Infective endocarditis at the Presbyterian Hospital in New York City from 1938–1967

REVIEWS

Infective Endocarditis at the Presbyterian Hospital in New York City from 19384967

C. E. CHERUBIN,

M.D.

H. C. NEU, M.D.” New York, New York

From the School of Public Health and the Department of Medicine, Columbia University, and the Presbyterian Hospital in the City of New York, New York, New York. Requests for reprints should be addressed to Dr. Harold C. Neu, Department of Medicine, Columbia University, 630 W. 168th St., New York, New York 10032. Manuscript received June 8, 1970. * Career Scientist, New York City Health Research Council.

Volume

51, July

1971

The medical records of 656 cases of infective endocarditis seen at the Columbia Presbyterian Medical Center, 19384967, were reviewed. Only a small decline in the number of cases has occurred over the thirty years. The mean age of patients has risen from thirty-one years in 1938 to fifty-two years by 1966. The frequency of a history of previous rheumatic fever has declined over the three decades whereas a history of murmur of unknown etiology has increased. The addition of narcotic addicts, patients who have undergone cardiac surgery and patients who have survived a previous episode of endocarditis has resulted in an increase in staphylococcal and fungal endocarditis in recent years. Neisseria and Diplococcus pneumoniae have essentially disappeared as causes of endocarditis at this hospital since the introduction of penicillin. Streptococcus viridans remains the most common etiologic agent, but enterococcal endocarditis has shown a significant increase. Abacteremic cases constitute about 12 per cent of the patients. Aortic valve involvement has markedly increased over the three decades, mitral valve involvement has shown a slight decline, and there has been a marked decline in combined mitral and aortic disease. The duration of symptoms prior to diagnosis has shortened; as a result, splenomegaly, petechiae and clinical evidence of major embolization are less frequently encountered today. The introduction of antibiotics has been the major factor in determining the outcome of the disease. Survival with Strep. viridans endocarditis has been excellent, with only minimal improvement in the last five years. Enterococcal endocarditis continues to have a bad prognosis, but survival rates in staphylococcal endocarditis have continued to show improvement over the past decade. The decline in rheumatic fever, the increased age of the patients with endocarditis, sophisticated medical and surgical procedures and the prolonged survival of patients with rheumatic heart disease have all been major factors in changing the nature of infective endocarditis. The particular effects of changes in the community population and the relations of the teaching hospital to the community on the nature of bacterial endocarditis are noted.

a3

INFECTIVE

ENDOCARDITIS

-

CHERUBIN.

NEU

Excellent reviews [l-9] of infective endocarditis have appeared in the last few years, documenting the changing clinical and bacteriologic picture of the disease. A variety of factors have been postulated as having influenced the nature of bacterial endocarditis. Foremost among the explanations has been that the introduction and widespread use of antibiotics, specifically penicillin, which has been such a significant factor in the reduction of the mortality of this dlisease, has also altered its clinical appearance. Hospital-acquired infections [2], drug addiction [lO,ll] and the development of cardiac surgery with their attendant sequelae [12-141 have also been cited as contributing to the new situation. Secondarily, the long-term decline in rheumatic fever [15,16] and the prolonged survival of patients with rheumatic heart disease have been thought to play a role. In fact, however, the changing nature of the disease was noted prior to the introduction of antibiotkzs [17], and the increasing age of the patients [18,19] (part of the aforementioned change) can be dated back over fifty years [l]. We wished to evaluate the factors that influenced the clinical presentation of infective endocarditis, as well as its outcome, at Columbia-Presbyterian Medical Center. Selection of the five year period before the introduction of antibiotics as well as the first five years of antibiotic therapy allowed us to compare the influence of these drugs and that of the changes in the Ipatient population. We found that the major factors in the altered features of the disease appeared to be the decline in rheumatic heart disease, the increasing age of hospitalized patients with this disease, and differences in diagnostic and hospital admission procedures. All these processes antedated the introduction of effective chemotherapy which has so vastly altered the outcome in endocarditis. METHODS The Columbia-Presbyterian Medical Center listed 1,056 chart numbers for bacterial and mycotic endocarditis for the thirty years, 1938-1967. Approximately 90 per cent of the charts were available and were reviewed. However, slightly more than 100 listings were for “healed,” “old” or “post” endocarditis, or for readmissions for the same episode of endocarditis or, occasionally, were miscoded charts. We were able to review about 800 episodes of endocarditis, clinically suspected or confirmed, of which we categorized 655 as clinically confirmed and considered the remaining 130 as having inadequate evidence for the diagnosis. The criteria for accepting a case were as follows: (1) Autopsy evidence

84

of infective endocarditis. (2) A clinical history compatible with the disease and the presence of two positive blood cultures prior to the initiation of adequate therapy or, in instances in which less than four cultures were taken prior to therapy, only one culture of a Strep. viridans, Staph. aureus or Pneumococcus was considered necessary. When more than twenty cultures were taken prior to therapy the organism had to be present in at least a tenth of them. (3) A compatible clinical history with evidence of macroor microembolism (petechiae, Osler nodes, Roth spots) and the demonstrated absence of other diseases that might produce the clinical picture (i.e., pneumonia, renal infection, systemic lupus erythematosus, blood dyscrasias) and a response to what would be considered an adequate regimen of therapy for the likely organism. Episodes which failed to meet the criteria were put into an unaccepted group, which contained only cases in which the diagnosis had been considered seriously enough to warrant clinical investigation and a course of therapy. If a patient had several admissions for endocarditis, these were considered as one episode in the absence of an asymptomatic interval of at least six months, or if there was less than a year between discharge and readmission with a continuation of symptoms. Conversely these were considered as separate episodes if the opposite were true. The information obtained was coded for all cases and subsequently tabulated by computer. The year was taken as that of the first admission for the particular episode of disease. The patients were divided as to ward and private services, with age, sex and race listed as on the admission sheet. Symptoms were taken as the longest compatible complaint given in the history obtained on admission. The duration of this complaint was also recorded. The temperature, white blood cell count and sedimentation rate were taken as of the day of admission. The presence of a palpable spleen, petechiae or other cutaneous or ocular embolic manifestations on admission was recorded from the admission and discharge notes. The items of importance in the patients’ past history which were abstracted were a history of dental extraction, recent surgery, a history of diabetes, a history of a previous episode of endocarditis, urologic infection or recent instrumentation, cardiac surgery, narcotic addiction, a history of rheumatic fever, heart murmur and a previous diagnosis of congenital or syphilitic heart disease. A description of the murmurs present on admission was recorded in terms of whether it emanated or was loudest at the apex, base or left sternal border or any combination of areas. The clinical assessment of the valves involved was taken as described in the discharge summary. The organism was recorded as given on the reports of the bacteriology laboratory with the following exceptions. During the late 1940’s and early 1950’s a designation of nonhemolytic streptococci was used. Or-

