Fundamentals The

prevention

of clinical and

treatment

cardiology of bacterial

endocarditis

George A. Pankey, New

Orleans,

M.D.

La.

Infective endocarditis may be caused by bacteria, fungi, rickettsia (Q fever), and possibly Chlamydiae and viruses’ multiplying on endocardial surfaces. In addition, trichinosis has been reported to cause extensive ventricular mural endocarditis with superimposed thrombosis.’ This review will consider only the bacterial form of the disease. Usually it is the endocardium of the heart valve that is involved by bacteria with infection of a cardiac prosthesis involving tissues surrounding the prosthesis or sutures. Rarely the suture or prosthesis alone is involved. The gross appearance of bacterial endocarditis usually results in lesions called vegetations. Microscopically, the vegetation is composed of masses of fibrin, platelets, and microorganisms with little cellular reaction. Research by Durack and Beeson indicates that the microorganisms are embedded within the fibrin-platelet meshwork and are therefore protected from the defense mechanisms of the host. Enhancing this problem is the reduced state of metabolic activity of the bacteria deep within the lesion, thus reducing the effectiveness of most antimicrobial agents directed against them. The polymyxins and amphotericin B are unique in that they act on contact with susceptible organisms regardless of metabolic activity. Unfortunately, they have limited usefulness in the treatment of bacterial endocarditis. Another factor that creates difficulty in therapy is depression of bactericidal activities of the

From the Department of Internal Diseases, Ochmer Medical Institutions, Received

for publication

July,

1979,

Section Orleans.

on

Infectious

Oct. 16, 1978.

Reprint requests: Dr. George A. Pankey, Highway, New Orleans, La. 70121.

102

Medicine, New

Vol.

98, No.

Ochsner

1

Clinic,

1514 Jefferson

polymorphonuclear leukocytes from untreated patients with bacterial endocarditis. The observation of a rapid return to normal bactericidal function during treatment indicates that the depression is an acquired consequence of the infectious process of bacterial endocarditis. Thus, this type of infection tends to perpetuate itself by depressing normal host-defense mechanisms. This depression may well explain the constancy of bacteremia until antibiotic therapy in most patients.’ The question of whether the lesion always occurs on previously damaged valves or sometimes on undamaged valves is controversial. The possibility that bacteria may invade a normal valve by passing through the vessels supplying that valve has been suggested,5-9 but normal appearing valves usually have little or no vascularization and bacterial endocarditis does occur on such valves. Another suggestion is that bacteria may settle on sterile thrombotic areas on valve surfaces.“‘-‘” This appears to be a more likely mechanism in those patients without previous valvular disease and has been shown to occur in an experimental rabbit mode1.14However, bacteria flowing past thrombotic areas in other parts of the body apparently do so without adherence and production of disease most of the time, so there must be something about the endocardium that is unique. Another mechanism of adherence to the endocardium is reported by Gould and colleagues’5: certain gram-positive pathogenic bacteria, such as enterococci, Staphylococcus aureus, Staphylococcus epidermidis, and alpha hemolytic streptococci have surface components that react with receptors on the endocardial cell surface. This finding correlates with the clinical observation

000%8703/79/070102

+

17$01.70/O

0 1979

The

C. V. Mosby

Co.

Prevention and treatment of bacterial endocarditis

that gram-positive bacteria cause endocarditis more frequently than gram-negative bacteria. However, adherence due to receptors is not the only determinant of the virulence of bacteria since some bacteria, such as Group A beta hemolytic streptococci, have good adherence properties but are not frequently associated with endocarditis. To complicate matters further, Cardiobacterium hominis, a slow-growing gram-negative bacillus, has rarely produced a recognizable disease in man other than endocarditis. The mechanism of this organ tropism is unknown.lG Improvement in the prevention. and therapy of bacterial endocarditis will come with better understanding of the pathophysiology of the lesion and the bacteria that produce it. Diagnosis

In modern times the diagnosis of bacterial endocarditis is difficult if one relies on descriptions of the disease prior to 1960.17.I8 Because today’s patients rarely allow symptoms to go untreated for a long time, the physician is usually confronted with vague symptoms that may easily be assigned to a more benign disease. Fever and heart murmur are enough to raise one’s suspicion of bacterial endocarditis, but demonstration of the causative microorganism at the site of the pathological lesion is the only definite means of diagnosing the disease. Because such demonstration is not possible except from surgical or pathological specimens, blood cultures that demonstrate the continuous presence of one or more microorganisms lead to a presumptive, but usually accurate, diagnosis of bacterial endocarditis. As emphasized recently by Miller and Casey,‘” the recognition of predisposing factors, such as congenital or valvular heart disease,recent heart surgery with or without insertion of a cardiac prosthesis, or narcotic addiction, can lead to the proper diagnosis in spite of the absence of the classical Osler’s nodes, splenomegaly, Roth’s spots, etc. In the final analysis, the clinical presentation is determined by the virulence and type of the infecting bacterium which influences the degree of dysfunction due to valve injury, complications of peripheral embolization, and vasculitic reactions presumably resulting from hypersensitivity. When the diagnosis of bacterial endocarditis is suspected, continuous bacteremia is usually rather easily confirmed. The patient with a heart

American Heart Journal

murmur and fever needs no more than five blood cultures drawn over a 48-hour (or less) period. Each sample is cultured both aerobically and anaerobically and the laboratory is requested to hold the cultures for at least two weeks and preferably three weeks. If a fastidious organism, such as Brucella abortus, is suspected, the laboratory should be informed. Drawing several blood samples improves the chance of identifying the actual causative bacterium, which will usually appear in all of the cultures, whereas a contaminant might appear in only one.“‘. L’lRarely, more than one bacterium appear in successive cultures. When this occurs, both bacteria should be considered causative and antibiotic therapy should be adequate for all bacteria repeatedly cultured. However, the likelihood of more than one bacterium being an etiological agent is small even in the case of immunologically suppressed patients. Continuous bacteremia associated with a heart murmur means bacterial endocarditis until proven otherwise. In the geriatric patient especially, fever may be absent and the initial manifestation may be the result of embolization, such as a cerebrovascular accident or organic psychosis, but bacteremia can be demonstrated. On the other hand a patient may have a heart murmur and continuous bacteremia with Brucella or Salmonella and not have endocarditis. Secondly, some patients with intermittent bacteremia caused by gram-negative bacilli from an intraabdominal abscess or other source frequently have murmurs and do not have endocarditis at autopsy. Nevertheless, in both of these situations endocarditis is also possible and the burden of proof rests on the physician who says that the disease does not exist. Diagnostic measures other than blood cultures usually cannot prove endocarditis but they can suggest it. Teichoic acid antibody tests have been found to be a rapid method of diagnosing Staphylococcus aureus endocarditis.“- ?‘( Nagel and associates” compared the agar diffusion and counterimmunoelectrophoresis (CIE) methods for detecting teichoic acid antibodies and their study showed the agar diffusion technique to be less sensitive than the CIE (85 per cent vs 96 per cent, respectively) with a longer preparation time (plates read in 18 to 72 hours vs 1 hour, respectively), but the agar diffusion technique did have a greater specificity (less than 5 per cent false-

