Prosthetic Valve Endocarditis WALTER R. WILSON, M.D., PIERRE M. JAUMIN, M.D., GORDON K. DANIELSON, M.D., EMILIO R. GIULIANI, M.D., F.A.C.P., JOHN A. WASHINGTON II, M.D., F.A.C.P., and JOSEPH E. GERACI, M.D., Rochester, Minnesota
From January 1963 until January 1974, 45 patients had prosthetic valve endocarditis. Symptoms of prosthetic valve endocarditis developed within 2 months after operation (early onset) in 16 patients (36%) and more than 2 months after operation (late onset) in 29 patients (64%). Overall mortality among the 45 patients was 56% (88% among those with early onset and 40% among those with late onset). Medical therapy alone was curative in 60% of the surviving patients. Combined medical and surgical therapy was curative in 40% of the survivors. The most frequent isolates in the early-onset group were Staphylococcus aureus (44%) and Gram-negative bacilli (38%); associated mortality was 86% and 83%, respectively. The most frequent isolates in the late-onset group were viridans streptococci (41%) and Gram-negative bacilli (31%); the mortality was 25% and 22%, respectively. Suggestions are offered for operative antimicrobial prophylaxis and for medical and surgical treatment of prosthetic valve endocarditis. Prompt surgical replacement of an infected prosthesis is necessary when medical therapy fails.
PROSTHETIC VALVE ENDOCARDITIS is an infrequent but
se-
rious complication of cardiac valve replacement (1-12). We present our experience with 45 such patients during an 11-year period. Also, we outline our approach to the recognition of this complication, to the operative antimicrobial prophylaxis for patients receiving prosthetic valves, and to the medical and surgical management of established prosthetic valve endocarditis. Materials and Methods We reviewed clinical records of patients with prosthetic valve endocarditis. The complication was judged to be present if there were at least two of the following: [1] at least two positive blood cultures with the same organism, [2] histopathologic evidence of bacterial endocarditis in surgical or autopsy specimens, and [3] at least two of the following clinical signs— fever, development of a new regurgitant murmur, newly developed splenomegaly, or peripheral emboli. One patient included in our series did not meet these criteria. Five days after an aortic Starr-Edwards valve implantation, Serratia marcescens bacteremia occurred. Early prosthetic valve endocarditis was suspected but not proved. After bactericidal kanamycin therapy for 2 weeks, the patient improved and was dismissed from the hospital. Approximately 2 months • From the Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
later, he had fever and rapidly progressive congestive heart failure, and he died. Postmortem examination (done elsewhere) showed valve dehiscence and vegetations on the prosthesis. It is possible that additional patients who received prosthetic valves during this period developed prosthetic valve endocarditis but did not return to the Mayo Clinic for evaluation or treatment. In establishing rigid criteria for the diagnosis of prosthetic valve endocarditis, we assume that some patients were excluded from our study; however, we chose to confine our investigation to those patients with documented evidence of the complication. Septic shock was defined as fever associated with a decrease in systolic blood pressure of at least 40 mm Hg in a normotensive patient or of at least 70 mm Hg in a hypertensive patient and sustained for at least 5 consecutive hours. All patients received "prophylactic" parenteral antimicrobial therapy, usually consisting of methicillin, oxacillin, or cephalothin administered preoperatively and for at least 5 days postoperatively. No uniform protocol for prophylactic therapy existed during this period. Patients were divided into two groups according to whether the prosthetic valve endocarditis occurred early (within 2 months postoperatively) or late (after 2 months postoperatively). Antimicrobial susceptibility tests were done by methods described elsewhere (12). Minimal inhibitory concentrations were determined by the agar dilution method. Minimal bactericidal concentrations were determined by the tube dilution method, and the results were expressed as the lowest concentration of antibiotic that killed at least 99.9% of the initial inoculum. Serum bactericidal titers were determined during the third day of treatment, on a sample taken 1 hour after parenteral antimicrobial administration, and the results were expressed as the greatest dilution of serum that killed at least 99.9% of the inoculum. In patients receiving continuous parenteral antimicrobial therapy in addition to divided doses, blood samples for the serum bactericidal titers were obtained 1 hour after the administration of the intermittent dose. An effort was made to ensure that the continuous antibiotic regimen was administered uniformly over a 24-hour period. Results From January 1963 until January 1974, 4706 prosthetic valves were implanted in 4586 patients in Mayo Clinicaffiliated hospitals. Follow-up has ranged from 6 months to 9 years. Prosthetic valve endocarditis developed in 45 (0.98%) patients, early in 16 (0.35%) and late in 29 (0.63%). The aortic valve was involved more frequently than the mitral valve, and this difference was statistically significant (P = 0.025) (Table 1). In patients with early prosthetic valve endocarditis, the mean time from operation to onset of symptoms was 17 days (range, 1 to 45 days). In the late group, the mean
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Table 1. Summary of Prosthetic Valve Implants and Prosthetic Valve Infections
Valve
Type of Prosthesis
Aortic Mitral Tricuspid Pulmonary
Prostheses Homografts Total Prostheses Homografts Total Prostheses Homografts Total Prostheses Homografts Total
Implants
Infections Patients Implants
no. 2386 258 2644 1774 13 1787 226 2 228 2 45 47
% 51 5 56 38 0.3 38 5 0.04 5 0.04 1 1
no. 30 4 34 10 1 11 0 0 0 0 0 0
% 1.3 1.5 1.3 0.56 7.7 0.61 0 0 0 0 0 0
time from operation to onset of symptoms was 26 months (range, 72 days to 10 years). Fever and chills were the most consistent clinical findings in both groups of patients (Table 2). Peripheral embolic phenomena (including Osier's nodes) were more common in the late group, and the development of a new regurgitant murmur occurred more frequently in the early group. Septic shock, by our definition, occurred only in the early group and always was associated with a fatal outcome. Other leading causes of death included the following: cardiac arrest, 11; renal failure, 3; ventricular fibrillation, 3; liver failure, 1; and cerebrovascular accident, 1. There were 25 deaths among our 45 patients with prosthetic valve endocarditis (mortality, 56%) (Table 3). The mortality was higher in the early group. Late aortic prosthetic valve endocarditis was associated with the best survival rate. Postmortem examinations were done in 24 of the 25 fatal cases, and histopathologic evidence of prosthetic valve endocarditis was present in all 24. Valve dehiscence was noted in 9 cases (6 in the early group and 3 in the late group). Streptococci were the most frequent isolates (16 of 45 patients) (Table 4). Streptococci of the viridans group were isolated from 41% of patients in the late group and were associated with the best survival rate; none of the patients in the early group had infections caused by these organisms. Five of the patients with viridans strepTable 2. Clinical Findings in Patients with Prosthetic Valve Endocarditis
