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Prosthetic valve endocarditis
J
THoRAc CARDIOVASC SURG
80:31-37, 1980
Prosthetic valve endocarditis The diagnosis, therapy, and complications of prosthetic valve endocarditis (PVE) in 48 patients seen between 1962 and 1978 are reviewed. Staphylococcus epidermidis and diphtheroids were the most common causes of both early and late PVE. These microorganisms were frequently resistant 10 the penicillins and cephalosporins but were uniformly sensitive to vancomycin. The mortality rate in this series was 69%, with 20% of the deaths attributed to central nervous system emboli and the remainder to cardiac causes. The mortality rate exceeded 75% in patients with any of the following findings: aortic valve infection, nonstreptococcal infecting microorganism, new or increased regurgitant murmurs, or significant congestive heart failure (CHF). The mortality rate was lowest in streptococcal PVE (29%) and in mitral valve PVE (47%). The unacceptably high mortality rate suggests that early replacement of infected prostheses should be considered in all patients except those with uncomplicated streptococcal or mitral valve PVE.
Henry Masur, M.D.,* and Warren D. Johnson, Jr., M.D., New York, N. Y.
Endocarditis is a serious complication of heart valve replacement despite advances in antimicrobial therapy, diagnostic techniques, and surgical procedures. The mortality rate of prosthetic valve endocarditis (PYE) has been 35% to 60% in recent reports;":" We have reviewed our experience with 48 patients with PVE seen at The New York Hospital-Cornell Medical Center between 1962 and 1978. The clinical and pathological features of PVE in these patients are described and recommendations for management are made. Patients and methods The records of all patients with PVE seen at The New York Hospital-Cornell Medical Center were reviewed. The diagnosis of PVE was established by one or both of the following criteria: (1) histopathological evidence of endocarditis in a surgical or autopsy specimen; (2) at least two positive blood cultures for the same organism in a patient with a compatible clinical syndrome and no other potential source for the bacteremia. PYE was considered to be "early" if clinical or From the Division of Infectious Diseases, Department of Medicine, The New York Hospital-Cornell Medical Center, New York, N. Y. 10021. Received for publication Sept. 6, 1979. Accepted for publication Dec. 18, 1979. Address for reprints: Warren D. Johnson, Jr., M.D., Department of Medicine, Division of Infectious Diseases, Cornell University Medical College, 1300 York Ave., New York, N. Y. 10021. ·Supported in part by National Institutes of Health Grant AI 00465.
bacteriologic evidence of onset occurred within 60 days of prosthesis implantation. A patient was considered to be a "survivor" if he completed his course of therapy and had no clinical or bacteriologic evidence of PVE upon discharge from the hospital. A "relapse" was defined as the redevelopment of the clinical syndrome of endocarditis plus blood culture or Gram stain evidence implicating the original microorganism. Blood cultures were obtained by inoculating 5 cc of blood into each of the following media: 90 cc of trypticase soy broth (Scott Laboratories, Fiskeville, R. I.), 90 cc of thioglycollate broth (Scott Laboratories), and 90 cc of heart infusion broth (The New York Hospital Microbiology Laboratory). Blood cultures were incubated at 37° C with 5% carbon dioxide for 21 days. Antimicrobial disc susceptibility tests were done by the Kirby-Bauer method. Minimum bactericidal antibiotic concentrations were determined by the tube dilution method, and the results were expressed as the lowest concentration of antibiotic that killed 99.9% of the inoculum (5 x 105 organisms) after 48 hours' incubation at 37° C. Peak bactericidal serum titers were drawn 45 to 90 minutes after antibiotic administration. The result was expressed as the highest dilution of serum which killed 99.9% of the inoculum after 48 hours. Statistical analyses were performed by means of the chi square test. Results Forty-eight patients were hospitalized at The New York Hospital with PYE between 1962 and 1978. Dur-
0022-5223/80/070031+07$00.70/0 © 1980 The C. V. Mosby Co.