The American

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of Medlclne

INFECTIVE

ganisms which were not further identified were separated into Strep. viridans and enterococci by their penicillin sensitivity. Those with minimum inhibitory concentrations below 1 unit/ml were considered to be Strep. viridans, those above 5 units/ml were called enterococci (group D streptococci). Only twenty-five cases required this separation. Microaerophilic streptococci have not been separated from other streptococci until the last ten years. Thus Strep. viridans would irtelude both Strep. viridans and microaerophilic streptococcal groups prior to 1963. Strep. pyogenes is treated separately. Information on antibiotic therapy was tabulated only for drugs used for at least five days. The duration of hospitalization was calculated as the time from the first admission to the day of discharge of the last admission of any episode of the disease. The outcome was categorized as lived and discharged improved, died, transferred to home or to another hospital with active disease (in most of the latter cases information about the death was recorded in the chart). Whether an autopsy was performed and what its pertinent findings were was also recorded. The total yearly admissions to the Columbia-Presbyterian Medical Center were available from 1930, with the admissions to the medical service separated as of 1940. The number of cross indexed charts with diagnosis of rheumatic fever, rheumatic heart disease and congenital heart disease were obtained for the years 1938, 1948, 1958 and 1967. Fifty consecutive listings of rheumatic heart disease for these years were reviewed for information on age, sex, race and ward or private service for changes that might have occurred over the three decades of the study. Data on fifty blindly selected ward service admissions to the medical service for these years were also reviewed for similar information. RESULTS 1938-1967. There was a long term rise in annual admissions over the first two decades to the Med,ical Center, with a leveling off during the past ten years (17,000 in 1938 to 30,. 000 in 1967). Admissions to the medical service rose less sharply from 3,800 in 1940 to 6,100 in 1953 and then fell to 4,300 in 1967. There have been notable changes in the past three decades in the age of patients admitted to the medical service and in the proportion of patients admitted to the Medical Center with the relevant diagnosis of rheumatic and congenital heart disease. The mean age of randomly selected patients admitted to the medical service increased by about four years over the three decades. This seemingly small increase conceals a major increase in patients over sixty years of age: 24 per

Admissions:

Volume 51. July

1971

ENDOCARDITIS

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CHERUBIN,

NEU

cent of the admissions in 1938 and in 1947, 39 per cent in 1957 and 46 per cent in 1967. This is a statistically significant increase (p
it was

0.40

per

cent

and

in 1958-1967

it

was 0.32

per cent. During the first decade only 20 per cent of these were private patients, whereas during the last decade this had increased to 40 per cent. If ward cases alone were considered there would have been a significant decline in the number of admissions for endocarditis. The relative decline of 40 per cent for all cases compares with a 60 per cent relative decline in admissions for rheumatic fever and a relative decline of 50 per cent in admissions for chronic rheumatic heart disease. Age, Sex and Service. The mean age of patients with endocarditis rose during the period under 25

220 Q 2

I ‘.,

f5 ‘5 Q

G -

E IO-

*.

..

-8.

.---------

:RHEUMATlC HEART DISEASE

e----

--CONGENITALHEART DISEASE =RHElJh!ATIC FEVER

-\.1 ‘. ‘.

‘.

*.‘,____________---------.--------_

0

_---

1938

P

_-------

co/

T

I

1947

1957

P 1967

YEARS

Figure 1. Admissions for rheumatic genital heart disease and rheumatic Presbyterian Medical Center.

heart disease, confever at Columbia-

85

INFECTIVE

ENDOCARDITIS

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CHERUBIN,

NEU

TABLE

I

Noncardiac Underlying Disease in Patients with Endocarditis (19364967) Per Cent of Patients

Condition SURVlVCftSHlP .

IWO 1962

19.55 19.57

YEARS

Figure 2. The age of patients with endocarditis and per cent survival in relation to the introduction of antibiotics.

study from

thirty-one years in 1938 to a peak of fifty-two years in 1966 (Figure 2). For the last five years studied (1963-1967) the mean age was 47.4 years compared to 34.8 years for the initial five years studied (1932-1942). This rise can be seen to antecede the introduction of antibiotics and the increase in survival. The over-all sex ratio was nearly equal, with men constituting 56.8 per cent of the patients with endocarditis. However a large imbalance between the sexes occurred among patients over filfty years of age, of whom ‘more than two-thirds were men, and for those under thirty years, of whom 60 per cent were women. As a result of the age changes in patients with endocarditis over the three decades the male-female sex ratio has steadily increased. In contrast the sex ratio of the samples of patients admitted to the medical service has been a,bout even for the past thirty years. For patients with rheumatic heart disease the ratio of females to males has increased so that females now constitute 60 per cent of the cases. Proportionately very few of the patients under fifty-five years of age were admitted to the private service, but nearly half of the patients over that age were. The change in age of the patients studied may have had an influence on the proportion admitted to ward and private services. Noncardiac Underlying Disease. The proportion of patients having a history of another disease has increased over the past thirty years, particularly in the past decade (Table I). Cardiac surgery, narcotic addiction, previous episodes of bacterial endocarditis and diabetes are all more common in present day patients. However, a history of dental extraction is less common now. The increase in ‘diabetes is probably the result

86

None Dental extraction Urologic infection Previous bacterial endocarditis Addict Diabetes Postoperative Cardiac surgery Noncardiac Miscellaneous

