Blood culture
For patients suspected of having endocarditis, identification of the microbial etiologic agent and determination of its antimicrobial susceptibility are of paramount importance for both diagnosis and treatment. In most patients with SBE, blood cultures drawn before initiation of antibiotic therapy will all be positive, reflecting the sustained bacteremia associated with an infected endothelial surface. To optimize the value of blood cultures, best-practice guidelines recommend careful antiseptic skin preparation to minimize contamination of the specimen with skin flora: cleaning, followed by application of 70% isopropyl alcohol, which is allowed to dry, followed by application of an iodophor or chlorhexidine, which is also allowed to dry.70 Blood should be drawn using three separate venipunctures, at three different sites, that are taken over several hours if the patient presents with a subacute syndrome or that are taken over a few minutes if acute endocarditis is suspected. The ideal volume for each specimen is 12 to 20 ml, which should be divided equally into two culture bottles, yielding six bottles in all. Obtaining a large volume of blood for culture maximizes the yield,70 but smaller volumes must be accepted from infants and small children. Use of both aerobic and anaerobic broth media also helps maximize yield. If the patient has recently received any antibiotic treatment, use of a medium that contains an antibiotic removal device such as resin will increase the yield by 5% to 15%.70 Blood cultures should be incubated for 5 days, because modern improved culture media will yield growth for the vast majority of relevant microorganisms within this period. This is true even for most of the so-called fastidious or slow-growing bacteria such as the HACEK group and the nutritionally variant streptococci (Abiotrophia species).
Culture-Negative Endocarditis
Blood cultures are negative in 5% to 20% of patients with infective endocarditis9,71 [see Tables 1 and 2]. In about half of these cases, blood cultures are negative as a consequence of previous antimicrobial therapy, even though the vegetation is still infected. Recovery of the causative organism from the blood of these previously treated patients may often be accomplished by repeating blood cultures several days after antibiotics have been discontinued, but some patients remain persistently blood culture negative. Blood cultures may also be negative in some cases of right-sided endocarditis caused by relatively noninvasive organisms. Currently, however, most cases of right-sided endocarditis occur in IDUs and are caused by pyogenic bacteria, such as S. aureus and P. aeruginosa, which are readily isolated from the blood. Culture of bone marrow or arterial blood does not provide materially more information than can be obtained from culture of venous blood.
Several additional factors can thwart isolation of the infecting agent from blood of patients with infective endocarditis. Bar-tonella species may require more than 5 days for isolation, and certain mycelial fungi such as H. capsulatum and Aspergillus species are difficult to isolate even with special techniques such as lysis centrifugation. Finally, isolation of C. burnetii and C. psittaci requires techniques beyond the capabilities of most laborato-ries.13,72,73 Endocarditis caused by Bartonella species, Legionella species, Brucella species, C. psittaci, and C. burnetii can be presumptively diagnosed with serologic tests. These tests should be performed in the evaluation of apparently culture-negative endocarditis, particularly when negative cultures cannot be attributed to prior antimicrobial therapy.73 Direct cultures on special media, histopathologic examination with special stains, and molecular techniques to recover DNA or 16S ribosomal RNA all can be used to determine etiology from examination of vegetations that have been removed from valves or, having embolized, from peripheral arteries.
Figure 2 Anatomic relations between the noncoronary cusp and left cusp of the aortic valve, interventricular septum, membranous septum, tricuspid valve, and mitral valve are shown schematically at the level of the aortic root.
Bacteremia in Patients with Prosthetic Heart Valves
As in native valve endocarditis, the diagnosis of PVE is usually based on history, physical examination, echocardiography, and the detection of bacteremia. However, only a subgroup of patients with a prosthetic valve who experience bacteremia subsequently develop PVE. Of bacteremic patients with a prosthetic valve whose initial positive blood culture is not sentinel evidence of active PVE itself, only 15% to 20% will develop PVE caused by that blood culture isolate.