Finding
Patients Early Group < —
Fever Chills New regurgitant murmur Shock Leukocytosis (> 12 000/mm8) Congestive heart failure Splenomegaly Peripheral emboli*
93 66 60 33 40 27 20 7
Late Group
%
•
96 74 37 0 30 30 19 26
* Includes Osier's nodes. 752
tococcal endocarditis had recently had antecedent trauma (2 patients), a surgical operation (2 patients), or dental work (1 patient). One of these 5 patients had undergone a cholecystectomy (elsewhere), and it is not known whether this patient received antibiotics before admission to the Mayo Clinic-affiliated hospital; the remaining 4 patients had received no prophylactic antibiotics. Two of the 4 patients with group D streptococcal endocarditis (both in the late group) had had urinary tract infections with group D streptococci; 3 of these 4 patients died. Staphylococci (10 patients with Staphylococcus aureus and 2 patients with S. epidermidis) accounted for 26% of the endocarditis cases (50% of the early group and 13% of the late group) and for 40% of the total number of deaths. Staphylococcal infections were associated with a poor outcome in both the early and late groups. Two of the 7 patients with early onset of S. aureus endocarditis had wound infections caused by S. aureus. Operative antistaphylococcal antimicrobial prophylactic therapy had been discontinued before the onset of symptoms of endocarditis in 6 of these 7 patients. The average time from operation to onset of symptoms in the 7 patients was 23 days, and the mean duration of postoperative prophylactic therapy was 8 days. Gram-negative bacilli were isolated from 33% of our patients and accounted for 28% of the total number of deaths. In the early group, these isolates included Enterobacter aerogenes in one patient, Serratia marcescens in two, Pseudomonas aeruginosa in one, and Escherichia coli in one. Haemophilus aphrophilus was isolated from the only survivor among the patients with early endocarditis caused by Gram-negative bacilli. Isolates in the late group were E. aerogenes in one patient, Alcaligenes faecalis in two, H. aphrophilus in two, Acinetobacter calcoaceticus in one, Klebsiella pneumoniae in one, P. aeruginosa in one, and Bacteroides fragilis in one. Late-onset infections by Gramnegative bacilli were associated with a relatively favorable outcome (78% survival); however, 83% of patients with early-onset infections by Gram-negative bacilli died. Wound infections by the same Gram-negative bacillus responsible for the endocarditis were present in three of the six patients in the early group. The portal of entry in the nine patients in the late group was unknown. None of these patients in the early group had received postoperative prophylactic antimicrobials effective against the Gram-negative bacillus causing the endocarditis. One patient had fatal late endocarditis of a prosthetic mitral valve caused by Candida parapsilosis; death from cardiac arrest occurred after treatment with 735 mg of amphotericin B. The patient did not have large systemic peripheral emboli. During the 11-year period of this study there was no standard protocol for the treatment of patients with prosthetic valve endocarditis. Selection of antimicrobial therapy was based on identification of the organism, in-vitro susceptibility tests, and, usually, the serum bactericidal titers against the blood culture isolate. Blood cultures showed negative results in only 1 of the 45 patients in our study. Sixteen different antimicrobial agents were used. The mean duration of therapy among surviving patients
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was 30 days (range, 21 to 63 days). Medical therapy alone was curative in 55% of the surviving patients (11 of 20). Combined medical and surgical therapy was curative in 45% (9 of 20). An effort was made to measure serum bactericidal titers on all patients with prosthetic valve endocarditis; however, because of early patient death (11 patients) or technical inability to test overly fastidious microorganisms (10 patients), these data were available for only 23 patients. Ten of the 11 patients in the late group with a serum bactericidal titer of 1:8 or greater survived; 2 of the 3 patients in the late group with a serum bactericidal titer less than 1:8 also survived. None of these 12 surviving patients had evidence of valve dehiscence. The outcome in the patients with early-onset endocarditis was poor irrespective of the serum bactericidal titers. Infected prosthetic valves were replaced in 8 of the 29 patients in the late group, and 6 of these 8 patients survived. The chief indications for reoperation were uncontrolled infection in 3 patients, progressive congestive heart failure with valve dehiscence in 3, and septic emboli in 2. One patient with early S. epidermidis endocarditis underwent replacement of an infected aortic prosthesis and died of a cardiac arrest postoperatively. There were three recurrences of prosthetic valve endocarditis, two in patients in the early group. One patient with early-onset aortic valve endocarditis due to S. aureus had had 5 weeks of parenteral therapy with methicillin (3 weeks) and oxacillin (2 weeks); the recurrence developed 2 weeks after the oxacillin was withdrawn. Treatment with methicillin, 2 g intravenously every 3 hours for 28 days, resulted in cure that now has continued for 9 years. In one other patient with early-onset aortic valve endocarditis, the recurrence was 1 week after discontinuance of a 9-week course of vancomycin therapy for infection with S. epidermidis; this patient died from cardiac arrest 3 days after onset of symptoms. One patient with late-onset mitral valve endocarditis with K. pneumoniae had multiple recurrences. After multiple attempts at medical cure, the infected mitral valve prosthesis was replaced. The patient was treated with cephalothin and gentamicin for 4 weeks postoperatively. At 2Vi years of follow-up there is no evidence of reinfection. Oral suppressive antimicrobial agents were not recommended after completion of therapy for the prosthetic valve endocarditis. The patients were advised regarding
Table 3. Mortality by Time of Onset of Infection and Site of Prosthetic Valve
Site
Group Aortic
Mitral
Total
%
11/13 85
3/3 100
14/16 88
%
7/21 33
4/8 50
11/29 38
%
18/34 53
7/11 64
25/45 56
Early no.* Late no. Total no.
