Infective Endocarditis

INFECTIOUS DISEASES

0749-0690/92 $0.00

+ .20

INFECTIVE ENDOCARDITIS Margaret S. Terpenning, MD

The term endocarditis refers to any inflammation of the protective mucosa of the heart's interior. This article focuses only on infective endocarditis (IE) due to bacterial seeding of injured endocardium. Although many other types of organisms, including fungi and rickettsiae, also can cause endocarditis, they are discussed only briefly herein. Most, but not all endocarditis occurs on or near one of three heart valves: the aortic, mitral, or tricuspid. Endocarditis also can occur on the endocardia1 wall in areas of turbulent flow. EPIDEMIOLOGY

IE is a disease with rapidly changing epidemiology.16When described by William Osler in the early years of internal medicine in the United States,3O it was a deadly disorder usually presenting in an advanced stage with heart valve destruction, cardiovascular decompensation, multiple peripheral manifestations, and death. This scenario of untreated IE is still seen today, but such severe manifestations are becoming unusual in developed countries. Recent surveys have shown that death directly due to or linked to IE is still seen in 45% of affected elderly patients.43The usual definition of elderly in this context is 60 years of age and older. Many undiagnosed cases of IE in elderly patients also have been noted at autopsy, but because of the low autopsy rate in this population, it is not possible to determine how many fatal cases may go undiagnosed. Recently, reported prevalence of IE show one case in 300,000 persons. There is now a marked shift in epidemiology of IE with an increased proportion of endocarditis cases occurring in older Moreover, an increasing proportion of elderly cases of bacteremia and endocarditis are nosocomial in origin.16*22*42 This is in large part due to more older people being subjected to immunosuppression related to planned drug protocols given for cancer, immunologic diseases, or transplants, as well as the use of invasive procedures and prosthetic materials in elderly patients. From the University of Michigan Medical School; and Department of Veterans Affairs Medical Center, Ann Arbor, Michigan

CLINICS IN GERIATRIC MEDICINE VOLUME 8 NUMBER 4 NOVEMBER 1992

903

904

TERPENNING

In addition to problems of reporting and detection, blood cultures are performed in different ways in different places, which has a profound effect on the ability to detect IE.3,4,21,50 Geographic location, referral bias, and socioeconomic mix can affect the types of IE seen in a ~ o m m u n i t y . ~ ~ , ~ ~ PATHOGENESIS Noninfective Endocarditis

Although IE is the focus here, thrombotic endocarditis, which can occur in elderly persons, needs to be m e n t i ~ n e dThe . ~ ~usual requirement for any endocarditis is an injury to the endocardium. Endocarditis has been associated with multiple defects of the heart valve or of the wall of the heart itself. In general, any heart defect capable of producing turbulent flow can be considered capable of producing injury to the e n d o c a r d i ~ m . ~ , ~ ~ Infective Endocarditis

The degree of endocardia1 injury, the duration and level of bacteremia, and the type of organism are all important considerations in the risk for IE.23,29,51 This is an active area of research in the cases of Staphylococcus aureus and Staphylococcus epidern~idis;~,~~ the risk of IE due to enterococcal bacteremia also is undergoing careful c o n s i d e r a t i ~ n . Bacteria ~ ~ , ~ ~ are capable of adaptations that promote their adherence to the endocardium. Adherence properties are now being studied for both gram-positive bacteria and for the increasingly common nosocomial gramnegative pathogens. The viridans group of streptococci has been shown to have special adherence properties, especially in the case of Streptococcus mu tan^.^^,^^ Pathologic changes in the endocardium that increase the risk of IE include some that are most commonly seen in older adults, such as calcific aortitis. Multiple other valvular changes in elderly persons may increase the risk of IE.2,22,43,47 Endocarditis can precipitate cardiac decompensation, renal damage, often of immune complex origin, and central nervous system damage in the form of stroke.1s,26,30,43,47 In geriatric patients, the damaging effects of these pathologic changes are increased by other injuries and coexisting disabilities or illnesses, which may make recovery and return to full function more difficult and less likel~.~~,~~ SOURCES OF INFECTIVE ENDOCARDITIS

