C1in. Cardiol.
1, 112-117 (1978)
© G. Witzstrock Publishing House Inc.
Practitioner's Comer
Antibiotic Prophylaxis in Patients with Rheumatic Heart Disease and
Prosthetic Devices
D. G. WYSE, M.D., PH. D., J. H. McANULTY, M.D.,
The Division of Cardiology, Department of Medicine University of Oregon Health Sciences Center,
Portland, Oregon, U. S. A.
Introduction
Prophylaxis is defined as: "measures designed to pre-
serve health and prevent the spread of disease" (18). Two
implicit parts to such a definition are first, that what is be-
ing prevented causes disease, and second, that the mea-
sure(s) proposed prevents this disease. We will briefly re-
view the evidence that patients with rheumatic heart dis-
ease and/or prosthetic cardiac devices are at increased risk
of morbidity and mortality from infection and further that
antibiotics reduce this morbidity and mortality. Antibiotic
prophylaxis is undertaken in patients with rheumatic heart
disease and in those with prosthetic devices for two pur-
poses: 1. prevention of recurrences of rheumatic fever;
and, 2. prevention of infective endocarditis. These are two
different issues which will be discussed separately.
Rheumatic Fever Prophylaxis
Group A beta-hemolytic streptococcal infections of the
upper respiratory tract (e.g. tonsillitis or pharyngitis) are
the precipitating cause of rheumatic fever. This subject has
been recently reviewed (14). Primary prevention (i. e. pre-
vention of the initial streptococcal infection) has resulted
in a decline in the incidence of rheumatic fever in the gen-
eral population beginning before the advent of antibiotics
and accelerating sharply in the 1950's when antibiotics
came into general use (14). Improved public health mea-
Address for reprints:
S. H. Rahimtoola, M. D.
Professor of Medicine
University of Oregon Health Sciences Center
3181 S. W. Sam Jackson Park Rd.
Portland, Oregon 97201, U.S.A.
Received: June 5, 1978
Accepted: June 29, 1978
S. H. RAHIMTOOLA, M. B.
sures and socio-economic factors played an important role
in the early decline of the incidence of rheumatic fever
from 1900 to 1940 before antibiotics were availble.
In patients who already have rheumatic heart disease,
secondary prevention is the goal and several studies have
documented the increased risk of further morbidity and
mortality from streptococcal infection and of the efficacy
of antibiotic treatment. Some of this data will be briefly
reviewed.
First, once a patient has had rheumatic fever he is at risk
to have recurrence of streptococcal infections and rheuma-
tic episodes. This risk is greatest from 6 months to 2 years
after an attack and the risk then declines each year until 5
years after the attack when it remains constant at approx-
imately 10 % per streptococcal infection. The risk of re-
currence is much higher if the heart was involved in the
previous rheumatic attack (16, 17). Second, it is known
that a large proportion (78%) of upper respiratory tract
streptococcal infections are asymptomatic and that if only
symptomatic streptococcal infections are treated, the re-
currence rate of rheumatic fever remains high, illustrating
that even asymptomatic streptococcal infections are a sub-
stantial risk to the patient with rheumatic heart disease
(6). Third, the risk of rheumatic recurrence is 3 times
higher in younger children (6).