19381941

19481957

19581967

All Years

69.8 10.3 4.7

62.3 7.2 5.9

41.7 6.3 4.8

59.8 7.9 5.2

3.3 0 1.4

8.5 0.4 0.4

9.2 3.9 6.7

7.0 1.4 2.9

0 1.4 9.1

2.9 3.8 8.2

9.1 1.9 14.4

4.0 2.4 9.4

of the older age of the patients, since juvenile diabetes was not encountered and all these patients were over fifty years of age. The “miscellaneous” category of underlying illness given in Table I includes tuberculosis (five cases), leukemia (three cases), malignancies (ten cases), lymphoma (two cases), carcinomas (two cases), pregnancy (three cases), postabortions (five cases), pneumonias (six cases) and a few other problems. History of Heart Disease. More than 30 per cent of the patients with endocarditis gave a history of clinically documented rheumatic fever (Table II). There appears to have been little change with time. The apparent stability of a history of previous rheumatic fever was achieved by the incorporation of an increasing number of patients with successfully treated episodes of endocarditis and those with endocarditis after cardiac surgery. Removal of these cases lowers the frequency of a history of rheumatic fever to 37.6, 35.9 and 22.5 per cent for each of the past three decades; for the most recent five year period it would be 18.6 per cent. TABLE

II

History of Heart Disease or Murmur in Patients with Endocarditis (19364967) Per Cent of Patients

Condition Murmur Rheumatic Congenital disease Syphilitic

fever heart

19481957

19581967

All Years

20.3 39.1

25.0 39.4

26.5 36.8

24.0 38.5

5.7

5.5

6.7

5.8

1.4

0.8

1.0

1.1

0 32.0

0 29.2

0.4 28.0

0.2 29.8

Journal

of Medicine

heart

disease Calcific heart disease Denied

19381947

The American

INFECTIVE

o---.-----

=NONE : RHEUMATIC FEMR

5or

20-29

o- 19

30-39 40-49 PATIENT AGE IN YEARS

Figure 3. The relation between valvular heart disease.

50-59

60+

patient age and history of

Thirty per cent of patients had no history of heart disease or murmur, and this group appears to have decreased slightly with time, whereas the number of ‘patients with a history of murmur of unknown etiology has clearly increased. The number of patients with documented congenital heart disease (previously investigated at this or other hospitals) has shown a relatively minor increase. Syph’ilitic and other heart disease diagnoses were uncommon. Figure 3 demonstrates that the older the patient the less frequent is an antecedent history of valvular heart disease. Patients under twenty years of age and those in their sixty’s more frequently had a previously heard cardiac murmur, of unknown etiology, than did those in other age groups. Thus the increasing numbers of older patients with endocarditis resulted in a lower frequency of a history of rheumatic fever and an increasing frequency of a history of unspecified murmur or no history of valvular heart disease at all. New Varieties of Endocarditis. The most recent decade of the study has produced patients who are addicted to narcotics and those who have under-

ENDOCARDITIS

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CHERUBIN,

NEU

gone cardiac surgery. In terms of numbers of cases they are of minor significance (Table I). However, they are tightly clustered in terms of age, time, organism and valvular involvement. Of the nine addicts all but one was under the age of thirty; four had tricuspid and four had aortic valve disease; six were infected with Staph. aureus, one with a Candida species. Of the twenty-six patients with endocarditis after cardiac surgery, nineteen were between thirty and fifty years of age; ten had Staph. epidermitis, three Staph. aureus, two Aspergillus, six various streptococci, and the remainder had no growth on culture. Eight had infection of the mi’tral valve, thirteen of the aortic valve, and in five there was combined valvular involvement or a ventricular septal defect as the site of infection. The clustering of these cases causes a disproportionate statistical influence on the younger age groups in the most recent decade. Thus in the considerations of the age specific changes with time, which follows, these categories of patients frequently will be separated in the discussion. Organism. The most notable change in organisms occurred during the first decade of the study with the elimination of Neisseria and the virtual disappearance of Pneumococci as causative organisms in endocarditis (Table Ill). This decline coincides with the introduction of penicillin. Strep. viridans infections showed a decline of 21 per cent whereas infections with enterococci (Figure 4) increased in the most recent decade. Staph. aureus isolations remained stable throughout the study period, but from 1952-1957 they accounted for 14 per cent of all cases. Infections caused by gram-negative bacilli have shown no increase. However, in the early years of the study hemophilus species, Streptobacillus moniliformis, etc. were found, whereas enteric bacteria are predominant today. The increase in Staph. epidermitis was related to the appearance of cases of endocarditis following cardiac surgery. TABLE III

Changes in Organism in Endocarditis (1938-1967)-Minor Organisms Total Isolates(no.)

Organism I

0

No organism

Sviridans

Enterococcus

S.OW.XlS

S. epidermitis

ORGANISM

Figure 4. Changes in the per cent of cases of infective endocarditis caused by Strep. viridans, enterococcus, Staph aureus and Staph. epidermitis.

Volume 51, July 1971

Neisseria Pneumococci Gram-negative rods Candida

19381942

19431947

19481952

19531957

19581962

19631967

6 5

0 3

0 1

0 1

0 0

0 0

4 0

5 0

3 0

3 0

3 0

4 3

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The over-all per cent of culture-negative cases was 12 per cent. During the second decade there was an increase in the percentage of patients from whom no organisms were recovered either during hfe or at postmortem. If postmortem bacteriologic findings are excluded we find that in 17 per cent of these cases an organism was not cultured during life. Considering only autopsy confirmed cases, in 30 per cent of these patients no organism was cultured during life, and further, half of these never had a positive culture. The percentage of patients in whom there was no growth on antemottem cultures was greatest for those who died soon after admission. However, of patients hospitalized for a month or more, in 27 per cent an organism was never identified during life. Although autopsy cases are a selected group, these findmings confirm that in a considerable proportion of cases an organism cannot be cultured by conventional methods. The nature of the underlying disease had a marked influence on the infecting organism. Postoperative patients had both Staph. aureus and enterococci 25 per cent of the time. Diabetic patients had enterococci and Staph. epidermitis three to five times more frequently than did other patients. Patients with urologic infection had enterococci in 33 per ,cent of cases and gramnegative organisms in 10 per cent. Thus a third of all patients with enterococcal endocarditis had documented preceding urologic infections. Patients with preceding dental work had Strep. viridans 69 per cent of the time, which is no more frequent than patients who had no preceding history of ,dental care. Age had a strong influence on the frequencies of different organisms (Figure 5). Strep. viridans was found most frequently in patients in their twenties and thirties, although it was present in 50 per cent or more of patients in all age groups. The presence of enterococoi seemed to increase progressively with age, as did Staph. epidermitis. Staph. aureus was found most frequently in the young and those in their fifth deca,de. Of the less common organisms, Pneumococci and diverse gram-negative organisms were most common in patients in the fifth decade, whereas Neisseria was encountered mainly in patients in the third decade and not thereafter. Negative blood cultures appeared to be most common in the young and the middle aged, and much less so in patients in other age groups. Since the ages of patients with endocarditis have increased and since age has an influence on