In elderly patients it has become particularly important to identify sites that are sources of bacteremia and subsequent IE. The sources for IE identified in aging patients include dental procedures, drainage of dental abscesses, abdominal sites, urinary catheterization or procedures, lung disease, central or peripheral intravenous catheters, and retained prosthetic materia1.4,23*42,43 Much research is now focusing on the severity or quantity of bacteremia due to invasive devices or procedure^.^^^^^^^^ Many issues remain yet unresolved about choices for prophylaxis in the setting of various invasive procedures. Based on the specific spectrum of organisms present and the exact nature of the procedure planned, more individualized prophylaxis guidelines for older patients can be expected over the next

CLINICAL MANIFESTATIONS

The clinical manifestations of IE can occur in almost any body l ~ c a t i o n . ~ ~ , ~ ~ These manifestations themselves may be changing in prevalence. In recent studies, overt emboli, hematuria, cardiac decompensation, and stroke with related dementia have been increasingly reported as presenting symptoms in geriatric patients A number of manifestations that have been helpful in diagnosing IE, with IE.43,46 such as fever, are less frequently seen in older patients. In a recent survey, 68% of elderly endocarditis cases were misdiagnosed on initial admission. Some cases were diagnosed as a noninfectious illness, whereas other patients were thought to have infection but not of a heart valve. Lack of fever in addition to the presence of confusion increases the risk of overlooking the diagnosis of IE in older patient^.^^,^^ Because the clinical manifestations can be protean, including fever; malaise; Osler nodes, Janeway lesions, Roth's spots, and other embolic phenomena; confusion; or symptoms of heart failure, strict criteria are needed before the diagnosis of IE can be established. Blood cultures are most critical. The multiple manifestations of native valve endocarditis have been discussed at length in recent studIt is now standard practice to apply the diagnostic criteria of Von Reyn ies.7,8,25,47,49 in order to make a clinical diagnosis of IE (Table The diagnosis of late prosthetic valve endocarditis also demands strict diagnostic criteria.20 Table 1. CRITERIA FOR INFECTIVE ENDOCARDITIS

Definite Direct evidence of infective endocarditis based on histology from surgery or autopsy, or on bacteriology (Gram's stain or culture) of valvular vegetation or peripheral embolus. Probable

Persistently positive blood cultures* plus one of the following: 1. New regurgitant murmur 2. Predisposing heart diseaset and vascular phenomena* Negative or intermittently positive blood cultures§ plus all of the following: 1. Fever 2. New regurgitant murmur 3. Vascular phenomena Possible

Persistently positive blood cultures plus one of the following: 1. Predisposing heart disease 2. Vascular phenomena Negative or intermittently positive blood cultures with all of the following: 1. Fever 2. Predisposing heart disease 3. Vascular phenomena For viridans streptococcal cases only: at least two positive blood cultures without an extracardiac source and fever. *At least two blood cultures obtained, with two of two positive, three of three positive, or at least 70% of cultures positive if four or more cultures are obtained. ?Definite valvular or congenital heart disease, or a cardiac prosthesis (excluding permanent pacemakers). *Petechiae, splinter hemorrhages, conjunctival hemorrhages, Roth's spots, Osler's nodes, Janeway lesions, aseptic meningitis, glomerulonephritis,and pulmonafy, central nervous system, coronary or peripheral emboli. §Any rate of blood culture positivity that does not meet the definition of persistently positive. Adapted from von Reyn CF, Levy BS, Arbeit RD, et al: Infective endocarditis. An analysis based on strict case definitions. Ann Intern Med 94506, 1981, with permission.