* Shown as deaths/patients at risk.
prophylactic antimicrobial treatment if they were to undergo dental work or other invasive procedures. Discussion
The overall mortality of 56% in our series approximates the rates previously reported (10, 11). The difficulty in treating infections of foreign implants is well recognized (2, 13, 14); however, our data and other reports indicate that early, aggressive, bactericidal medical therapy alone, or combined with early surgical intervention, can successfully cure a substantial number of patients with prosthetic valve endocarditis (10, 11, 15-18). Our data and those previously reported (10, 11, 19) suggest that the incidence of early-onset prosthetic valve endocarditis is low. The efficacy of operative prophylactic antimicrobial therapy has been emphasized (20-23), and prophylactic administration of antibiotics is common for patients undergoing valve replacement. However, the available data are insufficient to show conclusively how effective such therapy is in decreasing the incidence of this early complication (24, 25). Because the mortality in these patients is high (88% in our series), prevention may be as important as attempts to cure established infections (7, 16). Controlled studies on the value of prophylactic antimicrobial therapy for prosthetic valve surgery have not been carried out, but we believe, from our observations* and those published (10, 11), that operative prophylactic therapy should be directed against S. aureus and the Gramnegative bacilli. Against S. aureus, short-term, aggressive, * GERACI JE, WILKOWSKE CJ, MARCOUX A, et al: Unpublished data.
Table 4. Infecting Organisms: Frequency and Relation to Mortality
Organism
Isolations Early Group
Staphylococcus aureus Gram-negative bacilli Streptococci, viridans group Streptococci, group D Staphylococcus epidermidis Corynebacterium xerosis Candida parapsilosis
no. 1 6 0 1 1 1 0
%
44 37 0 6 6 6 0
Mortality
Late Group no. 3 9 12t 3 1 1 1
%
10 31 41 10 3 3 3
Early Group no.* 6/7 5/6 0 1/1 1/1 1/1 0
Late Group
Total no* 9/10 7/15 3/12f 3/4 1/2 1/2 1/1
% 90 47 25 75 50 50 100
Wilson et at. • Prosthetic Valve Endocarditis
753
% 86 83 0 100 100 100 0
no* 3/3 2/9 3/12f 2/3
o/i o/i
1/1
%
100 22 25 67 0 0 100
* Shown as deaths/patients at risk. t Alcaligenes faecalis also isolated from one patient.
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Table 5. Suggestions for Medical Treatment of Prosthetic Valve Endocarditis*
Organism
Antimicrobial Therapy
Alternatives
Streptococci, viridans group
PenG, 20 000 000 units i.v., plus Strep, 500 mg every 12 h, 4 wk
Ceph, 1 g i.v. every 4 h, or Clin, 600-1200 mg i.v. every 8 h, 4 wk
Enterococci—group D streptococci (nonenterococcal group D streptococci are treated as streptococci of viridans group)
PenG, 40 000 000 units i.v./day, plus Strep, 500 mg i.m. every 12 h, 4 wk; if SBT inadequate, do synergy studies with PenG and with Amp, Kan, and Gen; increase PenG if SBT not satisfactory
Van, 1 g i.v. every 12 h, plus Strep, 500 mg i.m. every 12 h, or Gen, 3 mg/kg body weight per day, 4 wk; if SBT not adequate, do desensitization to PenG
Staphylococcus aureus or S. epidermidis, MIC PenG, < 0.5 jug/ml
PenG, 20 000 000 units i.v./day, 4-6 wk; if PenG MIC = 0.5 /-eg/ml, do penicillinase test; if positive, PenG may not be adequate
Van, 1 g i.v. every 12 h, or Ceph, 2 g i.v. every 4 h, or Clin, 600-1200 mg i.v. every 8 h, 4-6 wk (selection depends on in-vitro studies)
S, epidermidis, MIC PenG, > 0.5 Mg/ml
If susceptible in vitro, Meth, 2 g i.v. every 4 h, 4-6 wk
Ceph, 2 g i.v. every 4 h, or Van, 1 g i.v. every 12 h, or Clin, 600-1200 mg i.v. every 8 h, 4-6 wk
S. aureus, MIC PenG, > 0.5 jug/ml
Meth, 2 g i.v. every 4 h, 4-6 wk
Van, 1 g i.v. every 12 h, or Ceph, 2 g i.v every 4 h, or Clin, 600-1200 mg i.v. every 8 h, 4-6 wk
Gram-negative bacilli t Fungi \ Negative blood cultures
PenG, 40 000 000 units/day i.v., plus Strep, 500 mg i.m. every 12 h; if response absent or equivocal, substitute Gen, 3-5 mg/kg body weight per day for Strep; if response absent or equivocal, substitute Carb, 30 g/day for PenG; if response absent or equivocal, add Clin, 600-1200 mg i.v. every 8 h, treat 4-6 wk
* Dosages depend on renal and hepatic function; those suggested here are for average-weight adult patients. PenG = penicillin G; i.v. = intravenously; Ceph = cephalothin; Strep = streptomycin; Clin = clindamycin; Van = vancomycin; i.m. = intramuscularly; SBT = serum bactericidal titers; Gen = gentamicin; Amp = ampicillin; Kan = kanamycin; MIC = minimal inhibitory concentration; Meth = methicillin; Carb = carbenicillin. t Selection of therapy is governed by in-vitro microbiologic studies; use bactericidal agents. For Pseudomonas, Gen, 3-5 mg/kg body weight per day, plus Carb, 30 g/day, 4 wk. J Early surgical replacement of valve plus amphotericin-B (minimum, 2- to 3-g course); if indicated, do MIC and minimal fungicidal concentration studies with 5-flucytosine and synergy studies with 5-flucytosine plus amphotericin-B.
