect the infected valve from further damage and may decrease the duration of bacteremia, thus reducing the risk of extracardiac infection. Extending the use of gentamicin beyond three to five days does not favorably affect the course.

Injection drug users with right-sided endocarditis caused by MSSA can be effectively treated with a two-week course of nafcillin or oxacillin and gentamicin.¹⁶ This regimen should be reserved for patients who have no evidence of left-sided involvement, extracardiac infection, renal insufficiency, congestive heart failure or other hemodynamic compromise. The results of a randomized clinical trial¹⁷ suggest that injection drug users with uncomplicated right-sided staphylococcal bacterial endocarditis can be effectively treated with four weeks of oral ciprofloxacin (Cipro) and rifampin (Rifadin). Injection drug users with left-sided involvement or any complications of right-sided endocarditis should be treated with at least four weeks of nafcillin or oxacillin.

Patients with prosthetic valve infection with MSSA should be treated with a combination of oxacillin or nafcillin and rifampin (300 mg orally every eight hours) for at least six weeks. In addition, gentamicin should be administered during the first two weeks of this course of therapy.

For patients allergic to penicillin, a first-generation cephalosporin (cefazolin [Ancef] 2 g intravenously every eight hours) or vancomycin should be used instead of nafcillin or oxacillin for the treatment of MSSA endocarditis.

Methicillin-resistant S. aureus (MRSA) is increasingly identified as a cause of bacterial endocarditis, particularly in patients with prosthetic valves, right-sided endocarditis secondary to intravenous drug use, and nosocomial endocarditis.⁸ These organisms are also resistant to cephalosporins. Patients with native valve endocarditis due to MRSA should be treated with vancomycin for four to six weeks.

Prosthetic valve infection with MRSA is frequently fatal and should be treated with a combination of vancomycin, rifampin and gentamicin. If the organism is resistant to all aminoglycosides, a fluoroquinolone should be used in combination with vancomycin and rifampin.¹²

Coagulase-negative staphylococci are a relatively common cause of infection of prosthetic valves.⁸ S. epidermidis is the species most likely to be involved. Because of frequent skin colonization with this organism, it is crucial to distinguish between true bacteremia and a contaminated specimen when the blood culture is positive for S. epidermidis. Recovery of the organism in more than one set of blood cultures strongly suggests bacteremia. Many coagulase-negative staphylococci are resistant to methicillin. If methicillin-susceptibility is clearly documented in vitro, treatment of prosthetic valve infection should consist of a combination of nafcillin or oxacillin and rifampin for at least six weeks and gentamicin for the first two weeks. For the more commonly encountered methicillin-resistant coagulase-negative staphylococci, a combination of vancomycin, rifampin and gentamicin is indicated. Table 5 summarizes the treatment of staphylococcal bacterial endocarditis.

HACEK ORGANISMS

Patients with endocarditis of a native valve caused by an organism in the HACEK group should be treated with ceftriaxone in a dosage of 2 g daily intravenously or intramuscularly for four weeks. Patients with infection of a prosthetic valve should be treated with ceftriaxone for six weeks.

Empiric Treatment

Antibiotic treatment is frequently initiated before the results of blood cultures and antibiotic sensitivity testing become available. To cover the possibility of infection with antibiotic-resistant enterococci or staphylococci, initial therapy should consist of vancomycin and gentamicin. Subsequent changes in the antibiotic regimen should be based on the results of cultures and sensitivity testing. Organisms from the HACEK group may not be identified in blood cultures for a week or longer, necessitating empiric antibiotic therapy during this period.

Complications

Patients with bacterial endocarditis should be monitored carefully. Blood cultures should be obtained to ensure eradication of the organism. Gentamicin blood levels should be monitored with dosage adjustments as indicated and renal function should be assessed frequently when an aminoglycoside is administered. If a prolonged course of gentamicin is planned, a hearing assessment should be performed.

Fever usually resolves within several days of initiation of effective antibiotic treatment, although fever may persist longer with S. aureus infection. Persistent fever after the first week of treatment suggests a septic embolic complication or inadequate antibiotic therapy. The recurrence of fever after an initial defervescence suggests a septic or nonseptic embolic event, a drug hypersensitivity reaction or the emergence of a resistant strain. Surgical replacement of an infected valve is necessary if congestive heart failure secondary to valvular regurgitation persists or worsens during antibiotic treatment. More extensive discussion of surgical management of bacterial endocarditis is available elsewhere.¹⁸

Final Comment

The diagnosis of bacterial endocarditis is based on clinical, laboratory and echocardiographic criteria. Empiric treatment is initiated in any patient who is suspected of having bacterial endocarditis. Once the causative organism is established, the appropriate antibiotic regimen can be started. By following the recommendations, most patients with bacterial endocarditis can be cured.