88

the etiologic agent, age-specific rates were used to determine whether the decline in the most common organism, Strep. viridans, was due to the age change in the population of patients. The ageadjusted rates, excluding addimcts afnd patients who underwent cardiac surgery, show that there has been no change. The age-adjusted rates for the three decades become 60.5, 63.3 and 58 per cent. Thus there has been no change in the proportion of patients in each age group from whom Strep. viridans was isolated; all of the decline in this organism is attributable to the increase in the patients’ age and to the introduction in the most recent decade of numbers of cases of endocarditis in addicts and in patients following cardiac surgery. The increase in endocarditis due to enterococci and Staph. epidermitis can be explained in like manner. The incidence of Staph. aureus endocarditis appears not to have changed greatly in our series, perhaps because we have included pediatric cases in our study. Uncommon Microorganisms. A number of rather unusual organisms were isolated during this period. There were three instances of Streptobacillus moniliformis, one of Cardiobacterium hominis and one each of Hemophilus aphrophilis, Lactobacillus acidophilus, Neisseria meningitidis, H. influenzae and several nonspeciated Hemophilus organisms. The gram-negative bacilli included five instances of Escherichia coli, two of Klebsiella pneumoniae, two of Proteus mirabilis and two of Pseudomonas aeruginosa. There were six examples of beta hemolytic streptococci of which one was a group G and one a group H, and six mi,croaerophile or anaerobic streptococci. Among the fungi were two cases involving Histoplasma capsulatum, two of Aspergillus fumigatus and one of Rhodotorula. The three decades have Valvular Involvement. seen an increase in aortic valve disease, a slight decline in mitral valve disease, and a marked decline in combined mitral and aortic disease and bilateral chamber disease (Table IV). These changes were clearly seen during the 1940’s and may have started earlier. Tricuspid valve endocarditis was uncommon, and endocarditis involving valves on both sides of the heart was a more frequent occurrence. Congenital heart disease comprised 11 per cent of the cases but showed no clear time trends, despite the increase in congenital heat-t disease seen at the Medical Center. The relative frequencies of valvular involvement with age is presented in Figure 6. Neither the de-

The

American

Journal

of

Medicine

lNFECTlVE

es-----w---.-. - --

f ! !

s g

ii F-

Correlation

F

of patients’

20-29

30-39

2nd DECADE

CHERUBIN,

NE!.j

50-59

40-49

60-69

70+

AGE IN YEARS

age and the infecting

Figure 6. The percentage of patients in each age group in terms of particular type of valve involvement.

A

B m

1st DECADE

-

NONE STAPHYLOZXCLJS ALU STAPHYLotoctUS ALJREUS STREPTOCOUXS WRIDANS ENTEROCOCCUS

AGE IN YEARS

Figure 5. organism.

ENDQCARDITIS

= 1st.Decade

(1938-1947)

=2ndDecode

(1946-1957)

=Jrd.Decode

(195.3-1967)

(1938-1947)

(1948~i95jl

t

m

c

PATIENT AGE IN YEARS

G

Aortic valve Mitral valve

m

Bilateral chamber

Uncertain

SITE OF INFECTION

C

F

Aortic and Congenital Mitral valves

= 1st. DECADE (1938-1947 1

ZndDECADEfl948-1957)

3rd DECADE (1958-1967)

G a 5

a 5

2 O

Noorganism

S.viridanr

S. aureus

S.albur

Enterococcur

ORGANISM

TABLE

IV

Changes in Valves Affected

Figure 7. A, the mean duration of symptoms by decade as related to patient age. 6, the mean duration of symptoms by decade as related to valvular involvement. C, the mean duration of symptoms by decade as related to infecting organism.

in Patients with Endocarditis

(19364967) Per Cent of Patients

Preantibiotic Era Site of Infection Aortic valve Mitral valve Mitral and aortic valves Tricuspid valve Bilateral chamber Congenital

Volume

51,

July

1971

1938-1942 5.3 44.6 35.1 0 3.1 5.3

Antibiotic Era

Early Antibiotic Era

1943-1947 12.7 39.8 22.9 0.8 3.3 13.5

1948-1957 22.9 41.6 19.1 0.4 1.2 11.8

1958-1967 26.8 37.6 15.4 2.4 1.4 11.7

Total 19.7 40.5 29.9 1.1 2.0 10.9

89

INFECTIVE

ENDOCARDITIS

degrees Fahrenheit

O-30

Figure 8. duration

31-60

-

CHERUBIN,

102 m

NEU

- 103.9

,04+

121-150 61-90 91-120 DURATION IN DAY3BEFORE ADMISSION

151-180

The relation of temperature on admission of symptoms in days before admission.

181 + and

cline in frequency of combined valvular disease nor the rise in aor-tic valve disease was merely an effect of an aging population of patients, for adjusting for age did not eliminate the changes. The age-adjusted rates for combined valvular disease during the three decades are 26.8, 18.1 and 17.3 per cent; the age-adjusted rates for sot-tic valve disease are 10.5, 18.1 and 21.0 per cent. In contrast, mitral valve disease has shown little change in its age adjustment rates: 37.2, 42.3 and 37.6 per cent. Duration of Symptoms. A marked diminution in the duration of patients’ symptoms prior to admission occurred within the study period. During the initial five years less than a third of the patients had symptoms for one month or less, whereas during the last five years nearly two thirds of the patients admitted were in this group. The mean duration of symptoms has been shorter in the younger patients, and the decline has been most marked in the adolescent and young adult (Figure 7A). The ‘decline in d.uration of symptoms in those over fifty years of age has been less marked and somewhat inconsistent, perhaps because of problems in obtaining an adequate history, and this may have obscured any actual change. The site of infection influenced the duration of symptoms. The most notable decline in duration of symptoms occurred among the patients with aortic valve disease (Figure 7B). The decline in duration of symptoms in patients with mitral, combined aortic and mitral, and congenital heart lesions has been less marked. The decline in duration of patients’ symptoms has occurred with all organisms cultured with the exception of Staph. aureus; symptoms of infections with this organism have always been of brief duration (Figure 7C).