operative prophylaxis with methicillin (12 g/day) would be appropriate, beginning the night before operation and continuing through the third postoperative day or until all intracardiac monitoring lines have been removed. On a theoretical basis, the best prophylaxis against the Gramnegative bacilli is gentamicin (3 mg/kg body weight per day in patients with normal renal function). Because of occasional toxic effects of respiratory paralysis, particularly when combined with various anesthetic agents, it is suggested that gentamicin therapy be begun immediately postoperatively and then continued, as with methicillin. Gentamicin administered in this way would not be present in the systemic circulation at the time of operation, when prophylactic antibiotics may be most effective (26-28). This combination would be effective against the majority of microorganisms causing early-onset prosthetic valve endocarditis, and the short duration of treatment would be unlikely to induce resistant bacterial flora and superinfection. Alternatively, cephalothin (6 g/day, schedule for methicillin) has been used for operative prophylaxis at the Mayo Clinic and elsewhere (11). Although it is effective in vitro against S. aureus and S. epidermidis, many Gramnegative bacilli are resistant to it in vitro, and cephalothin may predispose patients undergoing cardiac valve replace754
ment to superinfections other than endocarditis (29, 30). The rationale for prophylactic use of antimicrobials and the choice of these agents are controversial. Indeed, the most important modality in the prevention of prosthetic valve endocarditis may be meticulous care to prevent bacterial contamination during operation. Because the incidence of prosthetic valve endocarditis is low, the potential iatrogenic complications due to the suggested prophylactic antimicrobials may exceed the risk of infection. However, we think that the use of cephalothin or the combination of methicillin and gentamicin outlined above minimizes the risk of iatrogenic complications and may decrease the frequency of prosthetic valve endocarditis. Development of a rational therapeutic approach for the management of established prosthetic valve endocarditis is complicated by the relatively small numbers of patients available for study. Based on the data currently available, we have adopted several therapeutic guidelines. Our general approach is to classify the patients into two overlapping groups—medical and surgical: Medical Group (may be cured by medical therapy alone) 1. Early or late endocarditis with minimal cardiac change on physical examination, minimal hemodynamic changes, and no congestive heart failure;
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Table 6. Suggestions for Prophylactic Antimicrobial Therapy for Patients with Prosthetic Valves Undergoing Invasive Procedures
Procedure
Most Prevalent Organism
Prophylaxis *
Dental
Viridans group streptococci
On day before, day of, and day after procedure: procaine penicillin G, 1.2 X 106 units i.m. every 8 h, plus streptomycin, 500 mg i.m. every 8-12 h Alternatives: cephalexin, 500 mg orally every 6 h ; clindamycin, 300 mg orally every 6 h; erythromycin, 500 mg orally every 6 h (same schedule as above)
Genitourinary or liver biopsy
Group D streptococci; Gram-negative bacilli
On day before, day of, and day after procedure: procaine penicillin G, 1.2 X 106 units i.m. every 8 h, plus gentamicin, 3 mg/kg body weight per day i.m. every 8 h; for transurethral prostatectomy, continue program until 24 hours after urinary catheter removed
Dermatologic
Staphylococci
On day before, day of, and day after procedure: cephalexin, 500 mg orally every 6 h
Cardiac catheterization
Staphylococci
On night before procedure and day of procedure: cephalothin, 1 g i.v. every 4 h. For 1 day after procedure: cephalexin, 500 mg orally every 6 h
* On day of procedure, dose is given 1 hour before procedure, i.m. = intramuscularly; i.v. = intravenously.
valve replacement may be needed later. 2. Early or late endocarditis with no cardiac change on physical examination; has best prognosis; bactericidal antimicrobial therapy frequently curative. Surgical Group (requires prompt surgical replacement of valve plus medical therapy) 1. Early or late endocarditis with valve dehiscence and increasing signs and symptoms of congestive heart failure. 2. Early or late endocarditis with multiple systemic emboli. 3. Fungal endocarditis. 4. Early or late endocarditis with recurrent relapses, with or without cardiac change on physical examination; this subgroup usually is not cured by medical therapy alone; valve replacement together with medical bactericidal antimicrobial therapy is often curative. Prompt surgical replacement of an infected prosthetic valve is necessary when medical therapy fails, as evidenced by progressive uncontrolled infection, progressive congestive heart failure with valve dehiscence, or multiple emboli. Eight patients in our series required surgical intervention, and six of these patients survived. In patients with prosthetic valve endocarditis and extensive infection of the aortic root, and in whom reimplantation of a prosthetic valve in the infected aortic root is not indicated, radical reconstructive surgery may be necessary ( 3 1 ) . Most investigators think that fungal endocarditis cannot be cured with medical therapy alone, and surgical replacement of the infected prosthesis, together with antifungal chemotherapy, is indicated (32, 33). Table 5 outlines our approach to the medical treatment of patients with prosthetic valve endocarditis. The initial selection of antimicrobial agents depends on identification of the microorganism and in-vitro susceptibility tests. Once the antimicrobial therapy is begun, a serum bactericidal titer should be obtained. In our experience, 99.9% or 100% killing at a serum dilution of 1:8 or greater was associated with a favorable outcome in patients with late-
onset endocarditis. However, because none of our surviving patients in the late-onset group who had serum bactericidal titers of 1:8 or greater had valve dehiscence, the favorable outcome may have been related to this rather than to the serum bactericidal titers. In patients with early-onset endocarditis, the outcome was poor irrespective of the serum bactericidal titers. Few data are currently available concerning the need for long-term oral suppressive or prophylactic therapy after treatment for prosthetic valve endocarditis. Slaughter, Morris, and Starr (11) recommended antimicrobial therapy for 6 to 12 months in patients who have survived staphylococcal infection. In our review, the three patients who relapsed had recurrence of symptoms within 2 weeks after discontinuance of therapy. Currently, we do not recommend long-term suppressive therapy for our patients. We suggest that blood cultures be obtained at monthly intervals, for 3 months, in asymptomatic patients after discontinuance of parenteral antimicrobial therapy. If symptoms of relapse develop, the patient should be studied promptly. We think that antimicrobial prophylaxis is warranted for patients with prosthetic valves who are undergoing invasive procedures. Our recommendations for these patients are shown in Table 6. ACKNOWLEDGMENTS: Presented at the 14th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, California, 11-13 September 1974. Received 7 November 1974; revision accepted 10 March 1975. • Requests for reprints should be addressed to Walter R. Wilson, M.D., c/o Section of Publications, Mayo Clinic, 200 First St. SW, Rochester, MN 55901. References 1. GERACI JE, DALE AJD, MCGOON DC: Bacterial endocarditis
and endarteritis following cardiac operations. Wis Med J 62: 302-315, 1963 2. HERR R, STARR A, MCCORD CW, et al: Special problems fol-
lowing valve replacement: embolus, leak, infection, red cell damage. Ann Thorac Surg 1:403-410, 1965 3. NELSON TG, COOLEY DA: Prosthetic replacement of the mitral
or aortic valves: a preliminary report of 111 cases. Am J Cardiol 14:148-153, 1964 4. YEH TJ, ANABTAWI IN, CORNETT VE, et al: Bacterial endoWilson et al. • Prosthetic Valve Endocarditis
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ciated with intracardiac prostheses: diagnosis, management, and prophylaxis. J Thorac Cardiovasc Surg 51:36-47, 1966 9. DAVIS A, BINDER MJ, FINEGOLD SM: Late infection in patients
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valve endocarditis. / Thorac Cardiovasc Surg 60:540-548, 1970 11. SLAUGHTER L, MORRIS JE, STARR A: Prosthetic valvular endo-
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carditis after cardiopulmonary bypass surgery for the repair of cardiac valvular defects. Antimicrob Agents Chemother 3:643656, 1963 18. OKIES JE, VIROSLAV J, WILLIAMS TW JR: Endocarditis after
cardiac valvular replacement. Chest 59:198-202, 1971 19. KILLEN DA, COLLINS HA, KOENIG MG, et al: Prosthetic car-
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of aortic valve endocarditis and aortic root abscesses by insertion of prosthetic valve in ascending aorta and placement of bypass grafts to coronary arteries. J Thorac Cardiovasc Surg 67:443-449, 1974 32. MEYER RD, Fox ML: Aspergillus endocarditis: therapeutic failure of amphotericin B. Arch Intern Med 132:102-106, 1973 33. HARFORD CG: Postoperative fungal endocarditis: fungemia, embolism, and therapy. Arch Intern Med 134:116-120, 1974
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From January 1963 until January 1974, 45 patients had prosthetic valve endocarditis. Symptoms of prosthetic valve endocarditis developed within 2 months after operation (early onset) in 16 patients (36%) and more than 2 months after operation (late onset) in 29 patients (64%). Overall mortality among the 45 patients was 56% (88% among those with early onset and 40% among those with late onset). Medical therapy alone was curative in 60% of the surviving patients. Combined medical and surgical therapy was curative in 40% of the survivors. The most frequent isolates in the early-onset group were Staphylococcus aureus (44%) and Gram-negative bacilli (38%); associated mortality was 86% and 83%, respectively. The most frequent isolates in the late-onset group were viridans streptococci (41%) and Gram-negative bacilli (31%); the mortality was 25% and 22%, respectively. Suggestions are offered for operative antimicrobial prophylaxis and for medical and surgical treatment of prosthetic valve endocarditis. Prompt surgical replacement of an infected prosthesis is necessary when medical therapy fails.