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32
The Journal of Thoracic and Cardiovascular Surgery
Masur and Johnson
Table I. Microbial causes of PVE in 48 patients No. ofpatients
Early PVE*
Microorganism
LatePVE
Micrococcaceae
Staphylococcus epidermidis Staphylococcus aureus Micrococcus species Streptococci Yiridans Streptococcus Group D Streptococcus Pediococcus Diphtheroid species Gram-negative bacteria
8 I I
IS 2
o 4 2
I
5
3
Haemophilus aphrophilus Neisseria sicca Serratia marscescens Fungi
Candida albicuns Aspergillus species
Scopulariopsis brevicaulis
18t
Totals
32
Legend: PYE, Prosthetic valve endocarditis.
'Endocarditis occurring within 60 days of valve replacement. tTwo patients had early PYE caused by both a fungus and a bacterium.
Table II. Survival related to therapy, valve infected, and time of PVE onset Therapeutic regimen Onset of PVE and valve infected
Medical
Medical and surgical
Totals
Early PYE Aortic Mitral
III
0/7 2/3
1/12 3/4
Late PYE Aortic Mitral
6/14 3/9
1/7 1/2
7/21 4/11
Totals
1/5*
11/29
4/19t
15/48
Legend: PYE, Prosthetic valve endocarditis. *The numerator is survivors and the denominator is total number of patients.
tThree additional patients successfully had their valves replaced for PYE relapses after medical therapy.
ing this period, 1,390 prosthetic valves were implanted in 1,282 patients; 90% of implanted valves were Starr-Edwards types. There were no infections of homograft valves. The overall incidence of PYE was 3.7%. The number of PYE cases per year was quite constant, and there were no common source outbreaks or clustering of cases. There were 32 cases of PYE (12 early and 20 late) among the 695 patients with prosthetic aortic valves (4.6%) 16 cases of PYE (four early and
Table III. Indications for valve replacement and outcome of operation * Indication
No. ofpatients
Persistent sepsis Fungal PYE Relapse of PYE Prosthesis dysfunction
2/2t 0/2 3/3 2/15
Totals
7/22
Legend: PYE, Prosthetic valve endocarditis.
'Data from 48 patients with 53 episodes of PYE. tThe numerator is survivors and the denominator is total number of patients.
12 late) among the 673 patients with prosthetic mitral valves (2.4%). PYE developed in three of 94 patients with both mitral and aortic prostheses. The site of infection in these patients was determined to be the aortic valve in two and the mitral valve in one, and they are included in these groups. None of the 22 patients with a prosthetic tricuspid valve alone or in combination with an aortic or mitral valve developed PYE. The interval between prosthetic valve implantation and the onset of PYE in the 32 patients with late infections was 3 to 108 months (median 14 months). The interval between valve insertion and PYE exceeded I year in 15 patients. Clinical characteristics. Fever was the most common clinical finding, and only three of the 48 patients had a rectal temperature of less than 38° C during the first 24 hours of hospitalization. Twenty-six patients had temperatures of 39° C or more during the first week of hospitalization. Other physical findings associated with endocarditis included cutaneous or mucous membrane petechiae (16 patients), Osler nodes and Janeway lesions (one patient), and splenomegaly (five patients). A new or increased regurgitant murmur was noted in 24 patients (aortic 20 and mitral four). The total white blood cell count exceeded 12,000/mm 3 in 26 patients and was greater than 20,000/mm 3 in 10 patients. The magnitude of leukocytosis and temperature elevation did not correlate with outcome of infection. Causative microorganisms. The microbial cause of PYE in these 48 patients is shown in Table 1. The most common causative organism was Staphylococcus epidermidis, followed by diphtheroid species, streptococci, fungi, and gram-negative bacteria. The causative microorganism was identified by blood culture in 43 of the 45 patients with bacterial PYE. Two patients had persistently negative blood cultures (eight and 17 cultures obtained), but both had S. epidermidis cultures from vegetations on their surgically resected valves. The first blood culture obtained was positive in 39 patients (87%), and all blood cul-
Volume 80
Prosthetic valve endocarditis
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July, 1980
Table IV. Survival related to therapy, causative microorganisms, and time of PVE onset No. of patients Early PVE Microorganism
Medical
I
Late PVE
Medical and surgical
Medical
1/7
3/9
I
Medical and surgical
Micrococcaceae
Staphylococcus epidermidis Staphylococcus aureus Micrococcus species Diphtheroid species Gram-negative bacteria Streptococci Non-group D Group D Fungi Totals
1/1* 0/1
1/6
0/2
O/It
1/3
1/2
1/2
011
1/3 O/It
3/4
O/It
O/It
1/1 0/2
1/1 0/1
2/7
2/11
9/23
2/9
Legend: PVE, Prosthetic valve endocarditis.