LABORATORY FINDINGS Blood Cultures and Tests

Blood cultures are required by criteria for diagnosis of IE, and the procedures for the collection of blood cultures are extremely important. A minimum of three sets (aerobic and anaerobic culture media and conditions) of blood cultures should be obtained, ideally from different venous sites at different times of the day (in urgent situations, each set may be obtained 15 minutes apart). There are organisms that may not grow after 2 weeks of holding the cultures. In particular, some fastidious organisms such as Kingella kingae or nutritionally deficient streptococci may require a longer period of observations of In a clinical setting with fever and other signs of infection, a positive blood culture must not be ignored, even if it appears to be a nonpathogenic organism such as S. epidermidis or diphtheroids. Sometimes, positive blood cultures appear after long incubation periods or in a clinical setting that does not suggest infection. The epidemiology, risk factors for survival, and laboratory findings of patients with positive blood cultures have been reviewed recently.13,22,50,51 The laboratory findings that support the diagnosis of IE are often not definitive. The erythrocyte sedimentation rate is not always elevated. Other helpful but nondiagnostic tests include the presence of circulating immunoglobulins and rheumatoid f a ~ t o r . ~Although ~,~' anemia is to be expected, it is not always present. Noninvasive Studies

The search for vegetations has traditionally been a part of the attempt to diagnose IE. Vegetations may not always be seen, however, and the accuracy of examination for vegetations may be somewhat less in eIderly patients with IE.43 This may be because certain lesions common in older persons, such as calcific aortitis, are echo dense.46Calcific aortic stenosis, in some series, has been the most common valvular defect requiring valve replacement in geriatric patients.34Standard two-dimensional transthoracic echocardiography (TTE) has a diagnostic sensitivity for IE of approximately 60%.40Recently, transeosophageal echocardiography (TEE) has been shown to be more sensitive than TTE in identifying valvular v e g e t a t i ~ n s .This ~ ~ , procedure, ~~ however, is somewhat invasive and is not recommended for routine screening of IE. The role of TEE should be limited to c o n h ing valvular vegetations in clinically suspected cases of IE when the TTE is negative, to diagnose valvular abscess in the absence of a positive TTE, and to define vegetation in prosthetic valves.32 CAUSE

The organisms most commonly found in IE vary with the location and the age group reported. Overall, however, the major organisms in all age groups continue to be streptococci, which are seen in up to 60% to 80% of cases. The types of streptococci include viridans streptococci in 30% to 40% of cases, enterococci in 5% to 18%, and other streptococci in 15% to 25%. After streptococci, the most frequent pathogens are s t a p h y l o c o c ~ i ,including ~ ~ ~ ~ ~ ~coagulase-negative ~~~~~~~~ s t a p h y l o c o c ~ i .The ~ ~ ~rarer ~ ~ ~pathogens ~ ~ ~ ~ ~ in endocarditis include the aerobic gram-negative bacilli (1% - 13%);",28,52fungi (2%- 4 % ~ )other ; ~ ~ bacteria (5%7%); and "culture-negative" (5%-24%) cases. In older patients with IE, the microbiology is similar to that of the genera1

INFECTIVE ENDOCARDITIS

907

population with exception being perhaps a higher frequency of group D streptococci including both the non-enterococcal Streptococcus bovis and enterococcal Enterococcus f a e ~ a l i s S. . ~ bovis is particularly important clinically because of its high association with colorectal disease, especially c a r ~ i n o m aStaphylococcus .~~ aureus accounts for 25% to 45% of IE cases in older patient^.^,'^,^^