PROSTHETIC VALVE ENDOCARDITIS is an infrequent but
se-
rious complication of cardiac valve replacement (1-12). We present our experience with 45 such patients during an 11-year period. Also, we outline our approach to the recognition of this complication, to the operative antimicrobial prophylaxis for patients receiving prosthetic valves, and to the medical and surgical management of established prosthetic valve endocarditis. Materials and Methods We reviewed clinical records of patients with prosthetic valve endocarditis. The complication was judged to be present if there were at least two of the following: [1] at least two positive blood cultures with the same organism, [2] histopathologic evidence of bacterial endocarditis in surgical or autopsy specimens, and [3] at least two of the following clinical signs— fever, development of a new regurgitant murmur, newly developed splenomegaly, or peripheral emboli. One patient included in our series did not meet these criteria. Five days after an aortic Starr-Edwards valve implantation, Serratia marcescens bacteremia occurred. Early prosthetic valve endocarditis was suspected but not proved. After bactericidal kanamycin therapy for 2 weeks, the patient improved and was dismissed from the hospital. Approximately 2 months • From the Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
later, he had fever and rapidly progressive congestive heart failure, and he died. Postmortem examination (done elsewhere) showed valve dehiscence and vegetations on the prosthesis. It is possible that additional patients who received prosthetic valves during this period developed prosthetic valve endocarditis but did not return to the Mayo Clinic for evaluation or treatment. In establishing rigid criteria for the diagnosis of prosthetic valve endocarditis, we assume that some patients were excluded from our study; however, we chose to confine our investigation to those patients with documented evidence of the complication. Septic shock was defined as fever associated with a decrease in systolic blood pressure of at least 40 mm Hg in a normotensive patient or of at least 70 mm Hg in a hypertensive patient and sustained for at least 5 consecutive hours. All patients received "prophylactic" parenteral antimicrobial therapy, usually consisting of methicillin, oxacillin, or cephalothin administered preoperatively and for at least 5 days postoperatively. No uniform protocol for prophylactic therapy existed during this period. Patients were divided into two groups according to whether the prosthetic valve endocarditis occurred early (within 2 months postoperatively) or late (after 2 months postoperatively). Antimicrobial susceptibility tests were done by methods described elsewhere (12). Minimal inhibitory concentrations were determined by the agar dilution method. Minimal bactericidal concentrations were determined by the tube dilution method, and the results were expressed as the lowest concentration of antibiotic that killed at least 99.9% of the initial inoculum. Serum bactericidal titers were determined during the third day of treatment, on a sample taken 1 hour after parenteral antimicrobial administration, and the results were expressed as the greatest dilution of serum that killed at least 99.9% of the inoculum. In patients receiving continuous parenteral antimicrobial therapy in addition to divided doses, blood samples for the serum bactericidal titers were obtained 1 hour after the administration of the intermittent dose. An effort was made to ensure that the continuous antibiotic regimen was administered uniformly over a 24-hour period. Results From January 1963 until January 1974, 4706 prosthetic valves were implanted in 4586 patients in Mayo Clinicaffiliated hospitals. Follow-up has ranged from 6 months to 9 years. Prosthetic valve endocarditis developed in 45 (0.98%) patients, early in 16 (0.35%) and late in 29 (0.63%). The aortic valve was involved more frequently than the mitral valve, and this difference was statistically significant (P = 0.025) (Table 1). In patients with early prosthetic valve endocarditis, the mean time from operation to onset of symptoms was 17 days (range, 1 to 45 days). In the late group, the mean
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Table 1. Summary of Prosthetic Valve Implants and Prosthetic Valve Infections
Valve
Type of Prosthesis
Aortic Mitral Tricuspid Pulmonary
Prostheses Homografts Total Prostheses Homografts Total Prostheses Homografts Total Prostheses Homografts Total
Implants
Infections Patients Implants
no. 2386 258 2644 1774 13 1787 226 2 228 2 45 47
% 51 5 56 38 0.3 38 5 0.04 5 0.04 1 1
no. 30 4 34 10 1 11 0 0 0 0 0 0
% 1.3 1.5 1.3 0.56 7.7 0.61 0 0 0 0 0 0
time from operation to onset of symptoms was 26 months (range, 72 days to 10 years). Fever and chills were the most consistent clinical findings in both groups of patients (Table 2). Peripheral embolic phenomena (including Osier's nodes) were more common in the late group, and the development of a new regurgitant murmur occurred more frequently in the early group. Septic shock, by our definition, occurred only in the early group and always was associated with a fatal outcome. Other leading causes of death included the following: cardiac arrest, 11; renal failure, 3; ventricular fibrillation, 3; liver failure, 1; and cerebrovascular accident, 1. There were 25 deaths among our 45 patients with prosthetic valve endocarditis (mortality, 56%) (Table 3). The mortality was higher in the early group. Late aortic prosthetic valve endocarditis was associated with the best survival rate. Postmortem examinations were done in 24 of the 25 fatal cases, and histopathologic evidence of prosthetic valve endocarditis was present in all 24. Valve dehiscence was noted in 9 cases (6 in the early group and 3 in the late group). Streptococci were the most frequent isolates (16 of 45 patients) (Table 4). Streptococci of the viridans group were isolated from 41% of patients in the late group and were associated with the best survival rate; none of the patients in the early group had infections caused by these organisms. Five of the patients with viridans strepTable 2. Clinical Findings in Patients with Prosthetic Valve Endocarditis
Finding
Patients Early Group < —