90

Symptoms and Signs. The appearance and complaints of patients with endocarditis have changed, as have ‘many of the other characteristics of patients with this disease. Earlier descriptions of the disease may not be adequate for the contemporary situation. Of the symptoms fever was the most frequent and the longest in duration for half of the patients. This has not changed over the three decades. The next most frequent initial symptom was malaise, 11 ‘per cent. Malaise, anorexia and weight loss were most common among patients with the longest duration of symptoms and have thus declined in recent years (23 to 11 per cent). Complaints of joint or muscle pain and complaints referable to cardiac decompensation were more common among patients with a brief duration of illness and have increased over the past thirty years (14 to 27 per cent). The patient’s temperature on admission was inversely related to the duration of symptoms, a low grade fever being most frequently seen in patients with the longest duration of symptoms (Figure 8). Little change has occurred in admission temperatures over the past thirty years. About 15 per cent of the patients have temperatures of 99.9”F or less, 45 per cent have temperatures of lOO.O”F to 101.9”F and 40 per cent have temperatures of 102.O”F or more. The presence of splenomegaly and petechiae on admission was related to the patients’ duration of symptoms. Although only a third of patients with less than a month of symptoms were thought to have a palpable spleen, half of those with six months or more of illness had splenomegaly. Less than 25 per cent of recently admitted patients had an enlarged spleen whereas two decades ago it was noted in 40 per cent of the patients admitted. Petechiae are noted at present in 18 per cent of patients on admission as compared to 25 per cent of those admitted at the beginning of the study period. Neither the white blood cell count or erythrocyte sedimentation rate on admission showed any consistent relation to duration of illness, and consequently they have not altered remarkably over the past thirty years. Half of the patients have a white blood cell count of lO,OOO/cu mm or less on admission. Embolization and Neurologic Complications. Clinical evidence of major embolization has decreased over the past thirty years; it is seen now in 25 per cent of patients as compared to 40 per

The American

Journal

of Medielne

INFECTIVE

cent of patients twenty to thirty years ago. The percentage of patients with multiple emboli (usually cerebral and parenchymal) has decreased from 16 to 7 per cent. The reason for the decline in embolization appears to be secondary to its decline with increasing age. Embolization was most common in patients between twenty and forty years of age and less common in those over sixty years. Thus, since the age of patients has increased markedly over the study period, and the duration of symptoms has decreased, the observed rate of embolization has dropped. The rate of embolization is greater in patients with combined mitral and aortic disease (38 per cent), tricuspid disease (17 per cent) and bilateral chamber disease (54 per cent) than in those with aortic or mitral valve infection (28 and 25 per cent, respectively), and congenital heart disease, in which embolization was least of all (15 per cent). Of the patients in whom no organism was cultured or those with Strep. viridans or Staph. epidermitis, 25 per cent had emboli. Of those with Staph. aureus infections, 58 per cent had emboli; of those with gram-negative rods and Neisseria, 35 per cent; of those with enterococci, 15 per cent; and of those with Candida and other fungi, 60 per cent. Neurologic complications: Seventy-nine patients in this series (12 per cent) had major neurologic complications of their endocarditis. For the most part these were grossly evidenced by hemiplegias or paresis, but six patients had meningitis, presumably emfbolic in origin, and three patients had ocular embolization. Cerebral emboli were most common in patients in the fourth and fifth decade (14 per cent of patients), whereas of patients under twenty and over sixty years of age only 8 per cent had emboli. In general, cerebral embolization has decreased over the three decades. Twenty per cent of Staph. aureus infections produced emboli, whereas 12 per cent of Strep. viridans infections did. In terms of absolute numbers, however, cerebra’1 emboli occurred four times more frequently with Strep. viridans infection thamn with Staph. aureus endocarditis. Effect of Therapy. A high survival rate appears to have been achieved soon after the introduction of penicillin. Since that time the rate has fluctuated without dramatic improvement (Figure 2). Figure 9 shows the survival rates for each major etiologic organism. Patients with Strep. viridans and those in whom no organism was cultured

Volume

51.

July

1971

,M)

STREPTOCOCCUS

ENDOCARDITIS

VIRIDANS

IO0

-

CHERUBIN,

NEU

ENTEROCOCCUS

Z % :050 !? $

2 9 itj~ 5 %0

0

YEARS STAPHYLOCOCCUS AUREUS

B

100

STAPHYLOCOCCUS

ALBUS

100

z 2 : 0 50

2 2 ”

z “u

5

GRAM-NEGATIVE

RODS

050

z 0

0 YEARS

YEARS

Figure 9. Per cent survival as related to infecting ganism. A, no organism, Strep. viridans, enterococcus. Staph. aureus, Staph. epidermitis, gram-negative rods.

or6,

showed improved rates of survival with the introduction of penicillin, with slight subsequent improvement during the past five to ten years. Patients with enterococci began to survive only with the introduction of penicillin but have shown little improvement over the past twenty years. No survivor of Staph. aureus endocarditis was seen until 1950; thereafter there was a rapid increase in survival, particularly during the last five year period coincident with the use of new antistaphylococcal agents. Patients with Staph. epidermitis have evidenced relatively small ixmprovement in survival over the study period. Those infected with gram-negative rods, which halve changed bacteriologically in the course of thirty years, have shown a progressively improved rate of bacteriologic cure. The survival of patients with mitral valve disease reached high levels in the early 1950’s and has not changed greatly since that time (Figure 10). This is also the case in patients with combined mitral and aortic valve disease. Patients with aortic valve and congenital heart lesions act in a very

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Staph. aureus was also high. In only 11 per cent of patients from whom staphylococci were isolated and death occurred were autopsies not performed. COMMENTS

MITRAL

Figure 10. Survival valve involved.