'The numerator is survivors and the denominator is total number of patients. tPatients with PYE caused by two microorganisms.
tures were positive in 33 patients (73%). The initial positive blood culture in the other four patients was the second, fifth, seventh, and fourteenth culture obtained. The causative organisms in these latter patients were Neisseria sicca, Micrococcus species and two diphtheroid strains. Twenty of the 45 patients received antibiotics during the 2 week period before blood cultures were obtained. In these patients, 81 % of all blood cultures were positive. In patients who did not receive prior antibiotic therapy, 87% of the blood cultures were positive. Five patients had fungal PVE. The microorganism was identified by blood culture in two patients (Candida albicans), by histologic examination of the resected valve in two patients (Aspergillus species), and by examination of a peripheral embolus in one patient (Scopulariopsis brevicaulis). All patients received peri operative antibiotic prophylaxis at the time of initial valve implantation. In early PVE, only one of 18 causative microorganisms was sensitive to the antibiotics administered. In late PVE, 11 of 32 causative microorganisms were sensitive (p < 0.025). Most patients received either methicillin and ampicillin or else cephalothin alone for 12 hours prior to operation and for 3 to 6 days postoperatively. The 23 S. epidermidis isolates were uniformly sensitive to cephalothin by disc sensitivity testing, but only 10 were killed by :::::;6.25 IA-g/ml of cephalothin. Five isolates were sensitive to methicillin by disc testing, but only two were killed by es 12.5IA-g/ml ofthat antibiotic. Seven of the eight diphtheroid strains were sensitive to
cephalothin by disc testing, and six were killed by :::::; 12.5 IA-g/ml. All eight strains were sensitive to vancomycin by disc testing and were killed by :::::; 1.6 IA-g/ml. Therapy and outcome. The overall mortality rate of these 48 patients was 69% (Table II). Four of 16 patients with early PVE and 11 of 32 patients with late PVE were successfully treated. Peak serum bactericidal titers in the 15 survivors ranged from 1: 4 to 1 : 1,024 (median 1: 16). PVE involving the aortic valve was cured in eight of 33 patients (24%), and mitral valve PVE was successfully managed in seven of 15 patients (47%) (p < 0.01). Medical therapy alone was initially employed in 29 patients and 11 survived (38%). The mean duration of parenteral therapy was 6 weeks. Combined medical and surgical initial therapy resulted in the cure of four of 19 patients (21 %). Selection of antimicrobial agents was based on the identification of the microorganism, in vitro susceptibility tests, and the ability to achieve a peak serum bactericidal titer of at least 1: 8. For the entire group of 48 patients, the differences in survival according to time of onset of PVE, medical versus surgical therapy, and the titers of bactericidal activity achieved in serum were not statistically significant. Table III lists the indications for replacement of infected prosthetic valves. Two patients with recurrent or persistent S. epidermidis bacteremia despite 5 to 8 weeks of antimicrobial therapy underwent successful valve replacement. Three patients had a relapse after medical therapy and were cured following valve re-
The Journal of Thoracic and Cardiovascular Surgery
34 Masur and Johnson
Table V. Survival related to microbial cause of PVE and valve infected Valve infected
I
Aortic
Totals
3/3* 4/12
2/4 6/29
5/7* 1O/4U
7/15t
8/33t
15/48
Microbial cause
Mitral
Streptococcal Non-streptococcal Totals
Legend: PVE. Prosthetic valve endocarditis. 'The numerator is survivors and the denominator is total number of patients. tp < 0.01 for the two indicated groups. :j:p < 0.005 for the two indicated groups.