THERAPY

Therapy for IE in elderly patients must be started early. A number of excellent reviews have included a general approach to therapy for IE.36,49,53 In older patients suspected of IE who are clinically stable and have no complications of IE, antimicrobial therapy may be withheld for 48 hours until specific microbial identification is made. Thus, specific antibiotic treatment can be started. Empiric antibiotic therapy is indicated in elderly endocarditis patients who (1) are hypotensive or septic; (2) have congestive heart failure; (3) have a new regurgitant murmur due to IE; (4) have aortic valve involvement; or (5) develop emboli to major organs (e.g., brain, kidney, lung). Alternatively, some clinicians favor initiating empiric therapy in all suspected cases of IE in older adults. Once culture data indicate a specific cause, the empiric regimen should be changed to a more appropriate agent that is active against the pathogen. Empiric therapy may be begun with intravenous penicillin G (10-20 million units/day) or ampicillin (8-12 g/day), naficillin or oxacillin (8 g/day), and gentamicin (3 mg/kg/day or other aminoglycosides in equivalent doses). If penicillin allergy is present, treatment may be initiated with vancomycin (1.5 -2 g/day) plus gentamicin (3 mg/kg/day or other aminoglycosidesin equivalent dose). Long durations of antibiotic therapy are usually required for cure of IE. Four to six weeks of intravenous antimicrobial therapy are recommended, using an antibiotic that is microbicidal. In the case of a documented endocarditis with penicillin-sensitive streptococci (e.g., viridans streptococci), penicillin given intravenously in combination with an aminoglycoside over a 2-week period may be curative. Most older patients with IE require a minimum of 4 weeks of antimicrobial therapy, however. Generally, 6 weeks of antibiotics for native valve IE are recommended for patients with gram-negative bacillary endocarditis, aortic valve endocarditis (except if the organism is penicillin-sensitive streptococcus), and major complications of IE (e.g., heart failure, major emboli). Patients with fungal endocarditis may require antifungal treatment for periods exceeding 6 weeks. In general, parenteral antibiotics are far more useful than oral drugs because of the importance of adequate bactericidal or fungicidal activity. When a nonbactericidal antibiotic is used, such as tetracycline or erythromycin, the microbiologic failure rate as well as relapse rate is high. Table 2 summarizes antibiotic recommendations for the most common cause of IE in elderly patients. During the course of antimicrobial treatment for IE, careful attention must always be paid to complications that may require surgical intervention. Cardiac surgical consultation should be obtained early in the course of IE, especially if it is caused by a virulent organism, occurs on the aortic valve, or is associated with mild heart failure, so that surgeons can be alerted to any rapid clinical change and initiate urgent surgery when necessary. The sudden onset of multiple emboli, adverse hemodynamic changes, new-onset heart failure or worsening of heart failure, or new onset of a regurgitant murmur should be considered indications at least for urgent surgical evaluation and usually for cardiac surgery. Surgical intervention also may be needed for abscess drainage or debridement at embolic sites (e.g., spleen, limb).

908

TERPENNING

Table 2. ANTIBIOTIC RECOMMENDATIONS FOR PATHOGENS CAUSING INFECTIVE ENDOCARDITIS IN ELDERLY PATIENTS Organism Viridans streptococci, Streptococcus bovis Enterococci

Staphylococcus aureus;t coagulasenegative staphylococci* Gram-negative bacilli

Drug and Daily Dosage* Penicillin G 10-20 mu (add gentamicin 1 mg/kg/day if shock occurs or infection involves aortic valve or extracardiac foci) Penicillin G 10-20 mu (or ampicillin 8- 12 g) plus gentamicin 3 mg/kg (for penicillin allergy use vancomycin 1.5-2 g plus gentamicin 3 mg/day) Nafcillin (or oxacillin) 8-12 g (for penicillin allergy use vancomycin 1.5 -2 g) Gentamicin 5 mg/kg (or amikacin 15 mg/kg)plus piperacillin 12- 18 g (or ceftazidime 4-6 a)

"Dose for normal renal function; drugs given intravenously or intramuscularly. tGentamicin (3 mg/kg/day) is added the first 3 to 5 days for all cases; some recommend gentamicin for first 2 weeks for left-sided infective endocarditis and prosthetic valve endocarditis. SVancomycin 1.5 to 2 g sometimes is needed initially for this organism. mu = million units

If fever returns after an afebrile period, this may indicate a relapse of IE, development of extracardiac foci of infection, peripheral emboli, or drug fever. Drug fever also must be considered as a source of recurrent fever. New onset of renal failure during the course of therapy for IE should prompt additional evaluation. Renal failure may be due to either drugs, emboli, or immunologic damage. Throughout the course of antibiotic therapy, blood levels of antibiotics should be obtained to assure bactericidal levels. If aminoglycosides or vancomycin is administered, peak and trough serum concentrations of these drugs should be obtained at least weekly with careful monitoring of renal function as well as assessments of VIII nerve function. Repeat blood cultures should be done periodically to assure that they have become and remain sterile. Minimum inhibitory and bactericidal concentrations should be determined for the organisms to ensure that an appropriate regimen has been chosen. During prolonged antibiotic courses, the elderly patient need not be bedbound if this can be avoided. Even in the hospital, a rehabilitative approach is needed.43Home intravenous therapy, when available, can be very beneficial to maintain function in older patients.