Fever Chills New regurgitant murmur Shock Leukocytosis (> 12 000/mm8) Congestive heart failure Splenomegaly Peripheral emboli*
93 66 60 33 40 27 20 7
Late Group
%
•
96 74 37 0 30 30 19 26
* Includes Osier's nodes. 752
tococcal endocarditis had recently had antecedent trauma (2 patients), a surgical operation (2 patients), or dental work (1 patient). One of these 5 patients had undergone a cholecystectomy (elsewhere), and it is not known whether this patient received antibiotics before admission to the Mayo Clinic-affiliated hospital; the remaining 4 patients had received no prophylactic antibiotics. Two of the 4 patients with group D streptococcal endocarditis (both in the late group) had had urinary tract infections with group D streptococci; 3 of these 4 patients died. Staphylococci (10 patients with Staphylococcus aureus and 2 patients with S. epidermidis) accounted for 26% of the endocarditis cases (50% of the early group and 13% of the late group) and for 40% of the total number of deaths. Staphylococcal infections were associated with a poor outcome in both the early and late groups. Two of the 7 patients with early onset of S. aureus endocarditis had wound infections caused by S. aureus. Operative antistaphylococcal antimicrobial prophylactic therapy had been discontinued before the onset of symptoms of endocarditis in 6 of these 7 patients. The average time from operation to onset of symptoms in the 7 patients was 23 days, and the mean duration of postoperative prophylactic therapy was 8 days. Gram-negative bacilli were isolated from 33% of our patients and accounted for 28% of the total number of deaths. In the early group, these isolates included Enterobacter aerogenes in one patient, Serratia marcescens in two, Pseudomonas aeruginosa in one, and Escherichia coli in one. Haemophilus aphrophilus was isolated from the only survivor among the patients with early endocarditis caused by Gram-negative bacilli. Isolates in the late group were E. aerogenes in one patient, Alcaligenes faecalis in two, H. aphrophilus in two, Acinetobacter calcoaceticus in one, Klebsiella pneumoniae in one, P. aeruginosa in one, and Bacteroides fragilis in one. Late-onset infections by Gramnegative bacilli were associated with a relatively favorable outcome (78% survival); however, 83% of patients with early-onset infections by Gram-negative bacilli died. Wound infections by the same Gram-negative bacillus responsible for the endocarditis were present in three of the six patients in the early group. The portal of entry in the nine patients in the late group was unknown. None of these patients in the early group had received postoperative prophylactic antimicrobials effective against the Gram-negative bacillus causing the endocarditis. One patient had fatal late endocarditis of a prosthetic mitral valve caused by Candida parapsilosis; death from cardiac arrest occurred after treatment with 735 mg of amphotericin B. The patient did not have large systemic peripheral emboli. During the 11-year period of this study there was no standard protocol for the treatment of patients with prosthetic valve endocarditis. Selection of antimicrobial therapy was based on identification of the organism, in-vitro susceptibility tests, and, usually, the serum bactericidal titers against the blood culture isolate. Blood cultures showed negative results in only 1 of the 45 patients in our study. Sixteen different antimicrobial agents were used. The mean duration of therapy among surviving patients
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was 30 days (range, 21 to 63 days). Medical therapy alone was curative in 55% of the surviving patients (11 of 20). Combined medical and surgical therapy was curative in 45% (9 of 20). An effort was made to measure serum bactericidal titers on all patients with prosthetic valve endocarditis; however, because of early patient death (11 patients) or technical inability to test overly fastidious microorganisms (10 patients), these data were available for only 23 patients. Ten of the 11 patients in the late group with a serum bactericidal titer of 1:8 or greater survived; 2 of the 3 patients in the late group with a serum bactericidal titer less than 1:8 also survived. None of these 12 surviving patients had evidence of valve dehiscence. The outcome in the patients with early-onset endocarditis was poor irrespective of the serum bactericidal titers. Infected prosthetic valves were replaced in 8 of the 29 patients in the late group, and 6 of these 8 patients survived. The chief indications for reoperation were uncontrolled infection in 3 patients, progressive congestive heart failure with valve dehiscence in 3, and septic emboli in 2. One patient with early S. epidermidis endocarditis underwent replacement of an infected aortic prosthesis and died of a cardiac arrest postoperatively. There were three recurrences of prosthetic valve endocarditis, two in patients in the early group. One patient with early-onset aortic valve endocarditis due to S. aureus had had 5 weeks of parenteral therapy with methicillin (3 weeks) and oxacillin (2 weeks); the recurrence developed 2 weeks after the oxacillin was withdrawn. Treatment with methicillin, 2 g intravenously every 3 hours for 28 days, resulted in cure that now has continued for 9 years. In one other patient with early-onset aortic valve endocarditis, the recurrence was 1 week after discontinuance of a 9-week course of vancomycin therapy for infection with S. epidermidis; this patient died from cardiac arrest 3 days after onset of symptoms. One patient with late-onset mitral valve endocarditis with K. pneumoniae had multiple recurrences. After multiple attempts at medical cure, the infected mitral valve prosthesis was replaced. The patient was treated with cephalothin and gentamicin for 4 weeks postoperatively. At 2Vi years of follow-up there is no evidence of reinfection. Oral suppressive antimicrobial agents were not recommended after completion of therapy for the prosthetic valve endocarditis. The patients were advised regarding
Table 3. Mortality by Time of Onset of Infection and Site of Prosthetic Valve
Site
Group Aortic
Mitral
Total
%
11/13 85
3/3 100
14/16 88
%
7/21 33
4/8 50
11/29 38
%
18/34 53
7/11 64
25/45 56
Early no.* Late no. Total no.