placement. The other two patients (diphtheroid and group D Streptococcus) cured with medical and surgical therapy had prosthetic valve dysfunction. Cultures of valve materials or vegetations obtained at operation were positive in four of the seven patients successfully treated either initially or for relapse after medical therapy. The mean duration of antibiotic therapy after valve replacement in these seven patients was 5.4 weeks. Two of the 22 patients had extensive destruction of the aortic valve anulus and it was not possible to securely implant a new prosthesis. These two patients died despite attempts to secure a prosthesis in the ascending aorta. Table IV relates outcome and type of therapy with causative microorganisms and time of onset of PVE. Six of 27 patients with PVE caused by Micrococcaceae survived and three of eight patients with diphtheroid PVE were successfully treated. Five of seven patients with streptococcal PYE survived. All five patients with fungal PVE died. The worst prognosis was in patients with nonstreptococcal PYE involving the aortic valve, as only six of 29 patients survived (Table V). In contrast, all three patients with streptococcal PYE of the mitral valve survived, and two of four patients with streptococcal infections of the aortic valve survived. Evaluation of prosthetic valve function. Prosthetic valve dysfunction or cardiac failure or both was the primary cause of death in 25 of the 33 patients. A new or increased regurgitant murmur suggesting valve dehiscence and/or paravalvular leak was noted in 24 patients. Only five of these patients (21 %) survived, whereas 10 of the 24 patients (42%) without such murmurs were successfully treated (p < 0.025). Aortic valve PYE associated with a new or increased murmur (20 patients) was cured in only three patients (15%); by comparison, there was a success rate of 38% in 13 patients without new murmurs (p < 0.025). Two of the four patients with mitral PYE and new regurgitant
murmurs and five of II patients without such murmurs were successfully treated. Patients were evaluated for the presence of significant congestive heart failure (CHF) as defined by a requirement for increasing doses of digitalis and/or diuretics to control the CHF. Nineteen of 48 patients had significant CHF by these criteria and three survived (16%). The survival rate was 80% in patients without significant CHF (p < 0.001). The development of CHF was associated with clinical or radiologic evidence of valve dysfunction or dehiscence in 74% of patients with this complication. Prosthetic valve stability was evaluated by cinefluoroscopy in 30 patients. The procedure was performed routinely in some patients, and in other patients it was utilized to document possible valve dehiscence. At least four different views of the prosthetic valve were used. A valve was considered to be unstable and probably dehisced if valve motion had significantly changed when compared with a previous study. If a previous study was not available, valve rocking greater than 7 to 10 degrees was considered abnormal. According to these criteria, one half of the cinefluoroscopic studies were considered to show abnormalities (aortic 12 and mitral three). The cinefluoroscopic results confirmed the clinical impression of a stable or unstable valve in 20 of the 30 patients. Unexpected results were obtained in 10 patients. Four patients (three aortic valves and one mitral valve) had abnormal cinefluoroscopic studies but did not have new or increased regurgitant murmurs. These patients had their valves replaced because of relapse (one), recurrent bacteremia (one), or suspected prosthesis dysfunction (two). At operation, the infected prostheses were unstable, with I to 3 em dehiscences about the valve anulus. Six additional patients (five aortic valves and one mitral valve) had new or increased regurgitant murmurs but normal cinefluoroscopic results. Five of these six patients either died from neurologic causes or underwent cardiac operation for reasons other than valve dysfunction. In all five patients, the prosthesis was securely sutured to the anulus despite the presence of 0.3 to 2 em paravalvular leaks. The sixth patient (aortic valve) was treated medically and remains well 4 th years after therapy. Twelve of 15 patients (80%) with abnormal cinefluoroscopic results died, whereas only seven of 15 patients (47%) with normal cinefluoroscopic results died (p < 0.025). Angiography was performed in 12 patients who had either a new or changing murmur (seven patients) or an abnormal cinefluoroscopic study (five patients). In each case, angiography correctly identified whether or not the prosthetic valve was securely attached, as con-
Volume 80
Prosthetic valve endocarditis
Number 1 July, 1980