The efficacy of penicillin prophylaxis of rheumatic fever
has been amply demonstrated from the very earliest
studies which used less than ideal regimens and still clearly
showed a reduction of recurrence rate form 18% to 2%
per year (11). Table I summarizes the incidence of strep-
tococcal attacks and rheumatic recurrences with various
regimens of antibiotic prophylaxis. Penicillin, by monthly
injection, gave the best protection with only 0.7 rheumatic
recurrences per 100 patient years. Oral sulfadiazine and
twice daily oral penicillin were associated with rheumatic
recurrence rates of 1.0 per 100 patient years. It should be
pointed out, however, that the patients in this study (Ta-
ble I) were highly compliant (4) and higher recurrence
 D. G. Wyse et al: Antibiotic Prophylaxis in Rheumatic Heart Disease 113

Table I Comparison of various regimens for rheumatic fever Table III Adults at "high risk" for recurrence of rheumatic
prophylaxis fever
regimen streptococcal rheumatic recurrences 1. recent attack of rheumatic fever
infection attack per 100 patient years 2. multiple attacks of rheumatic fever
rate per 100 patient 3. rheumatic heart disease*
years 4. lower socio-economic status
monthly injection 5. parents of young children
1.2 million units 6. certain professions: school teachers, physicians, nurses,
6.5 0.7
penG allied medical personnel, military personnel
oral sulfadiazine *At risk even after prosthetic valve replacement
1 g daily 16.4 1.0
oral pen G 200,000
units
OD 16.2 2.6
BID 7.3 1.0 lower socia-economic status, parents of young children,
intermittent pen G and certain professions such as school teachers, physicians,
400,000 units OlD 39.5 10.4 nurses, allied medical personnel, and those in military ser-
for 10d each month vice, are at increased risk.
(Data from Feinstein et ai, 1968 (4»

Recommended Regimens
rates are to be expected in poorly compliant patients who The current recommendations of the American Heart
are given oral regimens. Oral penicillin given once daily Association for antibiotic prophylaxis of rheumatic recur-
was less protective and intermittent penicillin gave unac- rences (7) are summarized in Table IV. The most effective
ceptably high recurrence rates of 10.4 rheumatic recurr- proven prophylaxis is intramuscular long-acting penicillin
ences per 100 patient years. G given every 4 weeks. Both oral sulfadiazine and penicil-
Thus, the evidence cited above demonstrates the need lin G are acceptable alternatives in compliant patients. It is
for and efficacy of continuous antibiotic prophylaxis important to note that twice daily penicillin is needed
against rheumatic fever in patients with a prior history of when given orally. In the rare event a patient is unable to
rheumatic fever and/or rheumatic heart disease. This evi- take either sulfa or penicillin, erythromycin is recom-
dence is summarized in Table II. Data allows one to iden- mended but has not been proven to be effective.
tify certain groups of adults who are at "high-risk" for re-
currence of rheumatic fever (Table III). These include:
those who have had an attack of rheumatic fever within
the previous 5 years; those who have had multiple attacks
of rheumatic fever; and those who have rheumatic heart Table IV Recommendations for antibiotic prophylaxis for rheu-
matic fever recurrences*
disease. Patients probably continue to be at risk for recur-
most effective
rence of rheumatic fever even after prosthetic valve re-
benzathine penicillin G 1.2 million units intramuscularly every
placement. In addition, other patients such as those of a 4 weeks
acceptable oral
1. sulfadiazine - 1 g daily if weight> 60 Ibs
Table II Rationale for antibiotic prophylaxis in rheumatic patients 0.5 g daily if weight ~ 60 Ibs
2. penicillin G - 200,000 to 250,000 units twice a day
rheumatic patients . . . .. . increased strept URTI
unproven oral (patients allergic to both penicillin and sulfa)
symptomatic and asympto- increased rheumatic erythromycin 250 mg twice a day
matic strept URTI . . recurrence
increased rheumatic increased rheumatic * American Heart Association Recommendation, Circulation
recurrences · heart disease 55,223 (1977) (7)
optimally treated rheumatic recurrences
symptomatic infection · still occur
intermittent monthly rheumatic recurrences
antibiotics . . . . . . · still occur
Prophylaxis is optimally given for the whole of the pa-
long-term continuous rheumatic recurrences
prophylaxis · are reduced
tient's lifetime. However, it has to be acknowledged that in
many circumstances this is not feasible, partly because of
patient compliance. Therefore, it should be undertaken for
at least 5 years after the last rheumatic attack or until the
Long-term continuous antibiotic prophylaxis patient has reached the age of 40 to 45 years, whichever is
strept URTI = streptococcal upper respiratory tract infection longer. It must be emphasized that prophylaxis must be

Clin. Cardiol. Vol. 1, August 1978

114 D. G. Wyse et al: Antibiotic Prophylaxis in Rheumatic Heart Disease
given at least until age 40 to 45 years. For example, if a
patient is aged 10 years at the time of the last attack,
prophylaxis might be discontinued at age 15, using the 5
year rule, a "time when the patient is still at extremely high
risk for recurrence. Even the recommendation that an-
tibiotic prophylaxis be continued at least until age 40 to 45
years is not absolute and judgement must be exercised.