103

Pankey

positive vs 10 per cent false-positive, respectively). It has been recommended that both tests be used: the CIE for screening and the agar diffusion for confirmation. The teichoic acid antibody levels usually are high enough to be detected by the time of admission to the hospital and are useful in following therapy because they will fall and disappear with successful treatment. When the diagnosis is not sufficiently clear, or previous antimicrobial therapy has rendered the blood cultures negative, this test can give the clinician an early presumptive diagnosis to base therapy upon until the standard cultures are reported. Because the teichoic acid antibody test may be positive with other deep-seated Staphylococcus aureus infections, such as osteomyelitis, a thorough knowledge of the patient’s condition is mandatory before proper interpretation can be made. In addition, some false-positive results have been obtained when the infecting organism was Staphylococcus epidermidis but these probably are due to antibodies against the ribitol-teichoic acid. Recently, an solid-phase radioimmunoassay for the detection of Staphylococcus aureus antigen has been evaluated in rabbits with endocarditis.” A similar method has been useful in diagnosing cryptococcal meningoencephalitis in patients with negative cultures. Other diagnostic measures that are occasionally helpful include examination of gram stains of buffy coat preparations of peripheral blood, testing for elevated erythrocyte sedimentation rates, rheumatoid factor, and looking for circulating immune complexes.Z5 The erythrocyte sedimentation rate is a very sensitive test, being elevated in close to 100 per cent of cases,‘“, Z. x but, unfortunately, it is nonspecific. The test for rheumatoid factor is also not specific, but it correlates well with endocarditis lasting six weeks or 1ongeP and the titers for this test usually fall and disappear with adequate treatment. The function of the IgM rheumatoid factor in bacterial endocarditis is not understood. It appears to enhance bacterial agglutination in vitro, but inhibits opsonization of microorganisms when tested with autologous serum.‘!’ More likely it simply represents IgM response to the Fc fragment of the IgG involved in the initial coating of the offending bacterium for the classical complement pathway for opsonization and phagocytosis. Circulating immune complexes, especially in high titers, may be useful in diagnosis and are also believed to result in vascu-

104

litic lesions in the skin and kidney. A fall in serum complement is an early finding in these patients. Although the role of echocardiography in diagnosis of endocarditis is less than its potential usefulness in predicting which patient will require operation (those with large vegetations and/or premature closure of an infected mitral valve, especially with aortic incompetence, for example), echocardiography and gallium-67 imaging may be helpful diagnostically in the 15 per cent to 20 per cent of patients with bacterial endocarditis and negative blood cultures. A growing concern is the reported association of Streptococcus bovis endocarditis and colonic cancer, prompting several authors:‘“-:” to suggest a causal relationship between the two. Two hypotheses for the relationship have been suggested: (1) that carcinogens are elaborated by the infecting Streptococcus bovis organisms, and (2) that colon cancer induces an environment that allows an overgrowth of Streptococcus bovis, thus inducing a carrier state. In the carrier state, because of decreased local host defense mechanisms as the result of the tumor, bacteremia leading to infection of the endocardium may result. I favor the latter concept. In either case, Klein and co11eagueP recommend differentiating group D streptococci by species so that patients with Streptococcus bovis endocarditis can be investigated for gastrointestinal lesions and, in particular, colonic carcinoma. Prosthetic

valve

endocarditis

Involvement of the prosthetic valve, sutures, and especially the surrounding endocardium with bacteria is a special problem that has resulted from modern medical advances.33 These types of endocarditis are usually divided into early-onset (those casesoccurring two months or less postoperatively) and late-onset (those cases occurring longer than two months postoperatively).“” The organisms usually isolated from prosthetic valve endocarditis include Staphylococcus aureus, Staphylococcus epidermidis, alpha and betahemolytic streptococci, “diphtheroids,” gramnegative bacilli, and fungi, such as Candida and Aspergillus species. A substantial number of the early-onset cases are caused by gram-negative bacilli;‘;~ :i probably due to hospital-acquired infections. “. I” As a matter of fact, endocarditis due to gram-negative bacteria is infrequent except in this setting and in drug addicts.

July,

1979,

Vol.

98, No.

1

Prevention

The question then arises as to how to differentiate gram-negative bacteremia from gram-negative endocarditis in patients with prosthetic valves. According to Sande and co-workers,“’ if no definitive signs of endocarditis appear, such as a new or changing murmur, petechiae, or other signs of embolic phenomena, then the patient should be examined for extracardiac sources of infection, such as pneumonia, wound sites, intravascular or urethral catheters, phlebitis, or cellulitis, If the same organism that is causing the bacteremia can be isolated from any of these sites, then it is more likely that this is the source and the patient does not have prosthetic valve endocarditis. Obviously this can be a difficult clinical decision and one that may be helped by the use of echocardiography. All possible sites of bacteremia should be removed or treated since, when a bacteremia is present, a potential for prosthetic valve endocarditis is always there. Another complicating factor is that patients with early prosthetic valve endocarditis have almost invariably received prophylactic antibiotic(s) before operation. Therefore, the bacteria causing the endocarditis have most likely become resistant to the antibiotic(s) used for prophylaxis. Different antibiotics with bactericidal activity against the specific gram-negative bacillus are thus indicated. If no endocarditis is established, a short course of antibiotic therapy (7 to 10 days) should be sufficient to eradicate bacteremia, providing the source, such as an intravascular catheter, is removed. Bogart and colleaguesJ* have taken an opposing view. They concur about the high incidence of gram-negative bacteremia in prosthetic valve patients, but point out that the criteria used by Sande and associates*” may be too general. In Bogart and colleagues’ study,4l 20 per cent of cases of early prosthetic valve endocarditis were caused by gram-negative organisms, but in only about 50 per cent of these did a new or changing murmur develop. Thus, an extracardiac source of bacteremia should not militate against the chance of endocarditis and, in fact, may be the source of the endocarditis. They”’ conclude that any prosthetic valve patient with a gram-negative bacteremia should be treated as though he has endocarditis. Watanakunakorn4? has pointed out that medical progress in areas other than the installation of prosthetic valves has played a role in producing

American

Heart

Journal

and treatment

of bacterial

endocarditis

bacterial endocarditis. He is particularly concerned with the increasing incidence of Staphylococcus aureus endocarditis associated with intravenous lines, shunt infections in patients undergoing long-term hemodialysis, and in infections associated with permanent intracardiac pacemakers. Even intrauterine devices have been incriminated as a cause of bacteremia and endocarditis. Prophylaxis

Much emphasis is placed on the prophylaxis of bacterial endocarditis when bacteremia appears imminent in a patient with congenital or valvular heart disease. However, prevention of the heart disease itself would be a more desirable prophylaxis. Rheumatic fever is believed to account for most of the cardiac disease underlying endocarditis,43and its prevention would certainly lower the incidence of endocarditis. All group A beta-hemolytic streptococcal infections should be treated with suitable antibiotics. Prophylactic penicillin or sulfadiazine is helpful in preventing exacerbations of rheumatic fever44 in patients who did not have severe endocarditis with the original attack. Congenital heart diseaseis said to account for 6 to 24 per cent of predisposing cardiac problems, and perhaps even more, if mitral valve prolapse is considered congenital. Ventricular septal defect and patent ductus arteriosus are the congenital defects thought to have the highest risk of predisposing to endocarditis,‘j but it is estimated that at least 5 per cent of all women have a prolapsed mitral valve with a murmur and/or systolic click and more cases of endocarditis probably come from this group. Infection with rubella during the first trimester of pregnancy has been associated in the fetus with patent ductus arteriosus (58 per cent of cases), ventricular septal defect, tetralogy of Fallot, atria1 septal defect, and pulmonary stenosis, all of which are associated with endocarditis.‘” Thus, administration of rubella vaccine to all children should decrease if not eliminate, this problem. Other viruses, such as Coxsackie B, are also associated with congenital heart defects when infection occurs during pregnancy, especially in the third trimester. No vaccine is presently available for this group of viruses. Any patient with a heart murmur should receive pneumococcal vaccine at appropriate