Transient bacteremia with gram-negative bacilli from extra-cardiac sources usually does not result in colonization of prosthetic valves; however, recrudescent or sustained bacteremia that occurs after the extracardiac focus of infection has been eradicated suggests PVE, as does persistent gram-negative bacil-lary bacteremia with no identifiable extracardiac source, even if a new regurgitant murmur or other signs of endocarditis are lacking. Persistent or high-grade coagulase-negative staphylo-coccal bacteremia in a patient with a prosthetic valve strongly suggests PVE. Similarly, PVE is likely when coagulase-negative staphylococci that have been isolated sporadically from multiple blood cultures are shown by molecular techniques to belong to a single clone. Blood cultures are negative in about 6% of PVE cases. Negative cultures are usually the result of previous antibiotic therapy or reflect unique characteristics of the infecting organisms.
Adjunctive laboratory tests
Results of many laboratory tests are likely to be abnormal in patients with endocarditis because of the systemic impact of the infection and because of injury to various organs. Such tests include the complete blood count, urinalysis, blood urea nitrogen level, creatinine concentration, rheumatoid factor, quantitative immunoglobulins, complement levels, erythrocyte sedimentation rate (ESR), and C-reactive protein level. These adjunctive tests may offer clues to the diagnosis and may be useful for monitoring the progress of treatment for endocarditis, but they usually are not specific and are not critical in establishing a diagnosis; hence, they are not among the Duke diagnostic criteria.
Diagnostic features of cardiac complications
Heart failure is the most frequent cardiac complication of infective endocarditis and may result from a variety of factors. Preexisting valvular disease can be worsened by the effects of infective endocarditis, which can include tears, perforations, and obstruction of valves and rupture of chordae tendineae. These complications can also affect previously normal valves. Damage to the aortic valve by infection can cause rapidly progressive and severe hemodynamic impairment, more so than comparable damage to the mitral valve. Coronary artery embolism can cause silent or overt myocardial infarction, which can contribute to heart failure. A mycotic aneurysm of a sinus of Valsalva or an aortic annulus abscess may rupture through the membranous septum into the right atrium or ventricle [see Figure 2]. Flow through the resulting fistula causes a sudden rise in the jugular venous pressure and a continuous or to-and-fro murmur and thrill along the left sternal border. The lungs remain relatively clear. Valvular damage and subsequent dysfunction, as well as intracardiac fistula formation, can be accurately defined with two-dimensional and Doppler echocardiography from a trans-thoracic or transesophageal approach.
The development of new conduction abnormalities may signal the extension of infection into the septum, affecting its conduction tissues.33,52 PR interval prolongation, left bundle branch block, or right bundle branch block with left anterior hemiblock suggests the extension of infection from the aortic valve. The proximity of the weakest area of the aortic valve annulus to the membranous septum and the conduction system accounts for the development of these conduction abnormalities [see Figure 3]. Similarly, extension of infection from the mitral annulus, which is close to the bundle of His and to the atrioventricular node, may also produce conduction defects, but such extension occurs less frequently than extension from the aortic valve. In the absence of digitalis toxicity or a recent inferior myocardial infarction, the development of nonparoxysmal junctional tachycardia, a Wenckebach block, or complete heart block with a narrow QRS complex serves as a clue to the spread of infection from the mitral annulus into the AV node and proximal bundle of His. Ventricular premature beats in patients with endocarditis who do not have electrolyte abnormalities or digitalis toxicity may reflect myocarditis, myocardial abscesses, or coronary arterial emboli.
The presence of an annular abscess may be suggested by the recent onset of aortic regurgitation, persistent fever during appropriate antimicrobial therapy, and the development of peri-carditis.77,78 Pericarditis caused by extension of a valve ring abscess into the epicardium is more often hemorrhagic or fibrinous than purulent. Occasionally, pericarditis in the course of infective endocarditis is the result of transmural myocardial infarction secondary to coronary emboli. Transesophageal echocar-diography is the most sensitive and preferred noninvasive test for detecting valve-ring abscesses in both native valve endocarditis and PVE.
Differential Diagnosis
The possibility of infective endocarditis should be considered in any patient with a heart murmur and fever. The physician must be particularly alert for atypical cases in which the clinical findings reflect complications of endocarditis affecting organs other than the heart.