CONGENITAL

rates by five year intervals

for each

different manner: their survival is still progressively improving. Multiple Episodes of Endocarditis. Among the 655 patients with confirmed episodes were forty-five who had recurrent episodes of endocarditis for a total of forty-six episodes (one patient had three distinct episodes of endocarditis). In only thirtyseven patients were these new infections and not relapsing disease. In twenty patients the organism was Strep. viridans, as it was in the great majority of the initial episodes. Staph. aureus, Staph. epidermitis, enterococcus and Candida were each encountered once. The remainder had no clearly identified pathogenic organism. Twenty-three of the thirty-seven patients had a known history of rheumati’c fever. These recurrent episodes resembled those in the general group of endocarditis cases. Compared to the distribution of the Autopsy. affected valves in the entire series, that in the autopsy cases is quite different, since 32 per cent of these patients had aortic valve disease. Autopsies were performed on a full third of all patients with sot-tic valve disease. Autopsies were performed most frequently on patients over fifty years of age. In these cases the duration of symptoms was briefer than in the fatal cases in which no autopsy was performed. Thus the increase in aortic valve disease is especially notable among the autopsy cases. In a case series drawn primarily from the autopsy cases, aortic valve disease would be overrepresented. A clinical ‘history or denial of prior rheumatic fever was confirmed by autopsy 77 per cent of the time. Only 5 per cent of patients who claimed this history had no evidence for it on autopsy, and of those who had such evidence at postmortem examination two-thirds had given a history of rheumatic fever on admission. All the patients with D. pneumoniae who died were subject to autopsy. Autopsy in cases due to

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Aspects which a’ffect the nature of bacterial endocarditis as reported from large institutions rarely take into consideration factors which probably play i’mportant roles in the character of the patients. The relations of the hospital with the community, the number of referral patients, the aging of the population in the vicinity of the hospital, the replacement of the former population by a poorer but younger social group all could influence the type of patients the study would contain if it encompassed many years. The Columbia-Presbyterian Medical Center is not a municipal hospital (such as Boston City Hospital) nor a diagnostic referral center such as the Mayo Clinic; both of these have published similar long-term reviews of their patients with endocarditis [2,20]. Neither is this Medical Center a mixture of the two types of institutions, with its ward and private beds, serving the same geographic area, as do many voluntary hospitals. This Medical Center indeed has an area of responsibility for the hospital care of neighborhood residents, but it selects its ward patients not only from this population but also from its outpatient clinic population which, by referral, draws on a much larger area. Admissions to the ward service were frequently dependent on the “teaching value” and medical “interest” of the patients. Endocarditis is of course always of “value” and “interest.” Further, the population of the surrounding area and clinic has changed in the several decades covered by this study, from one predominantly Jewish and middle class to one with increasing proportions of impoverished ethnic minority groups. Less ‘can be specified about the private service except that it is drawn largely from the population in New York City, northern New Jersey and surrounding areas. There are no accurate population figures on which to determine the true incidence of endocarditis. Thus, although the number of cases of infective endocarditis has shown little decline at this institution in the past thirty years, this represents a 40 per cent decline in cases when total admissions are considered, which compares with a 60 per cent decline in admissions for rheumatic fever and a 50 per cent decline in admissions for rheumatic heart disease. This is in agreement with other studies [l-6]. If only ward cases were considered a precipitous decline would be noted. In-

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creasing numbers of private patients have kept the absolute numbers of admissions of endocarditis steady. This is no doubt related to the increasing age of patients with this diagnosis, since private patients are on the average several decades older than ward patients. The age distribution of our patients with infective endocarditis over the past thirty years has been steadily upward. Our current average age of 47.4 years compares with the 49.7 years of Lerner and Weinstein [l] and forty four years of Tompsett [21]. The most striking example of the increasing age of patients with endocarditis is the data of Robinson and Ruedy [22] which showed an average age in the 1930’s of thirty-nine and by the 1950’s an average age of fifty-five. There may be a leveling at this point since the newer cases of endocarditis in drug addicts and postoperative surgical patients occur in a younger age population. The increase would seem logically to be associated with two long-term medical and demographic changes. One is the rapidly decreasing incidence of rheumatic fever [15,16] and hence of rheumatic heart disease. This would result in an increasing average age of the population of people with this form of valvular heart disease, the major predisposing condition for the development of endocarditis. This indeed was verified from the Medical Center records. The second factor would be the increasing age of patients admitted to the hospital, which is secondary to the increasing age of our population. Indeed, the number of patients over sixty years of age admitted to the Medical Center has doubled in the past thirty years so that at present 46 per cent of patients admitted to the medical service are in this older age group. The over-all male-female ratio of our cases was nearly equal, unlike some reviews [1,2], but the preponderance of men described by Kerr [8] in the older age groups was also noted in our study. This disproportion of male patients with endocarditis at an older age balances a preponderance of female patients in the younger age groups. The latter seems related to an increased number of female patients with rheumatic heart disease (60 per cent) in this younger age group and suggests that the etiology of the heart disease in the older patients is quite different. It is interesting that a history of other diseases is more common today than in earlier decades. This is not entirely due to the older age of the patients since cardiac surgery, narcotic addiction and previous episodes of bacterial endocarditis are new items of medical history which have developed

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in the most recent decades. In contrast to data from some city hospital centers, pneumonia preceding the endocarditis was rare in our cases. The decrease in history of previous dental extraction could be related to both improved use of antibiotics to cover dental extractions and to less detailed patient histories. However, patients without such a history had the same frequency of Strep. viridans enadocarditis as those with such a history. If this organism was disseminated from the patient’s mouth during a dental procedure it is curious that there is so little retrospective evidence of the importance of this history even in the first decade of the study. As was expected, there had been a significant decline in the number of patients with a previous history of rheumati’c fever in new cases of endocarditis (excluding repeat episodes and postsurgical cases), with a fall from 37.6 per cent in the first five years to 18.6 per cent in the last five years. This is presumably also related to the increasing age of patients. The decreased frequency of endocarditis as a complication of rheumatic heart disease in the elderly has been noted in the autopsy studies of Wallach et al. [23] and Traut et al. [24]. The incidence of murmur without documented rheumatimc fever or congenital heart disease increases with age so that patients over sixty had the greatest frequency of previously heard cardiac murmur of unknown etiology of any group. This can be explained in light of our understanding of relative mitral insufficiency due to dilated mitral annulus [25] or arteriosclerotic or other degenerative lesions of the mitral valve [26]. Bacterial endocarditis superimposed upon a calcified mitral annulus [27] was not encountered. Kerr [8] has suggested that arteriosclerotic heart valves would be of importance in the development of endocarditis. Clearly the roughened endothelium of the mitral valve and shortening of papillary muscle and chordae tendineae predispose to the development of platelet fibrin thrombi. Regenerative changes are of special importance in the surface of the aortic valve and probably explain the increased incidence of aortic valve disease, particularly in the elderly. This emphasizes the importance of recognizing that bacterial endocarditis, whether acute or subacute, will most often be seen in the older patients without a history of rheumatic fever or documented heart disease. The disappearance of Neisseria and D. pneumoniae as causative agents of endocarditis coin-