105

Pankey

intervals and influenza vaccine annually. l’heoretically, if these diseases are avoided, there will be less opportunity for bacteremia from the upper respiratory tract. Both of these vaccines are well tolerated, influenza vaccine being absolutely contraindicated only to persons who are allergic to eggs. A frequently overlooked form of prevention of endocarditis is proper education of patients who are at risk. Persons with heart murmurs should be told to watch for symptoms of illness which may indicate bacteremia and to seek prompt treatment. Minor injuries, sore throats, and furuncles may seem innocuous to patients, but it has been shown that compressing a boil, use of a WaterPik, dental manipulations, and even chewing mint candy can result in transient bacteremia.” Obviously, it is impossible to maintain continuous prophylaxis; nevertheless, if the degree of bacteremia is likely to be great, in instances such as incision and drainage of an abscess or removal of an infected tooth, antibiotic therapy should be initiated. Antibiotic prophylaxis for patients at high risk of endocarditis remains controversial. The toxicity of the antibiotic(s) has to be weighed against the risk. It has been recommended that patients suspected of having nonbacterial thrombotic endocarditis”” (NBTE) and those suspected of having idiopathic hypertrophic subaortic stenosi@ receive antibiotic prophylaxis when facing potential bacteremia; however, not all authors agree on antibiotic prophylaxis for patients with mitral valve prolapse (MVP). Jeresaty”O and others”‘-“” stipulate that antibiotic prophylaxis is indicated for MVP patients only when a murmur of mitral insufficiency is heard. On the other hand, Aranda and colleagues”4 reported that antibiotic prophylaxis is justified in all patients with MVP, and De Silva and co-worker@ reported that they advised an MVP patient to take antibiotics before any procedures likely to cause bacteremia. My present policy is to recommend antibiotic prophylaxis for all patients with a murmur and also for all patients with a systolic click that is confirmed to be mitral valve prolapse by echocardiography. In 1965, the American Heart Association published a 3-page brochure on the prevention of bacterial endocarditis.“” The purposes for using antibiotics were simply stated: “to (1) prevent bacteremia or reduce its magnitude and duration should it occur; and (2) eradicate bacteria that 106

may implant on heart valves before a vegetation is formed.” In July of 1977 another American Heart Association Committee on the prevention of bacterial endocarditis published their recommendations.“” The committees were made up of different physicians even though many of the members of the 1965 committee are still active. The 1977 recommendations state: “Since there have been no controlled clinical trials, adequate data for comparing various methods for prevention of endocarditis in man are not available. However, an experimental animal model permitting consistent induction of bacterial endocarditis with microorganisms which often cause the infection in man has allowed experimental evaluation of both prophylaxis and treatment. Data from these studies, although derived from animal rather than clinical investigations, represent the only direct information on the efficacy of prophylaxis that is presently available.” For medicolegal purposes, the final warning paragraph of the committee’s report is very important: “Warning” “The committee recognizes that it is not possible to make recommendations for all possible clinical situations. Practitioners should exercise their clinical judgment in determining the duration and choice of antibiotic(s) when special circumstances apply. Furthermore, since endocarditis may occur despite antibiotic prophylaxis, physicians and dentists should maintain. a high index of suspicion in the interpretation of any unusual clinical events following the above procedures. Early diagnosis is important to reduce complications, sequelae, and mortality.“* My policy is to follow the recommendations of the 1977 American Heart Association Committee report (Table I), but I agree with Petersdorf’ that 24 hours is long enough for the antibiotic(s) to be given because bacteremia secondary to procedures rarely lasts longer than 15 minutes. Initial doses of penicillin should be administered in the physician’s or dentist’s office in order that, in the rare instance of anaphylactic reaction, appropriate treatment with epinephrine can be immediately instituted. Hunt and co-workers’” recently reported that erythromycin resistance is present in many oral alpha hemolytic streptococci, suggesting that erythromycin as an alternative to penicillin is not justified. I have given vanco*For complete details, Endocarditis,” published permission of American

see the statement “Prevention in Circulation 56:139A, 1977. Heart Association.

July,

of Bacterial Reprinted with

1979, Vol. 98, No. 1

Prevention and treatment of bacterial endocarditis Table

I. Prophylaxis against bacterial endocarditis*

A. For dental and upper respiratory

tract procedurest:

1. Penicillin therapy alone a. Parenteral-oral administration (1) Adults: Aqueous crystalline penicillin G (1 million units IM), mixed with procaine penicillin G (600,000 units IM). Give 30 min. to 1 hr. prior to procedure. Then give penicillin V (500 mg. PO) every 6 hr. for 8 doses. (2) Childrent: Aqueous crystalline penicillin G (30,000 units/Kg. IM) mixed with procaine penicillin G (600,000 units IM). Give 30 min. to 1 hr. prior to procedure. For children weighing less than 60 lbs., the dose of penicillin V is 250 mg. PO every 6 hr. for 8 doses. b. Oral administration (1) Adults: Penicillin V (2 g PO) 30 mm. to 1 hr. prior to procedure, then 500 mg. every 6 hr. for 8 doses. (2) Childrenz: Same. For children weighing less than 60 lbs., use ‘/z the dosage for the same time schedule. 2. Patients allergic to penicillin a. Adults: Vancomycin (1 g IV over 30 mm. to 1 hr.). Start infusion 30 min. to 1 hr. prior to procedure. Then give erythromycin (500 mg. PO every 6 hr. for 8 doses). b. Children$: Vancomycin (20 mg./Kg. IV over 30 min.-l hr.). Start infusion 30 min. to 1 hr. prior to procedure. Then give erythromycin (10 mg./Kg. PO every 6 hr. for 8 doses.)

or use c. Adults: Erythromycin (1 gm. PO, l&2 d. Childrenx: Erythromycin (20 mg./Kg. 3. Penicillin plus streptomycin a. Adults: Aqueous crystalline penicillin streptomycin (1 g IM). Give 30 min. 8 doses). b. Childrenf: Aqueous crystalline penicillin Plus, streptomycin (20 mg./Kg. IM). 8 doses).

B. For gastrointestinal

and genitourinary

hr. prior PO, 1.5-2

to procedure). Then give 500 mg. PO every 6 hr. for 8 doses. hr. prior to procedure). Then give 10 mg./Kg. every 6 hr. for 8 doses.

G (1 million units IM) mixed with procaine penicillin G (600,000 units IM). Plus, to 1 hr. prior to procedure, followed by penicillin V (500 mg. PO every 6 hr. for G (30,OCQ units/Kg./IM), mixed with procaine For children weighing less than 60 lbs., penicillin

penicillin G (600,000 units IM). V (250 mg. PO every 6 hr. for

tract procedures

1. Penicillin a. Adults: Aqueous crystalline penicillin G (2 million units IM or IV), or ampicillin (1 g IM or IV). Then give gentamicin (1.5 mg./Kg.-do not exceed 80 mg. IM or IV) or streptomycin (1 g IM). Give initial doses 30 min. to 1 hr. prior to procedure. If gentamicin is used, give similar dose of it and penicillin (or ampicillin) every 8 hours for 2 additional doses. If streptomycin is used, give a similar dose of it and penicillin (or ampicillin) every 12 hours for 2 additional doses. b. Childrenj.: Aqueous crystalline penicillin G (30,000 units/Kg. IM or IV) or ampicillin (50 mg./Kg. IM or IV). Then give gentamicin (2.0 mg./Kg. IM or IV) or streptomycin, (20 mg./Kg. IM). Timing of doses is the same as for adults. 2. For patients allergic to penicillin a. Adults: Vancomycin (1 g IV, given over 30 min.-l hr.) plus streptomycin (1 gm. IM). Give 1 dose, 30 min. to 1 hr. prior to procedure, and if thought necessary, repeat in 12 hours. b. Childrenj: Vancomycin (20 mg./Kg. IV given over 30 min. to 1 hr.) plus streptomycin (20 mg./Kg. IM). Timing of child’s dose is the same as for adults. Total dosage should not exceed 44 mgJKg.124 hours. In case of prolonged procedures or delays in healing, additional dosage may be necessary. 3. For patients with prosthetic valves a. Adults: Aqueous crystalline penicillin G (l,OOO,OOO units IM)

mixed with Procaine

penicillin

G (600,000

units

IM)

plus Streptomycin (1 gm. IM). Give 30 min. to 1 hr. prior to procedure; then penicillin b. Childrent: Aqueous ‘crystalline penicillin G (30,000 units/Kg.