COMPLICATIONS

The debilitating complications of left-sided endocarditis, including strokes and peripheral emboli, increase if the disease is not promptly diagnosed in elderly patients. Older patients with limb emboli may need amputation. Right-sided endocarditis complications include pulmonary emboli and abscesses. Other consequences of acute endocarditis include enucleation, cardiac valve replacement, cardiac abscess drainage, splenectomy, renal failure, and other surgery for emboli. Elderly patients with IE suffer permanent functional loss more often than younger patients.

INFECTIVE ENDOCARDITIS

909

PROSTHETIC VALVE ENDOCARDITIS

Many elderly prosthetic valve endocarditis (PVE) patients present with very little fever, with no peripheral manifestations, and sometimes not even with a high neutrophil c o ~ n t .Early ~ ~ ,bacterial ~~ PVE can often be prevented by antibacterial prophylaxis. The major pathogens causing PVE are Staphylococcus epidermidis, S. aureus, streptococci, enterococci, gram-negative bacilli, and diphtheroids. The relative frequency of each organism may vary depending on whether infection occurs early (within 60 days after valve replacement) or late (after 60 days).44These bacteria are more capable of preferential adherence to prosthetic material and Treatment of PVE due to various show lower virulence on native valves.34,38,39 pathogens has been r e v i e ~ e dEmpiric . ~ ~ antimicrobial ~ ~ ~ ~ ~therapy ~ ~ ~should ~ ~ be~ ~ initiated with vancomycin (1.5-2 g/day) and gentamicin (5 mg/kg/day) until a specific cause is identified.44Many clinicians also would add rifampin (600 mg/ day). As in other prosthetic device infections, it is frequently necessary to remove all prosthetic material before complete microbiologic cure can occur.14 Only in a minority of cases can cure be expected without s ~ r g e r y . ' ~ , ~ ~ , ~ ~ ANTIBIOTIC PROPHYLAXIS

Although prophylaxis is a controversial topic, progress has been made in standardizing it through the American Heart Association and the American Dental Association. Further development of specific prophylaxis for native valves and for prosthetic valves is now a focus for research. Excellent reviews exist concerning the prophylaxis recommendations for various procedure^.^,^,^^ Prosthetic valves probably require special prophylactic regimens at the time of insertion.37Prophylaxis guidelines continue to evolve and change as further research and clinical exverience are accumulated. There are several basic principles of chemoprophylaxis for IE that simplify the approach to decision-making on appropriate administration of antibiotics. Native valve damage (congenital or acquired) is associated primarily with gram-positive coccal infections but is uncommonly infected with gram-negative bacilli except in intravenous drug-associated IE. Thus, prophylaxis against gram-negative bacilli is generally not warranted under these conditions.

Table 3. HIGH-RISK PROCEDURES FOR CHEMOPROPHYLAXIS FOR INFECTIVE

ENDOCARDITIS Dental work producing gingival bleeding or performed in an infected mouth (e.g.,tooth abscess). Tonsillectomy and/or adenoidectorny. Surgical intervention or biopsy of respiratory mucosa. Incision and drainage of infected tissue. Genitourinary procedures (cystoscopy, prostatic surgery, urethral dilatation, urinary tract surgery, vaginal hysterectomy). Gastrointestinal (GI) procedures (gallbladder and colon surgeries, esophageal dilatation, scleral therapy for esophageal varices, colonoscopy, upper GI endoscopy with biopsy, or proctosigrnoidoscopy with biopsy). Data from Dajani AS, Bisno AL, Chung KJ, et al: Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA 2642919, 1990