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tides with the introduction of penicillin into general use. Since the completion of this study we have encountered our first case of N. gonorrheae endocarditis since 1942. The relative rarity of admission of elderly, alcoholic men with pneumonia to this hospital probably explains the absence of pneumococcal endocarditis here whereas it is still seen at the Cincinnati General Hospital [28] and at the Boston City Hospital [2]. An absence of pneumococcal cases was also noted in Lerner and Weinstein’s study at the New England Medical Center [l] and by Wilson at University Hospitals in Clevelan’d [29], both of which institutions would have admitted a patient population more similar to ours. Pneumococcal endocarditis is still occasionally seen in New York City at present in municipal hospitals in older single men who live alone [30]. It is also a cause of unappreciated endocarditis discovered in nonaddicts at autopsy at the New York City Medical Examiner’s Office, but at the rate of one to two cases per year [30]. remains the most common Strep. viridans etiologic agent, and, if age-adjusted rates are considered, its prevalence has not altered during the three decades. Its decline in frequency from 64 per cent to 49 per cent appears to be wholly attributable to the increasing age of patients. Previous studies [l] which have demonstrated a declining frequency of Strep. viridans endocarditis have not considered the effect of age in their patients. The incidence of Staph. aureus infections in our series of cases has not shown the marked increase reported by others [l-3]; it has remained at 8 to 9 per cent of our cases. This discrepancy with other series could be due to the type of patient we see or to a somewhat lower incidence of acute versus subacute endocarditis. The fact that only 17 per cent of autopsy cases’were due to Staph. aureus suggests that the data are real since Staph. aureus would be more common in fatal cases [2]. Indeed the number of cases of Staph. aureus endocarditis has not grown despite the inclusion of patients undergoing cardiac surgery, and heroin addicts. The fairly low mortality of 19 per cent for the past five years also suggests that staphylococci have not become as common in our series as in other groups. Cases of enterococcal endocarditis, however, have shown a marked increase from 3.9 per cent to 9.2 per cent of our total. This corresponds to the incidence in other series [31] and is consistent with the increased number of men among older patients. The marked increase in cases of Staph. epidermitis endocarditis would seem to be

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related almost entirely to the appearance of endocarditis following cardiac surgery as has been reported elsewhere [l]. The infrequent occurrence of gram-negative bacteria as etiologic agents has been commented upon [3]. This is surprising since septicemia today is most commonly Icaused by members of the enterobacteriaceae [32,33]. The frequency of a’bacteremic cases in our series is similar to that of others. The finding that in 30 per cent of the autopsy confirmed cases a confirmed positive blood culture was never obtained during life suggests that our figures for such cases (17 per cent) and that of others [1,4,6] are underestimates. Criteria for acceptance of cases into a study of infective endocarditis have indeed been variable [2-4]. We were of the opinion that restriction of cases to those proved to have bacteriologic findings would have omitted a number of important cases from the analysis. Since the 1930’s most reports of endocarditis have included from 7 to 27 per cent of cases in which blood cultures have been negative. Since we have included such cases there will be obvious differences in our data from those series in which only bacteriologically proved cases are included. The 17 per cent of patients who during life had negative cultures showed no differences from patients with either successfully treated bacteremic infections or autopsy proved endocarditis cases. In terms of age and survivorship they resemble mainly patients with Strep. viridans endocarditis. With respect to the valve involved the situation is more complicated. The marked decline in patients with combined mitral and aortic valve disease, even when age changes are adjusted for, is understandable since these patients had rheumatic heart disease, which has been declining in frequency and severity in recent decades. The marked increase in aortic valve disease has been noted and commented upon [3]. It is not ‘solely an effect of age, since the adjusted rates indicate a rise of 100 per cent. However, as the crude rates show an increase of 400 per cent, the increase in patients’ age must have had a major influence on the increase in aortic valve disease. Another major change in the nature of patients with endocarditis has been the extraordinary decrease in the duration of symptoms, This has had the effect that ‘patients today are far less frequently seen with petechiae or splenomegaly than they were decades ago when the duration of illness before therapy was several months more than it is now. When this factor is considered we found that

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the remaining increase in aortic valve disease existed only for patients with a brief duration of illness. During the initial years of the study period nearly all patients with endocarditis had a prior hospital admission, before being referred to the Medical Center. In the days of sulfonamides or the early days of penicillin therapy this was understandable. At the present time a prior hospitalization for the present illness in these cases is rare. Since aortic valve disease tends to be rapidly progressive, it becomes apparent why more patients with aortic valve disease would be admitted now than formerly. Although the over-all survival rate, which improved remarkably with the introduction of penicillin, has been stable in recent years, the real nature of the situation is different. We are in effect running a “Red Queen’s race.” We are treating progressively older, more precariously ill patients, with more fulminant endocarditis, year by year. By referring to the individual data on survival for each valve and organism, it can be seen that progress is being made with respect to cases with Staph. aureus, aortic valve involvement and congenital heart disease. It has often been asserted that prior antibiotic therapy may result in negative blood cultures. The large majority of patients admitted in recent years has received such therapy, yet positive cultures are obtained in nearly 85 per cent of cases, a figure not remarkably different from the early antibiotic era. One aspect of antibiotic care which has been little commented upon is the use of brief courses of antibiotics for brief febrile episodes, particularly in the elderly who have many other diseases, as already noted. The advent of oral antistaphylococcal agents and the increased susceptibility of Staph. aureus to erythromycin and chloramphenicol in recent years [35] will produce subacute Staph. aureus endocarditis, as we have seen on a number of occasions. The optimal therapy selected for bacterial endocarditis should be influenced by the nature of the