V (500 mg. PO every intramuscularly)

6 hrs. for 8 doses).

For children

60 lbs. the recommended

mixed with Procaine

penicillin

G (600,000

units

intramuscularly)

plus Streptomycin (20 mg./Kg. intramuscularly). Timing of doses for children is the same as for adults. of penicillin V is 250 mg. every 6 hours for 8 doses.

less than

*Recommendations of a Committee of the American Heart Association, 1977.55 Reproduced with permission. iIn unusual circumstances or in the case of delayed healing, additional doses of antibiotics may be needed even though available bacteremia rarely persists longer than 15 minutes after the procedure. The physician or dentist may also choose to use the administration for all of the doses in selected situations. $Doses for children should not exceed recommendations for adults for a single dose or for a 24-hour period.

American Heart Journal

oral

dose

data suggest that parenteral route of

107

Pankey

mycin intravenously before dental procedures for patients who are allergic to penicillin and believe it especially valuable for penicillin-allergic patients who have a prosthetic valve. Antibiotic prophylaxis is recommended by most clinicians for patients undergoing open heart surgery. We use cefazolin, whereas othen9 use cephalothin. Primarily because of broader spectrum especially for Staphylococcus epidermidis, the cephalosporins are preferred over the oxacillin, methicillin, and nafcillin group. It is doubtful that we will ever have any published, double-blind studies in man proving the efficacy of any antibiotic regimen in preventing bacterial endocarditis, but the bulk of indirect evidence indicates that such a regimen is useful for patients with congenital and valvular heart disease. If this procedure is to be effective, however, the patient must be educated and re-educated. Sipes and colleaguesGo recently published an excellent review of the prophylaxis of infective endocarditis with 134 references. Treatment Historic. Before the introduction of antibiotics, the treatment of bacterial endocarditis was difficult, if not impossible. Various combinations of sulfonamides and other agents were used with little or no success. An interesting attempt at treatment was the concurrent use of sulfapyridine and anticoagulant agents.61 It was hoped that the anticoagulants would break up the fibrin mass and aid the antimicrobial agent in getting to the bacteria. After preliminary reports of some success,“’ a high frequency of emboli, presumably from the breakdown of vegetations, and subarachnoid hemorrhages from leaking mycotic aneurysms62-“4 discouraged further use of this combination of drugs.65.66Of course, in these patients, the disease had persisted for a great length of time and one would suspect an increase of embolic phenomenon as well as mycotic aneurysms on that basis. Now it is recognized that sulfadiazine, and probably other sulfonamides, inhibit the breakdown of the third component of complement, decreasing the amount of C3b that is necessary for opsonization of bacteria prior to phagocytosis.67 If this host-defense mechanism is interfered with by medication, as well as by the disease itself, as suggested previously, one would expect failure of the infection to respond.

108

More recently, the combination of anticoagulants and antibiotics has been evaluated in patients who have prosthetic valves because these patients are frequently taking anticoagulants. Since the main fear has been that this combined therapy would produce bleeding from mycotic aneurysms in the brain, it is interesting that neurological complications are only occasionally described in patients with prosthetic valve endocarditis.“” In a more recent report by Karchmer and associates69on late prosthetic valve endocarditis (43 cases-32 gram-positive, seven gramnegative, one Candida albicans, and three culture-negative), 13 patients (30 per cent) had major CNS clinical events. Twelve of these occurred among the 42 patients who received anticoagulant therapy throughout their illness. Eight of these I2 died, five as a direct result of massive intracerebral hemorrhage or hemorrhagic infarcts. In three of these five, the prothrombin time exceeded twice the control value at the time of the CNS event. The sixth patient who died had multiple septic cerebral infarcts; the seventh, two subarachnoid hemorrhages secondary to septic vasculitis; and the eighth experienced a transient left hemiparesis but succumbed to hemodynamic complications. The four patients who survived had embolic strokes. The one patient who died but was not taking anticoagulants did so as a result of continued infection and a massive embolic cerebral infarction without hemorrhage. Karchmer and colleagues”” question the risks and benefits of anticoagulation during active late prosthetic value endocarditis but point out that other authors have reported a much lower incidence of central nervous system symptoms. The conclusion is that available data do not clarify the role (good, bad, or indifferent) of anticoagulant therapy. Surgical treatment. Surgical treatment of bacterial endocarditis is being employed more frequently and earlier in the disease than in the past. It is advocated for patients with refractory congestive heart failure, sudden valve incompetence,“‘, ?’ repeated embolization, or failure of the infection to respond to antibiotics. Operation should be preceded by as much antibiotic therapy as possible, and followed by two weeks or more of therapy. Cardiac catheterization, and weekly electrocardiograms, chest roentgenograms and echocardiograms have aided in making the decision of when to operate and are of importance in

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Prevention and treatment of bacterial endocarditis

following the patient’s progress. If surgical intervention is elected for patients with severe congestive heart failure secondary to valve incompetance, it should be done early. Especially in prosthetic valve endocarditis, in which mortality rates approach 60 per cent, early surgical intervention has reduced the mortality rate to 41 per cent in one study.” The indications for operation also include infections that are refractory to antibiotics or, in the case of prosthetic valve endocarditis, the presence of significant perivalvular leak in addition to the other criteria.” Parrott and associates’:’ reviewed the surgical management of bacterial endocarditis and pointed out that the mortality rate for infective endocarditis with congestive heart failure is high even with antibiotic therapy (79 to 89 per cent), whereas more aggressive surgical intervention can improve the prognosis. In some instances, patients can be cured by removal of an abscessor focus of infection outside the cardiovascular system.7”. 7-i Modern

principles

of

antibiotic

treatment.