For example, the grandmother with rheumatic heart dis-
ease who is continually exposed to streptococcal infection
in her grandchildren may need antibiotic protection for an
indefinite period of time.
Infective Endocarditis Prophylaxis
Antibiotic prophylaxis for infective endocarditis is widely
practiced which is certainly appropriate. However, its role
is much less precisely defined and its effectiveness is not as
clearly proven as antibiotic prophylaxis for rheumatic
fever.
It is germane to this topic to first consider some of the
features of infective endocarditis which have changed over
the last few decades before discussing antibiotic
prophylaxis. The epidemiology and microbiology of infec-
tive endocarditis have been recently reviewed (3) and
some salient features can be summarized briefly as follows.
The mortality from infective endocarditis has remained
unchanged from 1939 to 1967. Infective endocarditis was
uniformly fatal in the pre-antibiotic era; therefore, as the
mortality from infective endocarditis has remained un-
changed, it is reasonable to conclude that the incidence of
infective endocarditis has increased in the last few de-
cades, or certainly has not decreased. The average age of
patients with infective endocarditis has risen in recent
years and is now 50 years. The male to female ratio is 2: 1.
In spite of some changes in the types of causative or-
ganism isolated in recent years, streptococci remain the
most frequent cause of infective endocarditis. Of the strep-
tococci, enterococci are implicated in 11 % of all cases of
infective endocarditis whereas viridans and other strep-
tococci account for slightly more than 50% of the total.
Staphylococcus aureus accounts for virtually all
staphylococcal endocarditis and makes up 21 % of the to-
tal. The reported incidence of culture negative infective
endocarditis is at least 7%. Other organisms identified
contribute a small number of cases to the overall total.
There has been a clear change in the type of patient at
risk for infective endocarditis. Whereas in the past
rheumatic heart disease and, to some extent, congenital
heart disease were the major predisposing conditions, a
number of other etiological factors presently assume equal
importance. The latter include: other heart disease (e.g.
mitral valve prolapse, hypertrophic obstructive car-
diomypathy); previous cardiac surgery; drug addiction;
compromised host; and, chronic intravascular access (e.g.
hemodialysis).
Clin. Cardiol. Vol. I, August 1978
One of the problems which clearly makes infective en-
docarditis prophylaxis imprecisely definable is the inability
to recognize the site of entry of the organism. In acute in-
fective endocarditis, an entry site is recognized in approxi-
mately half of the cases but in the subacute form, a site of
entry is identified in only 20%.
The hypothesis upon which antibiotic prophylaxis for in-
fective endocarditis is based may be briefly summarized as
follows. There is a causal event leading to bacteremia
which, in the presence of a cardiac lesion, leads to infec-
tive endocarditis. The ability to control infective endocar-
ditis is on less certain ground for several reasons:
1. The causal events which lead to bacteremia are not
readily identifiable and predictable. Transient bacteremia
is a truly Ubiquitous event. In addition to the often re-
peated and well-known causes of bacteremia, are a
number of others such as chewing mint candy and brush-
ing one's teeth (9). Clearly the patient cannot be protected
from all bacteremias. Furthermore, the relationship be-
tween infective endocarditis and a well recognized cause of
bacteremia such as dental work can be alternatively stated:
it is the cause of 25 % of the cases of infective endocar-
ditis, whereas, the risk of acquiring infective endocarditis
from this source is 1 : 115,500 (3). Thus, although the in-
cidence of bacteremias that lead to infective endocarditis is
low, once infective endocarditis occurs it contributes sub-
stantially to morbidity and mortality. The risk of most
other causes of bacteremia is not well-defined and it is
necessary to again point out that in 80% of the cases of
subacute endocarditis an initiating event is not found. The
explanation for the latter observation may be that repeated
exposure to bacteremias, which have extremely low risk
and cannot practically be guarded against (e.g. brushing
teeth), may cause infective endocarditis in many patients.