* Shown as deaths/patients at risk.
prophylactic antimicrobial treatment if they were to undergo dental work or other invasive procedures. Discussion
The overall mortality of 56% in our series approximates the rates previously reported (10, 11). The difficulty in treating infections of foreign implants is well recognized (2, 13, 14); however, our data and other reports indicate that early, aggressive, bactericidal medical therapy alone, or combined with early surgical intervention, can successfully cure a substantial number of patients with prosthetic valve endocarditis (10, 11, 15-18). Our data and those previously reported (10, 11, 19) suggest that the incidence of early-onset prosthetic valve endocarditis is low. The efficacy of operative prophylactic antimicrobial therapy has been emphasized (20-23), and prophylactic administration of antibiotics is common for patients undergoing valve replacement. However, the available data are insufficient to show conclusively how effective such therapy is in decreasing the incidence of this early complication (24, 25). Because the mortality in these patients is high (88% in our series), prevention may be as important as attempts to cure established infections (7, 16). Controlled studies on the value of prophylactic antimicrobial therapy for prosthetic valve surgery have not been carried out, but we believe, from our observations* and those published (10, 11), that operative prophylactic therapy should be directed against S. aureus and the Gramnegative bacilli. Against S. aureus, short-term, aggressive, * GERACI JE, WILKOWSKE CJ, MARCOUX A, et al: Unpublished data.
Table 4. Infecting Organisms: Frequency and Relation to Mortality
Organism
Isolations Early Group
Staphylococcus aureus Gram-negative bacilli Streptococci, viridans group Streptococci, group D Staphylococcus epidermidis Corynebacterium xerosis Candida parapsilosis
no. 1 6 0 1 1 1 0
%
44 37 0 6 6 6 0
Mortality
Late Group no. 3 9 12t 3 1 1 1
%
10 31 41 10 3 3 3
Early Group no.* 6/7 5/6 0 1/1 1/1 1/1 0
Late Group
Total no* 9/10 7/15 3/12f 3/4 1/2 1/2 1/1
% 90 47 25 75 50 50 100
Wilson et at. • Prosthetic Valve Endocarditis
753
% 86 83 0 100 100 100 0
no* 3/3 2/9 3/12f 2/3
o/i o/i
1/1
%
100 22 25 67 0 0 100
* Shown as deaths/patients at risk. t Alcaligenes faecalis also isolated from one patient.
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Table 5. Suggestions for Medical Treatment of Prosthetic Valve Endocarditis*
Organism
Antimicrobial Therapy
Alternatives
Streptococci, viridans group
PenG, 20 000 000 units i.v., plus Strep, 500 mg every 12 h, 4 wk
Ceph, 1 g i.v. every 4 h, or Clin, 600-1200 mg i.v. every 8 h, 4 wk
Enterococci—group D streptococci (nonenterococcal group D streptococci are treated as streptococci of viridans group)
PenG, 40 000 000 units i.v./day, plus Strep, 500 mg i.m. every 12 h, 4 wk; if SBT inadequate, do synergy studies with PenG and with Amp, Kan, and Gen; increase PenG if SBT not satisfactory
Van, 1 g i.v. every 12 h, plus Strep, 500 mg i.m. every 12 h, or Gen, 3 mg/kg body weight per day, 4 wk; if SBT not adequate, do desensitization to PenG
Staphylococcus aureus or S. epidermidis, MIC PenG, < 0.5 jug/ml
PenG, 20 000 000 units i.v./day, 4-6 wk; if PenG MIC = 0.5 /-eg/ml, do penicillinase test; if positive, PenG may not be adequate
Van, 1 g i.v. every 12 h, or Ceph, 2 g i.v. every 4 h, or Clin, 600-1200 mg i.v. every 8 h, 4-6 wk (selection depends on in-vitro studies)
S, epidermidis, MIC PenG, > 0.5 Mg/ml
If susceptible in vitro, Meth, 2 g i.v. every 4 h, 4-6 wk
Ceph, 2 g i.v. every 4 h, or Van, 1 g i.v. every 12 h, or Clin, 600-1200 mg i.v. every 8 h, 4-6 wk
S. aureus, MIC PenG, > 0.5 jug/ml
Meth, 2 g i.v. every 4 h, 4-6 wk
Van, 1 g i.v. every 12 h, or Ceph, 2 g i.v every 4 h, or Clin, 600-1200 mg i.v. every 8 h, 4-6 wk
Gram-negative bacilli t Fungi \ Negative blood cultures
PenG, 40 000 000 units/day i.v., plus Strep, 500 mg i.m. every 12 h; if response absent or equivocal, substitute Gen, 3-5 mg/kg body weight per day for Strep; if response absent or equivocal, substitute Carb, 30 g/day for PenG; if response absent or equivocal, add Clin, 600-1200 mg i.v. every 8 h, treat 4-6 wk
* Dosages depend on renal and hepatic function; those suggested here are for average-weight adult patients. PenG = penicillin G; i.v. = intravenously; Ceph = cephalothin; Strep = streptomycin; Clin = clindamycin; Van = vancomycin; i.m. = intramuscularly; SBT = serum bactericidal titers; Gen = gentamicin; Amp = ampicillin; Kan = kanamycin; MIC = minimal inhibitory concentration; Meth = methicillin; Carb = carbenicillin. t Selection of therapy is governed by in-vitro microbiologic studies; use bactericidal agents. For Pseudomonas, Gen, 3-5 mg/kg body weight per day, plus Carb, 30 g/day, 4 wk. J Early surgical replacement of valve plus amphotericin-B (minimum, 2- to 3-g course); if indicated, do MIC and minimal fungicidal concentration studies with 5-flucytosine and synergy studies with 5-flucytosine plus amphotericin-B.