Table 4. INFECTIVE ENDOCARDITIS CHEMOPROPHYLAXIS FOR ORAL AND RESPIRATORY TRACT PROCEDURES Standard Regimen' Amoxicillin, 3 g orally, given 1 hour before procedure. Follow with 1.5 g orally 6 hours after initial dose. For penicillin-allergic patients, give erythromycin ethylsuccinate 800 mg or erythromycin stearate 1 g orally 2 hours before procedure. Repeat with one half the dose 6 hours later. Alternatively, clindamycin, 300 mg orally 1 hour before procedure and repeat 6 hours later with 150 mg. Alternative Regimens Ampicillin, 2 g intravenously or intramuscularly 30 minutes before procedure. Repeat in 6 hours with ampicillin 1 g intravenously or intramuscularly or with ampicillin 1.5 g orally. Clindamycin 300 mg intravenously 30 minutes before procedure. Repeat with intravenous or oral clindamycin 150 mg 6 hours later. Vancomycin, 1 g intravenously infused over 60 minutes, beginning 1 hour before procedure. No repeat dose necessary.

*Includesprosthetic heart valves and high-risk patients.

Prosthetic valves are at high risk for IE for both gram-positive coccal and gram-negative bacillary organisms, as well as w i t h low-level bacteremia. Conditions or procedures associated w i t h low-level bacteremia (e.g., liver biopsy, barium enema, proctosigmoidoscopy without biopsy) usually do not require chemoprophylaxis for native valve disease but should be considered for chemoprophylaxis for prosthetic valves. High-risk procedures that should be preceded b y chemoprophylaxis for naturally damaged or prosthetic valves are summarized in Table 3.9 Table 4 provides recommendations for chemoprophylaxis during oral and respiratory tract procedures, and Table 5 gives antibiotic prophylaxis recommendations for gastrointestin a l and genitourinary procedure^.^

ACKNOWLEDGMENT I would like to acknowledge the assistance of Judy Seeger in manuscript preparation. This work was supported by Geriatric Research, Education, and Clinical Center (GRECC), Ann Arbor Department of Veterans Affairs Medical Center; Health Services Research and Development, Department of Veterans Affairs; and National Institute of Dental Research, Program Project on Geriatric Dentistry.

Table 5. INFECTIVE ENDOCARDITIS CHEMOPROPHYLAXIS FOR GASTROINTESTINAL AND GENITOURINARY PROCEDURES Ampicillin 2 g intravenously or intramuscularly and gentamicin* 1.5 mg/kg (not to exceed 80 mg) intravenously or intramuscularly 30 minutes before the procedure. Repeat both drugs at same dose 8 hours later (adjust dose and interval for gentamicin in patients with renal dysfunction). (Amoxicillin 1.5 g orally 6 hours after initial dose may replace parenteral ampicillin.) In penicillin-allergic patients, ampicillin is replaced by vancomycin 1 g intravenously (infused over 60 minutes) before procedure. Repeat dose of vancomycin is administered 8 hours later (or adjusted for renal dysfunction). Gentamicin* is administered as previously described.

*Equivalentaminoglycoside may be substituted. Dajani AS, Bisno AL, Chung KJ, et al: Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA 2642919, 1990 Data from