In addition, there are some misconceptions. For example,
cardiac catheterization is thought by many to be a signific-
ant cause of infective endocarditis. There is no evidence
that properly performed (aseptic technique) and uncom-
plicated catheterization of the heart places the patient at
increased risk of infective endocarditis. Several studies (5,
11, 13, 15) which include large numbers of patients and
many high-risk patients such as those with congenital heart
disease (5, 13) and prosthetic heart valves (11) have
shown the risk of infective endocarditis from cardiac
catheterization is negligible in the absence of local wound
infection at the site of entry of the cardiac catheter.
2. The hypothesis supposes that all cardiac lesions are
recognized and that the potential of a wide spectrum of
cardiac lesions (e.g. secundum atrial septal defect versus
rheumatic mitral regurgitation) to predispose to infective
endocarditis is equal, or if unequal, is at least known. A
wide variety of cardiac disease predisposes to infective en-
docarditis. In some instances the risk has been relatively
well-defined. For example, actuarially determined curves
have demonstrated that patients with a mitral or aortic
valve prosthesis have an average risk of infective endocar-
 D. G. Wyse et al: Antibiotic Prophylaxis in Rheumatic Heart Disease
ditis of 1.1 and 0.7% per year (12). The latter data also
demonstrates that the risk of infective endocarditis con-
tinues indefinitely following valve replacement. In many
other instances the risk is much less well-defined although
it is known that some conditions are clearly at greater risk
than others. All cardiac lesions do not place the patient at
equal risk (2, 13). For example, rheumatic mitral regurgi-
tation places the patient at greater risk than does a secun-
dum atrial septal defect whereas the patient with saphen-
ous vein bypass grafts is at no increased risk. There is no
unanimity of opinion about which lesions make antibiotic
prophylaxis essential. Furthermore, several high-risk car-
diac lesions such as bicuspid aortic valve, idiopathic hyper-
trophic subaortic stenosis and coarctation of the aorta can
easily exist unrecognized for many years and in such cases
the patient might never be given infective endocarditis
prophylaxis.
3. The hypothesis presumes that antibiotic administra-
tion prevents or effectively treats the initiating event, that
is, bacteremia. The effectiveness of the recommended re-
gimens of antibiotic prophylaxis of endocarditis is un-
proven in man. In experimental endocarditis in rabbits,
many recommended prophylactic antibiotic regimens do
not prevent infective endocarditis (1). Kaye (9) has pre-
sented a theoretical argument that the effectiveness of an-
tibiotics in preventing infective endocarditis may be quite
low. His analysis is as follows. If one assumes that about
50% of patients with infective endocarditis do not have
previously recognized heart disease and thus would not be
given antibiotic prophylaxis; and further, that recom-
mended antibiotic regimens are designed to prevent strep-
tococcal infection which accounts for approximately 65 %
of subacute infecitve endocarditis; and finally, that in 80%
of the cases of subacute infective endocarditis the event
causing bacteremia is unrecognized; then, one can esti-
mate that at best only 7% of the cases of subacute infec-
tive endocarditis are preventable.
Thus, the dilemma of infective endocarditis prophylaxis
with antibiotics may be summarized as follows (Table V).