Figure 3 The close relation of the three cardiac valves and the cardiac conduction system, as seen in this superior schematic view, accounts for the appearance of conduction defects in endocarditis. (AV—atrioventricular)
Infective endocarditis can cause fever of undetermined origin (FUO), so the differential diagnosis includes the many other infections that may cause FUO. These include tuberculosis, salmo-nellosis, and various intra-abdominal and genitourinary infections [see 7:XXIV Hyperthermia, Fever, and Fever of Undetermined Origin].
A variety of noninfectious illnesses can mimic infective endocarditis, including immune-mediated diseases and rheumato-logic conditions such as juvenile rheumatoid arthritis and poly-myalgia rheumatica. Acute rheumatic fever can cause fever, cardiac murmurs, and heart failure, but acute rheumatic fever can be distinguished from infective endocarditis on clinical grounds and by negative blood cultures, raised anti-streptolysin O antibody titer, and response to salicylates [see 7:I Infections Due to Gram-Positive Cocci]. Marantic endocarditis, which can give rise to multiple embolic episodes and fever, is usually associated with an underlying neoplasm or chronic wasting disease. In polyarteritis nodosa, the presence of fever, anemia, and renal involvement may suggest SBE, and the findings on biopsy of a lesion in a large artery may even resemble those of a mycotic aneurysm. In both systemic lupus erythematosus and antiphos-pholipid antibody syndrome, the manifestations of fever, non-bacterial thrombotic vegetations, systemic emboli, and spontaneous thrombotic events can simulate infective endocarditis.
A cardiac myxoma, usually in the left atrium, may mimic infective endocarditis in both clinical and laboratory features, including low-grade fever, weight loss, arthralgias, cutaneous lesions, clubbing of the fingers, emboli to major arteries, and aus-cultatory findings suggesting mitral stenosis and regurgitation. Cardiac myxoma syndrome may further simulate infective endocarditis by giving rise to cerebral aneurysms at the sites of myxomatous emboli. Negative blood cultures and echocardiog-raphy can help establish the correct diagnosis.
Neoplasms may mimic infective endocarditis by inducing marantic endocarditis or by their hemodynamic effects. For example, richly vascular tumors may be associated with fever, anemia, and hyperdynamic circulation with flow murmurs. A left renal tumor mass may be mistaken for splenomegaly. Carci-noid tumors occasionally mimic endocarditis when they produce endocardial and valvular fibrosis that lead to tricuspid insufficiency and pulmonary stenosis.
Treatment
Two major modalities are used to treat endocarditis: (1) antibiotic therapy and (2) surgical debridement of vegetations and infected perivalvular tissue, with valve repair or replacement as needed.
Antimicrobial treatment
Effective antimicrobial treatment requires identification of the etiologic agent and determination of its antimicrobial susceptibility. Therefore, in the evaluation of a patient with subacute or indolent disease, it is usually best to delay antibiotic therapy until the results of blood cultures are obtained. If recently administered antibiotics have rendered the initial cultures negative, this delay provides an opportunity to obtain additional blood cultures after the antibiotics and their effects have dissipated. However, if the infection is fulminant or if there is valvular dysfunction that may require urgent surgical intervention, empirical antibiotic therapy must be initiated promptly after blood culture specimens have been obtained. Bactericidal antibiotics are used parenterally in high doses. With the exception of PVE caused by staphylococci, antimicrobial therapy for PVE caused by a specific organism utilizes the same drugs recommended for native valve endocarditis. However, therapy is usually administered over a longer period, typically 6 weeks. Patients must be evaluated frequently to assess the efficacy of antimicrobial therapy and the development of complications of therapy or infection.