Agents that are bactericidal, as opposed to those that are bacteriostatic, should be used because the rate of relapse is higher with the latter. However, even with in vitro bactericidal action, the bacteria in vivo may simply become quiescent until the drug is stopped and then become active again.‘” Parenteral administration of antibiotic(s) is preferred over oral administration to minimize individual variation in absorption and compliance and to insure a dose that will be sufficiently high to produce a serum bactericidal level after the serum is diluted eight times. However, adequate studies have not been done to prove that 1:8 or greater dilution of serum is an optimal bactericidal level. Antibiotic therapy should be of sufficient duration to avoid relapse and produce cure. Generally, at least four weeks of therapy is necessary but 6 weeks or longer have been recommended for certain bacteria, such as Staphylococcus aureus and enterococci. Antibiotic in vitro susceptibility of the bacteria involved should be determined using a broth dilution minimum inhibitory concentration and minimum bactericidal concentration. The inhibitory concentration may be considerably lower than the bactericidal concentration and it is the latter that is important, especially when using a

American Heart Journal

drug such as vancomycin. Obviously, it would be advantageous to be able to correlate these concentrations with the level of antibiotic in the plasma or serum, but practically, most laboratories cannot do so, with the exception of the radioimmunoassay for gentamicin, tobramycin, and amikacin. In the initial phases of antibiotic therapy for endocarditis, bed rest is important as it is for any serious infection. However, there is always the risk of pulmonary embolism and this again raises the question of the role, if any, of mini-dose heparin. The relationship of bacterial endocarditis and anticoagulation obviously needs further careful evaluation but the spectre of possible dangers remains. The antibiotic(s) should be able to penetrate fibrin to reach the bacteria deep within the vegetation. The success of the penicillins is perhaps due in part to their ability to penetrate fibrin better than most other antibiotics. Initial antibiotic therapy before positive identification of the bacterium should be directed against those bacteria most likely to be causing the infection in the particular patient under consideration. Alpha hemolytic streptococcal endocarditis remains the most frequent type. Because it is rarely fulminant, initial antibiotic therapy in the past was thought to be safely delayed until blood cultures were reported in 24 to 48 hours. However, we prefer to begin treatment as soon as five blood cultures are obtained in the patient with a strong suspicion of bacterial endocarditis. If the patient has a prosthetic valve or is a drug addict, therapy should definitely be started after no less than three blood samples are obtained and cultured for strict aerobes (Pseudomonas aeruginosa, micrococci) and anaerobes (most bacteria). Staphylococcus aureus, gramnegative bacilli, or yeast is more likely in these situations. Obviously of importance in therapy is the consideration of whether or not the patient is hypersensitive to the proposed antibiotic. This question most frequently arises if the patient is allergic to penicillin, thinks he is allergic to penicillin, or gives a history of rash following penicillin therapy, especially with oral ampicillin. Most of these patients do not have the type of hypersensitivity associated with immediate (Type 1) IgE-mediated reactions. However, they must be assumed to have such types until proven

109

Pankey

Table

I I. Antibiotic

treatment Clinically bacterial endocarditis

apparent 7

3-5 blood cultures via separate venipuncture

+ Acute presentation, + acute AI, narcotic addict, patient with renal failure on chronic dialysis, patients with prosthetic heart valves, gram-positive cocci in huffy coat

Add anti-Staphylococcus therapy ,

Begin therapy for enterococcal endocarditis .

NO

aureus ~

Result of blood culture pi .ai;gzyance of valve

Blood Kcult culture negative at 1 week

ure

positive

I Rx according to organism isolated

Obtain seroloe (1) Histoplasma & Aspergillus immunodiffusion (2) Teichoic acid antibody titers (3) Q fever CF (4) Brucella agglutinins (5) Arterial blood culture for fungi I Non-diagnostic: complete therapy for enterococcal AI = aortic

and staphylococcal

endocarditis

to for

microorganism

implicated

insufficiency.

otherwise because a hypotensive episode is obviously an increased risk for a patient already ill with bacterial endocarditis. A penicillin desensitization procedure is available if no alternative antibiotics are thought to be adequate. Several protocols are available. 76 Generally they start with low doses of penicillin G and gradually increase until massive doses can be given. Penicillin hypersensitivity reactions that develop during therapy are not of the anaphylactic type and usually can be suppressed with other medications, such as adrenal corticosteroids. The penicillin therapy should not be interrupted, because the risk of endocarditis is greater than the risk of any permanent damage from the penicillin reaction. Algorithms of treatment. In 1976 the Infectious Diseases Society of America appointed a commit-

110

1 Diagnostic: Change therapy appropriate

tee, chaired by Pierce Gardner, M.D., to investigate the feasibility of developing guidelines for antimicrobial therapy. Seven infectious disorders, including infectious endocarditis, were chosen as subjects for the initial effort. C. Glenn Cobbs, M.D., Director of Infectious Diseases at the University of Alabama in Birmingham, drafted the guidelines for infectious endocarditis and requested several of us to review the document.77 As a part of the guidelines (which were never published), algorithms for treatment were designed and are included here with some modifications (Tables II to VI). Most of the group believed that patients with bacterial endocarditis should be treated initially in the hospital and confined to bed during the early phase of their illness and

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98, No.

1

Prevention

II I. Antibiotic

Table

and treatment

of bacterial

endocarditis

treatment Suspected bacterial endocarditis

.

$5 blood cultures via separate venipuncture

Open heart surgery imminent and/or patient critically ill

YES

I NO

Begin

therapy

1 Antibiotic medication necessary for some other disorder

for

Staphylococcus aureus and enterococcal endocarditis

1

ZLtZs!b&Zar ante of valve at surgery

YES

-

Begin therapy for enterococcal endocarditis

.

I 1 No evidence endocarditis examination

1 Blood cultures sterile at 1 wk

of at of valve

I

I Observe without treatment

4 patient antibiotic

that resumption of activity should be gradual. The major complications included congestive heart failure, arrhythmias, renal failure, anemia, embolic phenomenon, and mycotic aneurysms. Congestive heart failure was thought to be the most serious complication (Table IV), especially if it was of sudden onset (either caused by obstruction of the valve in patients with natural valves or by paravalvular leak in patients with prosthetic valves). Earlier valve replacement was thought to be indicated by the group if a paravalvular leak was associated with endocarditis in a patient with a prosthetic valve. The algorithm designed for patients with infectious endocarditis who present with systemic embolization (Table V) depends for its validity upon the accuracy of the echocardiogram and its interpretation. Again,

American

Heart

Journal

I Blood cultures positive

I Continue appropriate treatment

or initiate antibiotic

if a prosthetic valve is involved, surgical intervention is considered earlier. As expected, those of us who reviewed the document were sometimes in disagreement. This is in no way an adverse reflection on the individuals but simply points out the lack of definitive knowledge in this area. One disagreement was whether trough (just before a dose of antibiotics) or peak (1 to 2 hours after a dose is completed) serum bactericidal levels should be used for in vitro determination of the adequacy of therapy. (Obviously, if a continuous infusion pump is used to administer an antibiotic, there should be no peak or trough.) Secondly, it was questioned whether there is a need to determine serum bactericidal levels at all when treating a patient with a bacterium that has a minimum inhibitory

111

Pankey

Table

IV. Surgical treatment

of valvular

bacterial endocarditis

Congestive heart presumed

failure (CHF) on admission due to valve damage

t I CHF severe (pulmonary edema, hypotension)

CHF

f present-not

Treat

Valve

I replacement

-

bactericidal level of less than 0.1 pg/ml., such as usually is the case with alpha hemolytic streptococcal disease. Thirdly, there was quite a bit of disagreement as to the appropriate agents for Straphylococcus aureus endocarditis. Some believed that penicillin G should never be used because only a small percentage of strains are susceptible and testing might be difficult for small laboratories. There was disagreement as to whether methicillin, nafcillin, or oxacillin was the best semisynthetic penicillin to use. Although most felt that a daily blood culture should be obtained following the initiation of antibiotic therapy to determine whether the organism has been eradicated, at least one reviewer felt that this might be unnecessary because the blood cultures would not be expected to be sterile in many instances until at least 2 or 3 days had passed. My experience suggests that blood cultures will be sterile after 3 days of appropriate antibiotic therapy. It was suggested that, at the completion of the antibiotic therapy, blood cultures should be obtained weekly for one month. In my opinion, this is of doubtful value in a patient who is asymptomatic. Certainly the onset of fever makes it necessary to obtain blood cultures because relapse is clearly possible. Recurrence or relapse of bacterial endocarditis necessitates reevaluation and reinstitution of antibiotic therapy, including retesting of antibiotic susceptibility of the bacterium involved, consideration of valve replacement, and possible extra sites of microbial persistence such as a splenic abscess(Table VI).