It is unknown whether all bacteremias should be treated
and furthermore this would seem to be an impossible goal.
Not all patients at risk are identified nor is the degree of
risk clearly quantifiable. The effectiveness of prophylaxis
is probably low, it places the patient at risk of drug reac-
tions, it costs money and is inconvenient. These negative
points must be balanced against the known problems of in-
fective endocarditis. Some patients with infective endocar-
ditis die even when treated adequately. The complications
of infective endocarditis are often disastrous and even af-
ter successful treatment, permanent and serious sequelae
may remain. On balance, the efficacy of antibiotic
prophylaxis for infective endocarditis has not been proven
but it should be admitted it has not been disproven. Furth-
ermore, how often infective endocarditis has been pre-
vented by antibiotic prophylaxis is completely unknown.
Therefore, at the present time antibiotic prophylaxis for in-
Clin. Cardio!' Vo!. 1, August 1978
115
Table V The dilemma of antibiotic prophylaxis for infective
endocarditis
problems of prophylaxis problems of infective endocardi tis
1. probable low effectiveness 1. mortality
a) bacteremia is ubiquitous
b) treat all bacteremias?
c) all patients at risk are not
identified
d) regimens may not prevent
bacteremia
2. cost and inconvenience 2. complications - may be
disastrous
3. efficacy - not proven or 3. sequelae - often permanent
disproven and serious
How often has infective endocarditis been
prevented by !pltibiotic prophylaxis??
fective endocarditis is essential on clinical grounds and
should be aggressively undertaken. There are a large
number of published recommendations for antibiotic
prophylaxis of infective endocarditis. The advantages of
one regimen over another are often subtle and are un-
proven. The recommendations of the American Heart As-
sociation represent the currently recognized standard of
practice in the United States (8). Conditions which would
require prophylaxis include:
1. most dental and upper respiratory tract procedures
2. lower gastrointestinal tract, gallbladder and genito-
urinary tract surgery or instrumentation
3. cardiac surgery;
4. other, i.e., all surgical procedures on any infected or
contaminated tissues.
Some procedures, although known to cause bacteremia
have rarely if ever been implicated as a cause of infective
endocarditis and do not routinely require antibiotic
prophylaxis. The latter include: first, dental flossing and
water pressure cleaning devices; second, uncomplicated
vaginal delivery, pelvic examination, dilatation and curet-
tage of the uterus, and insertion or removal of intrauterine
devices; third, upper gastrointestinal endoscopy (without
biopsy), percutaneous liver biopsy, proctoscopy and sig-
moidoscopy (without biopsy); and fourth, indwelling vas-
cular catheters, hemodialysis shunts, etc. The patient with
prosthetic heart valves is, however, a special case who is at
particular risk and prudently should probably be given an-
tibiotic prophylaxis in most of the instances listed above.
Patients with transvenous cardiac pacemakers are proba-
bly not at the same risk as those with prosthetic valves but
prudence again would suggest protection be given in high-
risk situations.
The regimen of antibiotic recommended by the Ameri-
can Heart Association (8) is complex and difficult to pre-
116 D. G. Wyse et al: Antibiotic Prophylaxis in Rheumatic Heart Disease

Table VI Initial and subsequent therapy for prophylaxis of infec- tract procedures or surgery can be given either regimen A
tive endocarditis (adults)· or regimen B. Regimen B is probably more effective. Re-
initial subsequent gimen A uses either oral or parenteral penicillin for initial
therapy therapy therapy and oral penicillin for subsequent therapy. For the
dental and upper respiratory patient allergic to penicillin, parenteral vancomycin or oral
tract procedures or SUlJery erythromycin is used for initial therapy and oral ery-
regimen A: aqueous crystalline penicillin V thromycin for subsequent therapy. Regimen B, which is re-
penicillin commended for patients at high risk, such as those with a
plus procaine
penicillin prosthetic valve, uses strictly parenteral initial therapy, ad-
or penicillin V penicillin V ding streptomycin to parenteral penicillin or using van-
or vancomycin erythromycin comycin alone in the allergic patient. Subsequent therapy
or erythromycin erythromycin is the same as regimen A.