Streptococci
Viridans streptococci, once mostly penicillin sensitive, have demonstrated increasing resistance to penicillin and the cephalosporins over the past 20 years.79 Accordingly, in the planning of endocarditis treatment, all streptococci must be evaluated for susceptibility to penicillin by determining the minimum inhibitory concentration (MIC). Various regimens provide effective treatment for endocarditis caused by those streptococci that are fully penicillin sensitive (MIC < 0.2 ^.g/ml) [see Table 5].80 One regimen employs parenteral penicillin alone in high doses for 4 weeks. A second regimen utilizes the synergism achieved against most strains of nonenterococcal streptococci by the combination of penicillin and gentamicin. This synergism allows effective treatment with only 2 weeks of combination therapy.80,81 The short-duration regimen should be considered only for selected cases of native valve endocarditis with favorable prognostic features: streptococcal infections that are not complicated by hypotension, renal failure, thrombocytopenia, mycotic aneurysms, or heart failure caused by valvular dysfunction. The etiologic species should be highly susceptible to penicillin (MIC < 0.2 ^g/ml) and should not be a nutritionally variant strain— that is, dependent upon pyridoxal or cysteine for growth. PVE should not be treated with the 2-week regimen. Ceftriaxone, given in a single daily intravenous dose for 4 weeks, is now often recommended for treatment of endocarditis caused by penicillin-sensitive streptococci because this regimen is easily adapted for outpatient treatment and has little toxicity.49,80 Although short-duration combination therapy for penicillin-susceptible streptococcal endocarditis using single daily doses of both ceftri-axone and an aminoglycoside has been successful, experience with this regimen is limited, and the regimen is not recommended for general use. S. bovis is highly penicillin sensitive and can be treated with regimens recommended for other penicillin-sensitive streptococci. When combination penicillin-gentamicin therapy is used to treat endocarditis caused by nonenterococcal streptococci, particularly when short-duration therapy is planned, the streptococcus should be screened for high-level resistance to gentamicin. Although rare in these organisms, high-level resistance would preclude bactericidal synergy and thus indicate the need for an alternative regimen.
Endocarditis caused by relatively penicillin-resistant (MIC = 0.2 to 0.5 ^g/ml) viridans or other nonenterococcal streptococci is treated with a higher dose of penicillin G, combined with gen-tamicin. If the strain is even more resistant to penicillin (MIC > 0.5 ^g/ml), the infection is treated with one of the standard regimens for enterococcal endocarditis [see Table 5]. Nutritionally variant streptococci (previously called S. adjacens or S. defectivus; now named Abiotrophia species) are often relatively penicillin resistant, so endocarditis caused by these organisms should be treated with the standard regimen for enterococcal endocardi-tis.49,80,82 Endocarditis caused by pneumococci or group A streptococci is treated with intravenous penicillin G in a dosage of 20 million units daily for 4 weeks.49,80 Pneumococci that are found to be the cause of endocarditis must be tested for susceptibility to penicillin. Vancomycin is the preferred treatment for endocarditis caused by penicillin-resistant strains with an MIC greater than 1.0 ^g/ml. When pneumococcal endocarditis is complicated by concurrent meningitis, the treatment regimen must ensure adequate penetration of antibiotic into cerebrospinal fluid.83 The ^-hemolytic streptococci belonging to groups B, C, and G have slightly reduced susceptibility to penicillin; for endocarditis, they should be treated as if they were relatively penicillin resistant, with MICs of 0.2 to 0.5 ^.g/ml.
Enterococci
Enterococci are relatively resistant to penicillin, ampicillin, and vancomycin and are fully resistant to cephalosporins. Antibacterial synergism is essential for optimal antimicrobial treatment of enterococcal endocarditis. To achieve this, the entero-coccus must simultaneously be exposed to a cell wall-active antibiotic such as penicillin, ampicillin, or vancomycin, at a concentration at or above the organism’s MIC, and to an aminoglycoside that will exert a lethal effect.49,80,85 The ability of some enterococci to grow in the presence of gentamicin at concentrations of 500 ^g/ml or higher indicates high-level aminoglyco-side resistance; against such organisms, combination therapy will fail to exert a lethal effect regardless of the cell wall-active antimicrobial agent employed. High-level resistance to gentam-icin is the consequence of aminoglycoside-modifying enzymes.