112

t Persistent progressive

or CHF

severe

I medicallq I CHF

controlled

Treat

1 endocarditis medically

Although there was general agreement by the committee on the algorithms, so much disagreement was evident when specific antibiotic therapy for specific microorganisms was considered that it was finally decided that it was not feasible to publish the antimicrobial therapy for infectious endocarditis. The following recommendations regarding antibiotic treatment of specific types of endocarditis, therefore, represent my own preferences although I have tried to present more than one alternative to therapy. Antibiotic carditis.

treatment

of specific

types

of endo-

Alpha hemolytic streptococcal endocarditis. Combined penicillin and streptomycin for the first two weeks of therapy followed by two weeks of penicillin G alone seems to be the most used and effective therapy with the least chance of relapse. Some authors’*. 71recommend 4.8 million units of penicillin G per day given intravenous piggyback (1.2 million units every 6 hours) for 4 weeks, with 1 gram of streptomycin (0.5 grams every 12 hours intramuscularly) daily for two weeks. I prefer to use penicillin G by continuous infusion with a pump for four weeks, adjusting the amount of penicillin depending on the serum bactericidal level (5 to 15 million units daily, the usual dose). Unless there is overt nephrotoxicity and/or eighth cranial nerve problems, I also use streptomycin for the first 2 weeks. Continuous intravenous infusion without the use of an infusion pump results in totally erratic serum levels.” Because the purpose of the penicillin is to eliminate bacterial growth, my belief is

July,

1979,

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1

Prevention and treatment of bacterial endocarditis V. Surgical treatment of valvular bacterial endocarditis Table

Table

VI. Antibiotic Infecting

Systemic Obtain

Large

I echocardiogram I

I More emboli

r No effective

I No vegetation identified I

f No additional emboli

t Advise surgical intervention

Continue therapy

I

+ Marginally effective regimen

regimen

I Advise surgical intervention

identified

medical alone

Effective

Advise s&gical intervention

I regimen

I

1 RX + Relapse

that a continuous high level of penicillin G surrounding the vegetation will make it more effective than temporarily very high levels followed by a trough that reaches zero. The intravenous site must be watched closely to avoid phlebitis. A pediatric scalp vein needle is recommended and the infusion system should be changed every 72 hours. Patients allergic to penicillin may be treated with vancomycin alone (0.5 gm. q 4 to 6 hr. IBPB) for 3 weeks, or, if the reaction to penicillin was not an anaphylactic one, with a cephalosporin administered with caution initially. Microaerophilic streptococci, peptostreptococci (anaerobic streptococci), and other non-D-groupable streptococci are all treated in a fashion similar to alpha-hemolytic streptococci. Group D streptococcal endocarditis. Bacterial endocarditis due to nonenterococcus Group D streptococci, such as Streptococcus bovis or equinus, is treated in a fashion similar to alphahemolytic streptococci with the exception that many would not use streptomycin for the first two weeks. However, recently, endocarditis caused by Streptococcus bovis resistant to the lethal effect of penicillin alone has been reported.?” Enterococcal endocarditis (group D streptococci of the enterococcus type [Streptococcus faecalis or faecium]) produces an especially refractory type of endocarditis. Generally 20 to 40 million units of penicillin G per day, given by infusion pump as a continuous intravenous drip for 6 weeks is indicated. The dose of penicillin G may

American Heart Journal

microorganism

1 Results of clinical experience and in Stro studies 1

embolus

f vegetation

versus surgical treatment

7 Cured

‘;” Relapse

Cured

Look for sites of metastatic localization

have to be adjusted depending on serum bactericidal levels. Because of well-established sy.nergism between streptomycin and penicillin G in activity against this organism, I had recommended 1 gram of streptomycin intramuscularly or intravenously every 12 hours for the first 2 weeks therapy followed by 0.5 gm. intramuscularly or intravenously every 12 hours for the next 4 weeks, but now prefer gentamicin 3 to 5 mg./Kg. body weight/day, depending on serum bactericidal levels, for six weeks. Gentamicin has been used successfully as a substitute for streptomycin and some studies suggest an increased synergism with penicillin.“” Rahal”’ has published an excellent review on antibiotic combinations. Patients who are allergic to penicillin G may be given vancomycin (0.5 gm. q 4 to 6 hr. intravenous piggyback for 4 to 6 weeks) although the development of phlebitis usually limits how long this antibiotic can be given. Ototoxicity is a problem, but nephrotoxicity is not. However, it is advisable to get serum creatinine levels two to three times weekly when vancomycin is being administered for endocarditis because it is excreted by the kidneys. Although minimum inhibitory concentrations of vancomycin may be achievable, minimum bactericidal concentrations may be much higher. Vancomycin and gentamicin appear to be ‘synergistic for enterococci but both antibiotics are ototoxic. Desensitization to penicillin may have to be performed, and in some cases, a vegetation may have to be surgically removed

113

Pankey

even though the valve is not replaced. Several good reviews on vancomycin have been published recently.‘+” Vancomycin has also occasionally been useful in the therapy of other types of endocarditis. One patient was reported to be cured with vancomycin after clindamycin had failed to eradicate a group B streptococcal endocarditis.“” Cephalosporins with or without aminoglycosides are not effective in the treatment of enterococcal endocarditis,;” ;I. ‘II Staphylococcus aureus endocarditis. Endocarditis due to Staphylococcus aureus requires the use of penicillinase-resistant penicillins, such as methicillin, nafcillin, or oxacillin, with the dose being at least 2 gm. intravenously by the rapid infusion method every 4 hours for six weeks.7D. ‘I I prefer oxacillin because of the well-recognized interstitial nephritis and cystitis associated with methicillin as well as an increasing number of reports of hepatotoxicity and bone marrow suppression (reversible) with nafcillin. Even if the particular strain appears to be a nonpenicillinase producing one, I use oxacillin because at least 80 per cent of the strains isolated in our hospital are resistant to penicillin G and a laboratory error with this particular organism would be disastrous. Failure of response suggests either an oxacillin resistant or tolerant Staphylococcus aureus and vancomycin may be necessary. Staphylococcus aureus may be tolerant to various antibiotics, resulting in failure of response to a single agent.x7 A combination of vancomycin with rifampin has been used successfully in such a patient who failed to respond to therapy that should have worked based on in vitro studies.** In the penicillin allergic patient, a cephalosporin could be administered with the cautions previously mentioned. I prefer to use cefazolin but opinions vary as to its use in the treatment of staphylococcal endocarditis,7”, ‘l because in vitro it is slightly more rapidly inactivated by Staphylococcus aureus beta lactamase than is cephalothin. In man this inactivation is probably not important because of the dosage used (1 to 2 gm. by rapid intravenous infusion every 4 to 6 hours). I have had uniformly successful results with the use of cefazolin and prefer it to the less reliably administered cephalothin which also is fairly rapidly metabolized in the liver. Others have used cephalothin in a dose of 12 to 18 grams/day successfully” and continue to recommend it as the cephalosporin of choice. If a patient has had