regimen B: aqueous crystalline For gastrointestinal or genito-urinary tract surgery or in-
(prosthetic valves) penicillin strumentation, the recommended regimen for both initial
plus procaine
penicillin
and subsequent therapy, is parenteral aqueous crystalline
plus streptomycin penicillin V penicillin in twice the dose used for dental procedures or
or vancomycin erythromycin ampicillin parenterally plus an aminoglycoside (gentamicin
gastrointestinal or streptomycin). Thus, both for initial and subsequent
and genitourinary therapy for gastrointestinal or genito-urinary procedures,
surgery or instrumentation aqueous crystalline aqueous the patient must be given a combination of antibiotics. If
penicillin crystalline the patient is allergic to penicillin, vancomycin plus strep-
penicillin or
ampicillin
tomycin is given parenterally for both initial and subse-
quent therapy. We strongly recommend the readers to re-
or ampicillin
view the original recommendations published in Circula-
plus plus
gentamicin gentamicin tion (8).
or streptomycin or streptomycin Since the need for and effectiveness of antibiotic
, or prophylaxis of infective endocarditis is not clearly proven,
vancomycin vancomycin clinical judgment is required in each situation. Further-
plus plus more, a high index of suspicion of infective endocarditis is
streptomycin streptomycin necessary in the presence of any unusual clinical events
• American Heart Association Recommendations, that follow procedures, and early diagnosis of infective en-
Circulation 56, 139A, (1977) (8) docarditis is extremely important in order to reduce its
complications, sequelae and mortality.
sent briefly but is summarized in Tables VI and VII.
Physicians likely to use this information should carry a
copy with them rather than rely on memory. Each therapy Role of tbe Pbysician in Antibiotic Propbylaxis
is divided into an initial therapy given 112 to 1 h prior to
the procedure and subsequent therapy given after the pro- The minimum role of the physician in ensuring effective
cedure. Patients undergoing dental or upper respiratory antibiotic prophylaxis includes the following:

Table VII Dosages of antibiotics for infective endocarditis prophylaxis (adults) ***
initial dose subsequent doses
l/:rl h pre-procedure dose frequency
penicillin
aqueous crystalline I,OOO,OOOU IM** SID • 12 hourly x 2
procaine 600,OOOU 1M
penicillin V 2g orally 500mg 6 hourly x 8
streptomycin 1g 1M SID· 12 hourly x 2
vancomycin Ig IV SID· 12 hourly x 1
erythromycin 1g orally 500mg 6 hourly x 8
ampicillin Ig IV or IM SID· 8 hourly x 2
gentamycin 1.5 mg/kg IVorIM SID· 8 hourly x 2
(~80 mg)

.. SID = same as initial dose

** Double this amount for gastrointestinal or genitourinary procedures
... American Heart Association Recommendations, Circulation 56, 139A, (1977) (8)

Clin. Cardiol. Vol. 1, August 1978

 D. G. Wyse et al: Antibiotic Prophylaxis in Rheumatic Heart Disease
1. the physician must be knowledgeable, for example,
about the risk to the patient, the need for prophylaxis, etc;
2. it is mandatory that the physician recognizes his or
her role is important and crucial;
3. the physician must explain to the patient the need for
prophylaxis and also when, what, and how to take the var-
ious therapeutic regimens; and
4. it is essential that the physician reinforce the impor-
tance of prophylaxis at each patient visit.
Unless the physician is knowledgeable, concerned and
aggressive, and conveys his enthusiasm for prophylaxis to
the patient, it is unlikely that patient compliance will be
obtained. Thus, in this important issue of antibiotic
prophylaxis the role of the physician is a central and cru-
cial one.
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