operative prophylaxis with methicillin (12 g/day) would be appropriate, beginning the night before operation and continuing through the third postoperative day or until all intracardiac monitoring lines have been removed. On a theoretical basis, the best prophylaxis against the Gramnegative bacilli is gentamicin (3 mg/kg body weight per day in patients with normal renal function). Because of occasional toxic effects of respiratory paralysis, particularly when combined with various anesthetic agents, it is suggested that gentamicin therapy be begun immediately postoperatively and then continued, as with methicillin. Gentamicin administered in this way would not be present in the systemic circulation at the time of operation, when prophylactic antibiotics may be most effective (26-28). This combination would be effective against the majority of microorganisms causing early-onset prosthetic valve endocarditis, and the short duration of treatment would be unlikely to induce resistant bacterial flora and superinfection. Alternatively, cephalothin (6 g/day, schedule for methicillin) has been used for operative prophylaxis at the Mayo Clinic and elsewhere (11). Although it is effective in vitro against S. aureus and S. epidermidis, many Gramnegative bacilli are resistant to it in vitro, and cephalothin may predispose patients undergoing cardiac valve replace754
ment to superinfections other than endocarditis (29, 30). The rationale for prophylactic use of antimicrobials and the choice of these agents are controversial. Indeed, the most important modality in the prevention of prosthetic valve endocarditis may be meticulous care to prevent bacterial contamination during operation. Because the incidence of prosthetic valve endocarditis is low, the potential iatrogenic complications due to the suggested prophylactic antimicrobials may exceed the risk of infection. However, we think that the use of cephalothin or the combination of methicillin and gentamicin outlined above minimizes the risk of iatrogenic complications and may decrease the frequency of prosthetic valve endocarditis. Development of a rational therapeutic approach for the management of established prosthetic valve endocarditis is complicated by the relatively small numbers of patients available for study. Based on the data currently available, we have adopted several therapeutic guidelines. Our general approach is to classify the patients into two overlapping groups—medical and surgical: Medical Group (may be cured by medical therapy alone) 1. Early or late endocarditis with minimal cardiac change on physical examination, minimal hemodynamic changes, and no congestive heart failure;
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Table 6. Suggestions for Prophylactic Antimicrobial Therapy for Patients with Prosthetic Valves Undergoing Invasive Procedures
Procedure
Most Prevalent Organism
Prophylaxis *
Dental
Viridans group streptococci
On day before, day of, and day after procedure: procaine penicillin G, 1.2 X 106 units i.m. every 8 h, plus streptomycin, 500 mg i.m. every 8-12 h Alternatives: cephalexin, 500 mg orally every 6 h ; clindamycin, 300 mg orally every 6 h; erythromycin, 500 mg orally every 6 h (same schedule as above)
Genitourinary or liver biopsy
Group D streptococci; Gram-negative bacilli
On day before, day of, and day after procedure: procaine penicillin G, 1.2 X 106 units i.m. every 8 h, plus gentamicin, 3 mg/kg body weight per day i.m. every 8 h; for transurethral prostatectomy, continue program until 24 hours after urinary catheter removed
Dermatologic
Staphylococci
On day before, day of, and day after procedure: cephalexin, 500 mg orally every 6 h
Cardiac catheterization
Staphylococci
On night before procedure and day of procedure: cephalothin, 1 g i.v. every 4 h. For 1 day after procedure: cephalexin, 500 mg orally every 6 h
* On day of procedure, dose is given 1 hour before procedure, i.m. = intramuscularly; i.v. = intravenously.
valve replacement may be needed later. 2. Early or late endocarditis with no cardiac change on physical examination; has best prognosis; bactericidal antimicrobial therapy frequently curative. Surgical Group (requires prompt surgical replacement of valve plus medical therapy) 1. Early or late endocarditis with valve dehiscence and increasing signs and symptoms of congestive heart failure. 2. Early or late endocarditis with multiple systemic emboli. 3. Fungal endocarditis. 4. Early or late endocarditis with recurrent relapses, with or without cardiac change on physical examination; this subgroup usually is not cured by medical therapy alone; valve replacement together with medical bactericidal antimicrobial therapy is often curative. Prompt surgical replacement of an infected prosthetic valve is necessary when medical therapy fails, as evidenced by progressive uncontrolled infection, progressive congestive heart failure with valve dehiscence, or multiple emboli. Eight patients in our series required surgical intervention, and six of these patients survived. In patients with prosthetic valve endocarditis and extensive infection of the aortic root, and in whom reimplantation of a prosthetic valve in the infected aortic root is not indicated, radical reconstructive surgery may be necessary ( 3 1 ) . Most investigators think that fungal endocarditis cannot be cured with medical therapy alone, and surgical replacement of the infected prosthesis, together with antifungal chemotherapy, is indicated (32, 33). Table 5 outlines our approach to the medical treatment of patients with prosthetic valve endocarditis. The initial selection of antimicrobial agents depends on identification of the microorganism and in-vitro susceptibility tests. Once the antimicrobial therapy is begun, a serum bactericidal titer should be obtained. In our experience, 99.9% or 100% killing at a serum dilution of 1:8 or greater was associated with a favorable outcome in patients with late-
onset endocarditis. However, because none of our surviving patients in the late-onset group who had serum bactericidal titers of 1:8 or greater had valve dehiscence, the favorable outcome may have been related to this rather than to the serum bactericidal titers. In patients with early-onset endocarditis, the outcome was poor irrespective of the serum bactericidal titers. Few data are currently available concerning the need for long-term oral suppressive or prophylactic therapy after treatment for prosthetic valve endocarditis. Slaughter, Morris, and Starr (11) recommended antimicrobial therapy for 6 to 12 months in patients who have survived staphylococcal infection. In our review, the three patients who relapsed had recurrence of symptoms within 2 weeks after discontinuance of therapy. Currently, we do not recommend long-term suppressive therapy for our patients. We suggest that blood cultures be obtained at monthly intervals, for 3 months, in asymptomatic patients after discontinuance of parenteral antimicrobial therapy. If symptoms of relapse develop, the patient should be studied promptly. We think that antimicrobial prophylaxis is warranted for patients with prosthetic valves who are undergoing invasive procedures. Our recommendations for these patients are shown in Table 6. ACKNOWLEDGMENTS: Presented at the 14th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, California, 11-13 September 1974. Received 7 November 1974; revision accepted 10 March 1975. • Requests for reprints should be addressed to Walter R. Wilson, M.D., c/o Section of Publications, Mayo Clinic, 200 First St. SW, Rochester, MN 55901. References 1. GERACI JE, DALE AJD, MCGOON DC: Bacterial endocarditis
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lowing valve replacement: embolus, leak, infection, red cell damage. Ann Thorac Surg 1:403-410, 1965 3. NELSON TG, COOLEY DA: Prosthetic replacement of the mitral
or aortic valves: a preliminary report of 111 cases. Am J Cardiol 14:148-153, 1964 4. YEH TJ, ANABTAWI IN, CORNETT VE, et al: Bacterial endoWilson et al. • Prosthetic Valve Endocarditis
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of aortic valve endocarditis and aortic root abscesses by insertion of prosthetic valve in ascending aorta and placement of bypass grafts to coronary arteries. J Thorac Cardiovasc Surg 67:443-449, 1974 32. MEYER RD, Fox ML: Aspergillus endocarditis: therapeutic failure of amphotericin B. Arch Intern Med 132:102-106, 1973 33. HARFORD CG: Postoperative fungal endocarditis: fungemia, embolism, and therapy. Arch Intern Med 134:116-120, 1974
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