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hospital and the type of patients. At the Medical Center the use of high dose penicillin therapy, 6,000,OOO to 20,000,OOO units of penicillin G/day intramuscularly or intravenously, is favored. High dose intravenous therapy became routine in the late fifties. Oral therapy has not been used. This may account for the excellent recovery rate. During the late 1950’s, when tetracycline, erythromytin and chloramphenicol were used in patients with severe cases who were allergic to penicillin, survival was poor, as has been noted by Finland [36]. It has been our policy in recent years to use antihistamines and steroids if necessary so penicillin or cephalothin can be used in penicillin-allergic patients. Patients unable to tolerate either of these agents have received vancomycin successfully. At the Harlem Hospital we frequently use an antistaphylococcal agent in combination with penicillin because of the number of narcotic addicts admitted with endocarditis. This review of infective endocarditis at one institution shows that the nature of a disease can change as the population served by a hospital changes and as the patients with the illness become older. It is clear that antibiotic therapy has been the major factor in determining the outcome in endocarditis, but the nature of the disease has been altered significantly by the increasing age of patients with rheumatic heart disease, the development of cardiac surgery and the growth of drug addiction. ACKNOWLEDGMENT This article is dedicated to Yale Kneeland, Jr., M.D., F.A.C.P., Professor of Medicine, College of Physicians and Surgeons, Columbia University. Many of these patients were seen over the three decades by Professor Kneeland. His advice and sage guidance accounted in no small way for the excellent survival of patients with infective endocarditis seen at this institution. Countless students and one of us (H.C.N.) owe a debt of gratitude to this teacher who was always ready to discuss another case of bacterial endocarditis.

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Lerner PI, Weinstein L: Infective endocarditis in the antibiotic era. New Eng J Med 274: 199, 259, 323,388, 1966. Finland M, Barnes MW: Changing etiology of bacterial endocarditis in the antibacterial era. Ann Intern Med 72: 341, 1970. Uwaydah MM, Weinberg AN: Bacterial endocarditis -a changing pattern. New Eng J Med 273: 1321. 1965. Blount JG: Bacterial endocarditis. Amer J Med 38: 309, 1965.

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Ravinovich S, Evans J, Smith IM, January LE: A long-term view of bacterial endocarditis: 337 cases 1924 to 1963. Ann Intern Med 63: 185, 1965. Vogler WR, Dorney ER, Bridges HA: Bacterial endocarditis. Amer J Med 32: 910, 1962. Wilson L: Etiology of bacterial endocarditis before and since introduction of antibiotics. Ann Intern Med 58: 946, 1963. Kerr A: Bacterial endocarditis-revisited. Mod Cone Cardiovasc Dis 33: 831. 1964.

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Kaye D, McCormack RC, Hook EW: Bacterial endocarditis: changing pattern since introduction of penicillin therapy. Antimicrob Agents Chemother, p 37, 1961. Cherubin C, Boden M, Kavalier F, Lerner S, Cline W Infective endocarditis in narcotic addicts. Ann Intern Med 69: 1091, 1968. Louria DB, Hensle T, Rose J: The major medical complications of heroin addictions. Ann Intern Med 67: 1, 1967. Hoffman FG, Zimmerman SL, Bradley EA, Lapidus B: Bacterial endocarditis after surgery for acquired heart disease. New Eng J Med 260: 152, 1959. Amoury RA: Infection following cardiopulmonary bypass, Cardiac Surgery (Norman JC, ed), New York, Appleton Century Crofts 1967, p 476. Stason WB, DeSanctis RW, Weinberg AN, Austen WG: Cardiac surgery in bacterial endocarditis. Circulation 38: 514, 1968. Wilson MG, Lim WN, Birch A McA: The decline of rheumati’c fever. Recurrence rates of rheumatic fever among 782 children for twenty-one consecutive calendar years (1936-1956). J Chron Dis 7:

183, 1958. 16. 17. 18. 19. 20. 21. 22. 23.

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Massell BF, Amezcua F, Pelargonio S: Evolving picture of rheumatic fever. JAMA 188: 287, 1964. Kerr A Jr: Subacute Bacterial Endocarditis (Pullen RL, ed), Springfield, Ill, Charles C Thomas, 1955. Cummings V, Furman S, Dunst M, Rubin IL: Subacute bacterial endocarditis in the older age group. JAMA 172: 137, .1960. Gleckler WJ: Subacute bacterial endocarditis in old persons. Geriatrics 15: 152, 1960. Geraci JE: The antibiotic therapy of bacterial endocarditis. Med Clin N Amer 42: 1101, 1958. Tompsett R: Diagnosis and treatment of bacterial endocarditis. DM p 1, 1964. Robinson MJ, Ruedy J: Sequelae of bacterial endocarditis. Amer J Med 32: 922,‘1962. Wallach JB, Glass M, Lukask L, Angrist AA: Bacterial

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endocarditis in the aged. Ann Intern Med 42: 1206, ,1955. Traut EF, Carter JB, Gumbiner SH, Hench RN: Bacterial endocarditis in elderly: report of 94 autopsied cases. Geriatrics 4: 205, 1949. Cheng TO: Some new observations on the syndrome of papillary muscle dysfunction. Amer J Med 47: 924, 1969. Joffe S, Feil H: Subacute bacterial endocarditis arising in mural thrombi following myocardial infarction. Circulation 12: 242, 1955. Korn D, DeSanctis RW, Snell S: Massive calcification of mitral annulus: clinicopathological study of fourteen cases. New Eng J Med 267: 900,1962. Straus AL, Hamburger M: Pneumococcal endocarditis in the penicillin era. Arch Intern Med (Chicago) 118: 190, 1966. Wilson LM: Pathology of fatal bacterial endocarditis before and since the introduction of antibiotics. Ann Intern Med 58: 84, 1963. Cherubin C: Unpublished observations. Koenig MG, Kaye D: Enterococcal endocarditis. New Eng J Medl264: 257, 1961. McHenry MC, Martin WJ, Wellman WE: Bacteremia due to gram-negative bacilli: review of 113 cases encountered in five-year period 1955 through 1959. Ann Intern Med 56: 207, 1962. DuPont HL, Spink WW: Infections due to gram-negative organisms: an analysis of 860 patients with bacteremia at the University of Minnesota Medical Center, 1958-1966. Medicine (Balt) 48: 307, 1969. Friedberg CK, Goldman HM, Field LE: Study of bacterial endocarditis: comparison of ninety-five cases. Arch Intern Med (Chicago) 107: 6, 1961. Bulger RJ, Sherris JC: Decreased incidence of antibiotic resistance among Staphylococcus aureus. Ann Intern Med 69: 1099, 1968. Finland M: Treatment of bacterial endocarditis. New Eng J Med 250: 372,!419,1954.

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