Previously, synergistic bactericidal therapy could be reliably anticipated when gentamicin was combined with penicillin, ampicillin, or vancomycin. This provided regimens for treatment of enterococcal endocarditis49,80 [see Table 5].
Currently, antimicrobial resistance in enterococci presents a complex problem that must be carefully considered in the selection of therapy for enterococcal endocarditis.85 The causative strain must be screened for high-level resistance to gentamicin. Use of gentamicin in combination therapy in the face of high-level resistance exposes the patient to potential toxicity and is without therapeutic benefit. Furthermore, resistance to cell wall-active agents has become increasingly prevalent in entero-cocci. Intrinsic resistance to penicillin and ampicillin (MIC > 32 ^.g/ml) is prevalent in E. faecium. Penicillin and ampicillin resistance caused by ^-lactamase production, which is not detectable with MIC tests but requires screening with the chromogenic cephalosporin nitrocefin, is occasionally seen in E. faecalis. Finally, vancomycin resistance (MIC > 16 ^g/ml) is being encountered increasingly in E. faecalis and E. faecium. If an enterococcus is resistant to a cell wall-active agent, that agent cannot participate in the synergistic killing of the strain. Vancomycin is a suitable cell wall-active agent for combination therapy when organisms have intrinsic or |-lactamase-mediated resistance to penicillin or ampicillin; ampicillin-sulbactam is suitable when ente-rococci have resistance that is mediated by | -lactamase. Entero-cocci that are resistant to vancomycin may be susceptible to penicillin and ampicillin but more often are resistant to these antibiotics as well. For a few of these enterococci, teicoplanin, a gly-copeptide antibiotic that has not been approved for use in the United States but is available elsewhere, remains an effective cell wall-active antimicrobial.80,85 Endocarditis caused by van- comycin-resistant enterococci that are not susceptible to ampi-cillin requires special, individualized regimens, chosen with the assistance of an infectious disease consultant. All enterococci that cause endocarditis must be tested for susceptibility to antimicrobials that have therapeutic potential. Thereafter, a bactericidal synergistic combination of a cell wall-active agent (e.g., penicillin, ampicillin, vancomycin, ampicillin-sulbactam, or te-icoplanin) plus gentamicin can be selected. Single daily dosing of gentamicin should not be used in treating enterococcal endocarditis. If a synergistic combination is not possible because of high-level resistance to gentamicin, prolonged therapy (8 to 12 weeks) with high doses of an effective cell wall-active agent should be administered. To prevent or minimize possible toxici-ty of gentamicin or vancomycin, it is important to monitor serum levels, renal function, and otologic symptoms every 3 to 5 days throughout therapy.49,80
Table 5 Antimicrobial Therapy for Endocarditis in Adults49,80,114
|
Infectious Agent |
Drug |
Dosage and Route of Administration |
Duration of Therapy* (wk) |
|
Penicillin-susceptible viridans and other non-enterococcal streptococci (minimum inhibitory concentration [MIC] < 0.2 ^g/ml) |
Preferred Regimen Penicillin G |
12-18 million units I.V. daily (in divided doses q. 4 hr) |
4 |
|
or Penicillin G |
12-18 million units I.V. daily (in divided doses q. 4 hr) |
2 |
|
|
plus gentamicin or |
3 mg/kg I.M. or I.V. daily (in divided doses q. 8 hr)+ |
2 |
|
|
Ceftriaxone |
2 g I.V. daily (as a single dose) |
4 |
|
|
Alternative Regimen* Vancomycin |
30 mg/kg I.V. daily (in divided doses q. 12 hr) |
4 |
|
|