References 1. Arber N, Militianu A, Ben-Yehuda A, et al: Native valve Staphylococcus epidermidis endocarditis: Report of seven cases and review of the literature. Am J Med 90:758,1991 2. Baddour LM, Phillips TN, Bisno AL: Coagulase-negative staphylococcal endocarditis. Occurrence in patients with mitral prolapse. Arch Intem Med 146:119, 1986 3. Bamham M: Invasive streptococcal infections in the era before the acquired immune deficiency syndrome: A 10 year compilation of patients with streptococcal bacteraemia in North Yorkshire. J Infect 18:231, 1989 4. Bayliss R, Clarke C, Oakley CM, et al: The microbiology and pathogenesis of infective endocarditis. Br Heart J 50:513, 1983 5. Bayliss R, Clarke C, Oakley C, et al: The teeth and infective endocarditis. Br Heart J 50:506, 1983 6. Brennan RO, Durack DT: Therapeutic significance of penicillin tolerance in experimental streptococcal endocarditis. Antimicrob Agents Chemother 23:273, 1983 7. Cantrell M, Yoshikawa TT: Infective endocarditis in the aging patient. Gerontology 30:316, 1984 8. Caputo GM, Archer GL, Calderwood SB, et al: Native valve endocarditis due to coagulase-negative staphylococci: Clinical and rnicrobiologic features. Am J Med 83:619, 1987 9. Dajani AS, Bisno AL, Chung KJ, et al: Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA 264:2919, 1990 10. Durack D: Prophylaxis of infective endocarditis. In Mandell GL, Dougas RG, Bennett JE (eds): Principles and Practice of Infectious Diseases. New York, John Wiley & Sons, 1979, p 701 11. Ellner JJ, Rosenthal MS, Lerner PL, et al: Infective endocarditis caused by slow-growing fastidious, gram-negative bacteria. Medicine (Balt) 58:145, 1979 12. Espersen F, Frimodt-Muller N. Staphylococcus aureus endocarditis. A review of 119 cases. Arch Intern Med 146:1118, 1986 13. Feder HM, Garibaldi RA: The significance of nongonococcal nonmeningococcal Neisseria isolates from blood cultures. Rev Infect Dis 6:181, 1984 14. Gayet JL, Etienne J, Malquarti V, et al: Indices of effectiveness of medical and surgical treatment in 40 cases of prosthetic valve endocarditis. Eur Heart J 5:133, 1984 15. Hamada S, Slade HD: Biology, immunology, and cariogenicity of Streptococcus mutans. Microb'iol Rev 44:331, 1980 16. Hayward GW. Infective endocarditis: A changing disease. Br Med J 2:706, 1973 17. Henriksen SD: Moraxella, Neisseria, Branhamella, and Acinetobacter. Annu Rev Microbiol 30:63, 1976 18. Joubert, Van Gelder AL, Darazs B, et al: The cardiovascular status of the black stroke patient. S Afr Med J 76:657, 1989 19. Karchmer AW, Archer GL, Dismukes WE: Staphylococcus epidermidis causing prosthetic valve endocarditis: Microbiologic and clinical observations as guides to therapy. Ann Intem Med 98:447, 1983 20. Karchmer AW, Dismukes WE, Buckley MJ, et al: Late prosthetic valve endocarditis. Clinical features including therapy. Am J Med 64:199, 1978 21. Lemer PI, Weinstein L: Infective endocarditis in the antibiotic era. N Engl J Med 274:199, 1966 22. Maki DG: Nosocomial bacteremia: An epidemiologic overview. Am J Med 70:719, 1981 23. Maki DG, Agger WA: Enterococcal bacteremia: Clinical features, the risk of endocarditis, and management. Medicine (Balt) 67:248, 1988 24. Malquarti V, Saradarian W, Etienne J, et al: Prognosis of native valve infective endocarditis: A review of 253 cases. Eur Heart J 5:11, 1984 25. Mandell GL, Kaye D, Semon ME, et al: Enterococcal endocarditis: An analysis of 38 patients observed at the New York Hospital Cornell Medical Center. Arch Intern Med 125:258, 1970 26. Mayer KH, Schoenbaum SC: Evaluation and management of prosthetic valve endocarditis. Prog Cardiovasc Dis 25:43, 1982 27. McKinsey DS, Ratts TE, Bisno AL: Underlying cardiac lesions in adults with infective endocarditis. The changing spectrum. Am Med 82:681, 1987 28. Meyer DJ, Gerding DN: Favorable prognosis of patients with prosthetic valve endocarditis caused by gram negative bacilli of the HACEK group. Am J Med 85:104, 1988 29. Meyers BR, Sherman E, Mendelson MH, et al: Bloodstream infections in the elderly. Am J Med 86:379, 1989