114

an immediate type of hypersensitivity reaction to the penicillins, then vancomycin in a dosage of 0.5 gm. by rapid intravenous infusion every 4 to 6 hours would be the drug of choice. I agree with Watanakunakorn”’ that clindamycin, a bacteriostatic antibiotic, is undesirable for the treatment of staphylococcal endocarditis. Staphylococcal epidermidis endocarditis. Staphylococcal epidermidis is the causative bacterium in some patients with prosthetic valve infections as well as in some patients who have congenital or valvular heart disease. Such infections are frequently difficult to treat and often the valve must be removed in order to obtain a cure. Many strains of Staphylococcus epidermidis that are resistant to the penicillins and cephalosporins may respond to vancomycin. Recent information suggests that the combination of rifampin with either gentamicin, nafcillin, or vancomycin may be useful in treating this type of endocarditis as synergism apparently occurs.“” Pneumococcal or Gonococcal Endocarditis. Endocarditis caused by Diplococcus pneumoniae or Neisseria gonorrhoeae can be treated with penicillin G (10 to 20 million units per day by the continuous infusion route using an infusion pump for four weeks),7”, ;I Pneumococcal endocarditis usually results in aortic insufficiency due to aortic root and aortic valve ring involvement”‘. !$I.H?and surgical treatment is frequently indicated. Pneumonococcal meningitis and pneumonia often accompany the endocarditis. Although gonorrhea has been rampant, the classical gonococcal endocarditis patient with two spikes of temperature daily is rarely seen and I have not recognized a case in 15 years at Ochsner Clinic. Gram-negative bacillary endocarditis. Gramnegative bacillary endocarditis is rare, but is often associated with serious complications. Monitoring the effectiveness of antimicrobial agents with serum bactericidal tests is controversial,‘“. !I’~.‘iA but if done, it is recommended that the bactericidal level be kept at a 1:8 dilution or higher. My current recommendations for treating various gram-negative bacillary endocarditis are given in Table VII.“” Frequently this type of infection requires surgical removal of the valve. An exciting discovery that may be of use in this particular type of endocarditis is the isolation of clavulanic acid, a potent beta lactamase-inhibiting compound derived from Streptomyces clavuligerus which is now available as sodium

Prevention and treatment of bacterial endocarditis

clavulanate through the Beechum Laboratories.“” Recently, in vitro studies have demonstrated that ticarcillin-resistant E. coli, Klebsiella pneumoniae, Enterobacter, and Proteus mirabilis species were made susceptible with the addition of clavulanic acid.“’ If this material proves to be as synergistic in uiuo, it may be of usefulness not only in the treatment of gram-negative bacillary endocarditis but also in the treatment of staphylococcal endocarditis associated with beta lactamase production. Responses to therapy. In the absence of complications, a drop in temperature should occur within a few days to a week, accompanied by conversion of blood cultures from positive to negative. The patient should feel better and appetite should increase. The erythrocyte sedimentation rate will fall, and if the rheumatoid factor was positive initially, it also should fall. An insufficient course of antibiotic(s) will also bring about these changes, but they will be transient. If the patient is truly free from infection, observation after the cessation of treatment will confirm it. If relapse occurs, it is usually within two to four weeks after the end of therapy.‘O Endocarditis in the same patient beyond that time usually represents reinfection. Other

agents

as adjuncts

to antibiotic

therapy.

Special problems arise in patients taking other drugs, such as anticoagulant or fibrinolytic agents, when endocarditis develops. Since most authorities advise against the use of anticoagulants or fibrinolytic agents during endocarditis !iR-l’i’ physicians usually stop the adjunctive therapy, until the endocarditis can be brought under control. However, no well-controlled studies have been conducted on the efficacy of antibiotic and anticoagulant therapy and the advice against it appears to be based on the reports mentioned earlier on the use of sulfonamides and anticoagulants.6’3, (i(iThe antimicrobial agent (sulfapyridine) worked poorly. In addition, the anticoagulants were of questionable quality and the methods for monitoring their use were not yet fully developed. It was common practice to use sufficient anticoagulation to extend the clotting time from ‘/z to 1 hour, and keep it at this level for up to two weeks or more.““, M. lCli When penicillin G became available, initial studies of low dose penicillin G and heparin or dicumarol did not demonstrate much difference from earlier studies using sulfonamides and anti-

American

Heart

Journal

VII. Antibiotic treatment of adults with endocarditis caused by gram-negative bacilli* Table

Bacteria Pseudomonas aeruginosa

Drug/dosage* Ticarcillin

18 g/day

Tobramycin Ampicillin

3-5 mg./Kg. 12 g/day

ph

Enterobacteriaceae

BW/day

Or

Ticarcillin Cefazolin

18 g/day or 4-8 g/day ph

Gentamicin or another Ampicillin

Salmonella

Bacteroides

fragilis

3-5 mg./Kg. aminoglycoside 12 g/day ph Gentamicin 3-5 mg./Kg. Ticarcillin 18 g/day plus Metronidazole 4 g/dayt$

BW/day

BW/day

*All antibiotics are administered intravenously. tAvailable for experimental use only from Searle Laboratories. An intravenous form is available. &See Galgiani, J. N., Busch, D. F., Brass, C., et al.: Bacteroides fragilis endocarditis, bacteremia and other infections treated with oral or intravenous metronidazole, Am. J. Med. 65:284, 1978.

coagulants. But as larger doses of penicillin with anticoagulants were used, greater success rates were seen.7” However, the older reports of the dangers involved with anticoagulant therapy remained, and because penicillin G alone produced good success rates, it became the rule not to use anticoagulants at all.“‘6 Today, however, the concurrent use of anticoagulants is sometimes unavoidable in patients with prosthetic heart valves,107in those with deep leg vein thrombosis, or in those undergoing fibrinolytic therapy for pulmonary emboli. At this institution we are currently reviewing the experience in treating those patients who were receiving anticoagulant therapy at the time of diagnosis of treatment of endocarditis. Some evidence suggests an efficacious role for anticoagulant and antibiotic treatment of bacterial endocarditis. In an experimental model using rabbits, Thorig and associates,‘ox and Hooke and Sandelo9 demonstrated a reduction in size of the valvular lesions when anticoagulant therapy was used. In addition, Hooke and Sande’“” showed that rabbits that were pretreated with anticoagulants had their endocarditis lesions cleared with antibiotics faster than rabbits having the antibiotic treatment alone. Even if it could not be

115

Pankey

proven that anticoagulant therapy is helpful in the treatment of bacterial endocarditis, it would be extremely useful to know if it does indeed play any detrimental role. The role of fibrinolytic therapy as an adjunctive measure to antibiotic treatment of endocarditis also needs to be explored. Work in rabbit and dog models has shown the possibility of reducing the size of the endocardial lesion with fibrinolytic drugs.“O Therefore, the addition of aggressive antibiotic therapy to a carefully prepared fibrinolytic regimen may significantly shorten the treatment time of endocarditis, as well as lessen the untoward secondary manifestations of the disease. Measures to decrease platelet numbers or function have not been effective in altering the course of the infection in experimentally produced endocarditis. The use of aspirin to alter platelet function did not change the size of the endocardial lesion or the course of the infection.“’ The administration of antiplatelet sera to induce thrombocytopenia has likewise failed to alter the localization of the organisms onto the valve lesion in the experimental rabbit model of endocarditis.lOg Conclusion

A paper that purports to summarize the prevailing opinions regarding a controversial subject, such as the prophylaxis and therapy of bacterial endocarditis, will obviously raise the eyebrows of readers who differ with the author. I have no apologies for my choice of references or for my approach to the treatment of patients. I welcome all comments that may help me improve the care of patients who are unfortunate enough to contract bacterial endocarditis.

6.

7.

8. 9.

10. 11.

12.

13.

14.

15.

16.

17.

18.

HEART J. 64:583, 1962. 19.

21.