Relatively penicillin-resistant streptococci |
|||
|
MIC 0.2-0.5 ^g/ml |
Preferred Regimen Penicillin G |
20-30 million units I.V. daily (in divided doses q. 4 hr) |
4 |
|
plus § gentamicin’ |
3 mg/kg I.M. or I.V. daily (in divided doses q. 8 hr)+ |
2 |
|
|
MIC > 0.5 ^g/ml |
Penicillin G plus gentamicin |
Dosages same as in previous regimen |
4 |
|
Alternative Regimen* Vancomycin’ |
30 mg/kg I.V. daily (in divided doses q. 12 hr) |
4 |
|
|
Preferred Regimen Penicillin G |
20-30 million units I.V. daily (in divided doses q. 4 hr) |
4-6 |
|
|
plus gentamicin |
3 mg/kg I.M. or I.V. daily (in divided doses q. 8 hr)+ |
4-6 |
|
|
or Ampicillin |
12 g I.V. daily (in divided doses q. 4 hr) |
4-6 |
|
|
Enterococci" |
plus gentamicin |
3 mg/kg I.M. or I.V. daily (in divided doses q. 8 hr)+ |
4-6 |
|
Alternative Regimen* Vancomycin |
30 mg/kg I.V. daily (in divided doses q. 12 hr) |
4-6 |
|
|
plus gentamicin |
3-5 mg/kg I.M. or I.V. daily (in divided doses q. 8 hr)+ |
4-6 |
|
|
Preferred Regimen Nafcillin or oxacillin plus |
12 g I.V. daily (in divided doses q. 4 hr) |
4-6 |
|
|
gentamicin (optional; see text) |
3 mg/kg I.M. or I.V. daily (in divided doses q. 8 hr)+ |
3-5 days |
|
|
Staphylococci (methicillin susceptible) in the absence of prosthetic material |
Alternative Regimens* Cefazolin |
12 g I.V. daily (in divided doses q. 4 hr) |
4-6 |
|
plus gentamicin (optional; see text) |
3 mg/kg I.M. or I.V. daily (in divided doses q. 8 hr)+ |
3-5 days |
|
|
or Vancomycin |
30 mg/kg I.V. daily (in divided doses q. 12 hr) |
4-6 |
|
|
Staphylococci (methicillin resistant) in the absence of prosthetic material |
Vancomycin |
30 mg/kg I.V. daily (in divided doses q. 12 hr) |
4-6 |
|
Staphylococci (methicillin susceptible) in the presence of prosthetic material |
Nafcillin or oxacillin |
12 g I.V. daily (in divided doses q. 4 hr) |
6-8 |
|
rifampin plus gentamicin# |
300 mg p.o., q. 8 hr 3 mg/kg I.M. or I.V. daily (in divided doses q. 8 hr) |
6-8 2 |
|
|
Staphylococci (methicillin resistant) in the presence of prosthetic material |
Vancomycin |
30 mg/kg I.V. daily (in divided doses q. 12 hr) |
6-8 |
|
rifampin plus gentamicin# |
300 mg p.o., q. 8 hr 3 mg/kg I.M. or I.V. daily (in divided doses q. 8 hr) |
6-8 2 |
|
|
HACEK organisms |
Ceftriaxone** |
2 g I.V. daily (as a single dose) |
4 |
^Treatment programs are longer for prosthetic valve endocarditis (6-8 wk).
+Peak serum gentamicin concentration should be approximately 3 ng/ml and trough concentrations < 1 ng/ml. Some authorities prefer a gentamicin dosage of 1.5 mg/kg q. 8 hr, which results in peak concentrations of approximately 5 ng/ml.
*Alternative regimen is for use in patients with a history of penicillin hypersensitivity.
§Some investigators recommend omission of gentamicin if the MIC is > 0.2 but < 0.5 ng/ml; the role of gentamicin in combination with vancomycin has not been fully established. ‘Enterococci have become increasingly antibiotic resistant (see text); clinical isolates must be fully evaluated for microbial resistance to select optimal therapy. #Administer during the initial 2 weeks (see text).
**Cefotaxime or another third-generation cephalosporin at a comparable dosage could be used.
Bactericidal synergistic therapy for enterococcal endocarditis is associated with cure rates approaching 85%. Treatment with an effective cell wall-active agent alone results in cure rates of 40% to 50% at best.80,86 If bactericidal synergistic therapy is not available, patients with enterococcal endocarditis in whom treatment with a cell wall-active agent alone has failed should undergo excision of the infected valve while suppressive antibiotic therapy is continued.