30. Osler W: Gulstonian lectures on malignant endocarditis. Lancet 1:415, 1885 31. Panwalker AP: Unusual infections associated with colorectal cancer. Rev Infect Dis 10:347, 1988 32. Pearlman AS: Transesophageal echocardiography-sound diagnostic technique or twoedged sword? N Engl J Med 324:841, 1991 33. Peat EB, Lang SDR: Infective endocarditis in a racially mixed community: A 10 year review of 78 cases. N Z Med J 102:33, 1989 34. Rahimtoola SH, Cheitlin MF, Hutter AM Jr: Valvular and congenital heart disease. J Am Coll Cardiol 10:60, 1987 35. Roberts RS, Krieger AG, Schiller NL, et al: Viridans streptococcal endocarditis: The role of various species including pyridoxal-dependent streptococci. Rev Infect Dis 1:955, 1979 36. Sande MA, Scheld WM: Combination antibiotic therapy of bacterial endocarditis. Ann Intern Med 92:390, 1980 37. Santinga JT, Kirsh M, Fekety R: Factors affecting survival in prosthetic valve endocarditis. Review of the effectiveness of prophylaxis. Chest 85:471, 1984 38. Scheld WM, Sande MA: Cardiovascular infections. In Mandell GL, Douglas RG Jr, Bennett JE (eds): Principles and Practice of Infectious Diseases. New York, John Wiley & Sons, 1979, p 653 39. Scully BE, Spriggs D, Neu HC: Streptococcusagalactiae (group B) endocarditis-a description of twelve cases and review of the literature. Infection 15:169, 1987 40. Shapiro SM, Bayer AS: Transesophageal and Doppler echocardiography in the diagnosis and management of infective endocarditis. Chest 100:1125, 1991 41. Steckleberg JM, Melton J, Ilstrup DM, et al: The influence of referral bias on the apparent clinical spectrum of infective endocarditis. Am J Med 88:582, 1990 42. Terpenning MS, Buggy BP, Kauffman CA. Hospital-acquired infective endocarditis. Arch Intern Med 148:1601, 1988 43. Terpenning MS, Buggy BP, Kauffman CA. Infective endocarditis: Clinical features in young and elderly patients. Am J Med 83:626, 1987 44. Threlkeld MG, Cobbs CG: Infectious disorder; of prosthetic valves and intravascular devices. In Mandell G, Douglass RG Jr, Bennett JE (eds): Principles and Practices of Infectious Diseases, ed 3. New York, Churchill Livingstone, 1990, p. 706 45. Ullman RF, Miller SJ, Strampfer MJ, et al: Streptococcus mutans endocarditis: Report of three cases and a review of the literature. Heart Lung 17:209, 1988 46. Varma MPS, McCluskey DR, Khan MM, et al: Heart failure associated with infective endocarditis. A review of 40 cases. Br Heart J 55:191, 1986 47. Von Reyn CF, Levy BS, Arbeit RD, et al: Infective endocarditis: An analysis based on strict case definitions. Ann Intern Med 94:505, 1981 48. Watanakunakorn C, Tan JS, Phair JP: Some salient features of Staphylococcus aureus endocarditis. Am J Med 54:413, 1973 49. Weinstein L, Rubin RH: Infective endocarditis- 1973. Progr Cardiovasc Dis 16:239,1973 50. Weinstein MP, Reller LB, Murphy JR, et al: The clinical significance of positive blood cultures: A comprehensive analysis of 500 episodes of bacteremia and fungemia in adults. I. Laboratory and epidemiologic observations. Rev Infect Dis 5:35, 1983 51. Weinstein MP, Murphy JR, Reller LB, et al: The clinical significance of positive blood cultures on comprehensive analysis of 500 episodes of bacteremia and fungemia in adults. 11. Clinical observations with special reference to factors influencing prognosis. Rev Infect Dis 5:54, 1983 52. Wieland M, Lederman MM, Kline-King C, et al: Left-sided endocarditis due to Pseudomonas aeruginosa. Medicine (Balt) 65:180, 1986 53. Wilson WR, Geraci JE: Antibiotic treatment of infective endocarditis. Annu Rev Med 34:413, 1983 54. Wolff AH, Ullman RF, Strampfer MJ, et al: Kingella kingae endocarditis: Report of a case and review of the literature. Heart Lung 16:579, 1987 Address reprint requests to Margaret S. Terpenning, MD Clinical Director, GRECC Ann Arbor VAMC 2215 Fuller Road Ann Arbor, MI 48105