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M. H., and Casey, J. I.: Infective endocarditis: diagnostic techniques, AM. HEART J. 96:123,

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The assistance of David R. Burgin, Janet Putney, Juanita Gehler, Vivian Harmeyer, and Theresa Setze in the preparation of this manuscript is greatly appreciated.

G. A.: Effect of viruses on the cardiovascular system, Am. J. Med. Sci. 250:103, 1965. Andy, J. J., O’Connell, J. P., Daddario, R. C., and Roberts, W. C.: Trichinosis causing extensive ventricular mural endocarditis with superimposed thrombosis. Evidence that severe eosinophilia damages endocardium, Am. J. Med. 63~824, 1977. Durack, D. T., and Beeson, P. B.: Experimental bacterial endocarditis. II. Survival of bacteria in endocardial vegetations, Br. J. Exp. Pathol. 53:50, 1972. Repine, J. E., Clawson, C. C., Burchell, H. B., and White, J. G.: Reversible neutrophil defect in patients with bacterial endocarditis, J. Lab. Clin. Med. 88:780, 1976. Wallach, J. B., and Borgatta, E. F.: Rheumatic Heart

Disease, Springfield, Ill., 1962, Charles C Thoma;, Publisher. Wallach, J. B., Lukash, L., and Angrist, A. A.: Mechanism of death in rheumatic heart disease in different aee periods, Am. J. Clin. Pathol. 26:360, 1956. Jones, T. D., and Bland, E. F.: Rheumatic fever and heart disease; Completed lo-year observations on 1000 patients, Trans. Assoc. AM. Physicians 57265, 1942. Clawson, B. J.: Rheumatic heart disease: An analysis of 796 cases, AM. HEART J. 20:454,1940. Gross, L., and Friedberg, C. K.: Lesions of cardiac valve rings in rheumatic fever, Am. J. Pathol. 12:469, 855, 1936. Angrist, A. A., and Oka, M.: Pathogenesis of bacterial endocarditis, J.A.M.A. 183:249, 1963. Angrist, A. A., and Oka, M.: Experimental endocarditis, in Bajusz, E., and Jasmin, C. eds.: Methods and Achievements in Experimental Pathology, vol. 2, Base1 and New York, 1966, S. Karger. Angrist, A., Oka, M., and Nakao, K.: Vegetative endocarditis. in, Sommers, S., ed.: Pathology Annual, New York, 1967, Appleton-Century-Crofts, Inc., pp. 155-212. Grant, R. T., Wood, J. E., Jr., and Jones, T. D.: Heart valve irregularities in relation to subacute bacterial endocarditis, Heart 14247, 1928. Durack, D. T., and Beeson, P. B.: Experimental bacterial endocarditis. I. Colonization of a sterile vegetation, Br. J. Exp. Pathol. 53:44, 1972. Gould. K.. Ramirez-Ronda. C. H.. Holmes. R. K.. et al.: Adherence of bacteria to heart valves in b&o, J. Clin, Invest. 56:1364, 1975. Pankey, G. A., and Horton, J. M.: Cardiobacterium hominis endocarditis, J. Miss. State Med. Assoc. 19:107, 1978. Pankey, G. A.: Subacute bacterial endocarditis at the University of Minnesota Hospital, 1939 through 1959, Ann. Intern. Med. 55:550, 1961. Pankey, G. A.: Acute bacterial endocarditis at the University of Minnesota Hospitals 1939-1959, AM.

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Weinstein, L., and Rubin, R. H.: Infective endocarditis-1973, Progr Cardiovasc. Dis. 16:239, 1973. Lerner, P. I., and Weinstein, L.: Infective endocarditis in the antibiotic era, N. Engl. J. Med. 274:199, 259, 323, 388, 1966.

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Prevention

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Messner, R. P., Laxdal, T., Quie, P. G., et al.: Rheumatoid factors in subacute bacteria1 endocarditis-Bacteriurn, duration of disease or genetic predisposition? Ann. Intern. Med. 68:746, 1968. Messner, R. P., Laxal, T., Quie, P. G., et al.: Serum opsonin, bacteria, and polymorphonuclear leukocyte interactions in subacute bacterial endocarditis. Antiy-globulin factors and their interaction with specific opsonins, J. Clin. Invest. 47:1109, 1968. Klein, R. S., Recco, R. A., Catalano, M. T., et al.: Association of Streptococcus bouis with carcinoma of the colon, N. Engl. J. Med. 297:800, 1977. Brooks, R. J., Ravreby, W. D., Keusch, G., et al.: More on Streptococcus bovis endocarditis and bowel carcinona (Letter to the Editor), N. Engl. J. Med. 298:572, 1978. Levy, B. S., von Reyn, C. F., Arbeit, R. D., et al.: More on Streptococcus bovis endocarditis and bowel carcinoma (Letter to the Editor), N. Engl. J. Med. 298:572, 1978. Quenzer, R. W., Edwards, L. D., and Levin, S.: A comparative study of 48 host valve and 24 prosthetic valve endocarditis cases, AM. HEART J. 9235, 1976. De Silva, M., Rubin, S. J., Lyons, R. W., et al.: Haemophilus paraphrophilus Endocarditis in a prolapsed mitral valve, Am: J. Clin. Pathol. 66:922, 1976. Kave. D.: Pronhvlaxis of endocarditis. in Kave. D. ed.: Infective Endocarditis, Baltimore, i976, University Park Press, pp. 245265. Durack, D. T., and Petersdorf, R. G.: Chemotherapy of experimental streptococcal endocarditis. I. Comparison of commonly recommended prophylactic regimens. J. Clin. Invest. 52:592, 1973. Durack, D. T., Petersdrof, R. G., and Beeson, P. B.: Penicillin prophylaxis of experimental Streptococcus viridans endocarditis, Trans. Assoc. Am. Physicians 85:222, 1972. Arnett, E. N., and Roberts, W. C.: Prosthetic valve endocarditis. Clinicopathologic analysis of 22 necropsy patients with comparison of observations in 74 necropsy patients with active infective endocarditis involving natural left-sided cardiac valves, Am. J. Cardiol. 38:281, 1976. McCabe, W. R., and Jackson, G. G.: Gram negative bacteremia, Adv. Intern. Med. 19:135, 1974. Sande, M. A., Johnson, W. D., Hooke, E. W., and Kaye, D.: Sustained bacteremia in patients with prosthetic cardiac valves, N. Engl. J. Med. 286:1067, 1972. Bogart, D. B., Hodges, G. R., Lewis, H. D., Jr., et al.: Prosthetic valve endocarditis-reviewing the problem, Postgrad. Med. 62:119, 1977. Watanakunakorn, C.: Infective endocarditis as a result of medical progress, Am. J. Med. 64:917, 1978. Kaye, D.: Definitions and demographic characteristics, in Kaye, D., ed.: Infective Endocarditis, Baltimore, 1976, University Park Press, pp. l-10. Hellmuth, G. A.: Preventing rheumatic fever and rheumatic heart disease, Am. Family Physician 7:129, 1973. Roberts, W. C.: Characteristics and consequences of infective endocarditis (active or healed or both) learned from morphologic studies, in Rahimtoola, S. H., ed.: Infective Endocarditis, New York, 1978, Grune & Stratton, Inc., pp. 55-123. Hurst, J. W., Logue, R. B., Schlant, R. C., et al. eds.: The Heart, Arteries, and Veins, New York, 1978, McGraw-Hill Book Company, Inc. Levinson, M. E.: Pathogenesis of infective endocarditis, in Kaye, D.: Infective Endocarditis, Baltimore, 1976, University Park Press, pp. 29-41.

American

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48.

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and trecrtment

of bacterial

en&ward&i

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