firmed by operation or autopsy. In three patients, angiography clarified the apparent paradox between a new insufficiency murmur and a normal result of cinefluoroscopy by demonstrating a stable valve with a paravalvular leak. No clinical embolic events or other complications were associated with angiography. Neurologic and cardiac complications. Fifteen patients (31 %) had clinical evidence of neurologic complications related to PVE. Nine of the 15 patients had autopsy confirmation of the findings. The neurologic lesions were consistent with emboli in 14 of the 15 patients. Eight patients (17%) died of their neurologic complications (one early PVE and seven late PVE). In none of these patients was there any evidence that prosthesis instability or cardiac failure contributed to their death. One patient died of a ruptured mycotic aneurysm and the other seven exhibited unilateral hemiparesis, followed by coma and then death. One patient with late PVE survived an embolus to the middle cerebral artery. Clinically silent bland or septic embolic infarcts were noted in three of eight autopsies in early PVE and three of 14 autopsies in late PVE. Eleven of the 15 patients with neurologic complications had bacterial PVE (four fungal), and 11 had infections involving the aortic valve. All patients were receiving warfarin sodium (Coumadin) at the time of their neurologic complication or death. Prothrombin times, usually 1.5 to 2.5 times control values, did not correlate with the amount of hemorrhage associated with embolic lesions. Cardiac disease was assessed in 36 patients at autopsy (14 patients), valve reoperation (14 patients), or from both autopsy and operative reports (eight patients). The prosthetic valve was detached from the anulus in 20 patients (17 aortic and three mitral valves). Valve dehiscence was associated with extension of the infection into the myocardium or aorta in 10 of 11 patients. Two patients had new septal defects complicating the infection. Twenty-seven patients had positive prosthesis cultures (25) or Gram stains (two) at operation or autopsy, despite up to 70 days of prior antimicrobial therapy. Relapse. Five patients who apperared to be cured and were discharged from the hospital had a relapse within 2 to 16 weeks of discontinuing antibiotic therapy. Four had received medical therapy alone and three of them were subsequently cured with a combination medical and surgical therapy (Streptococcus faecalis, Streptococcus mitior, and S. epidermidis). The two other patients having a relapse (S. aureus and S. epidermidis) died while receiving medical therapy. The 15 survivors have been followed for 2lh to 8
35
years without evidence of recurrent infection. Two patients died of cerebrovascular accidents and another patient died when replacement of a noninfected, unstable prosthesis was attempted. Therefore, the maximum 5 year survival rate that can be achieved in the original group of 48 patients is now 25%. Discussion Endocarditis continues to be a devastating complication of heart valve replacement. At The New York Hospital, endocarditis developed in 3.7% of patients receiving prosthetic valves, and 69% of these patients died. The diagnosis of PVE was not difficult to establish in most patients. Clinical findings were helpful, although usually not diagnostic. Fever was present in almost all patients. Leukocytosis, hematuria, petechiae, and new or increased regurgitant murmurs were present in one third to one half of the patients. The diagnosis of bacterial PVE was readily confirmed by blood cultures. At least one of the first five blood cultures obtained yielded the causative microorganism in 91 % of patients, and only two patients (4%) had persistently negative blood cultures. The causative microorganisms (S. epidermidis) were cultured from the surgically resected valves of the latter two patients. One of these patients had recently received antibiotics. The administration of antibiotics during the 2 week period before blood cultures were obtained was associated with a modest decrease in the percentage of positive cultures. Eighty-seven percent of blood cultures were positive in patients who did not receive antibiotics and 81% were positive in the group receiving antibiotics. A comparable effect of prior antimicrobial agents on the proportion of positive blood cultures has been reported in patients with endocarditis involving natural heart valves." As noted by others," blood cultures are frequently negative in fungal PVE, and in these patients the diagnosis is often established by histologic examination of the resected heart valve or peripheral emboli. Cinefluoroscopy was useful in assessing the stability of prosthetic valves, and the results were often in disagreement with auscultatory findings. The cinefluoroscopic results in one third of the patients studied indicated either a stable valve in the presence of a new or increased regurgitant murmur, or an unstable valve in the absence of any change in heart murmur. The lack of correlation between auscultation and valve dehiscence in some patients has been attributed to alterations in cardiac output, stable paravalvular leaks, and valve thrombi or vegetations. 10-13 The microbial cause of PVE at this institution differs
36
Masur and Johnson
from that previously reported in most other large series. S. epidermidis was the etiologic agent in 48% of patients and was the most common cause of both early and late PYE. This microorganism was responsible for only 6% to 35% of cases of PYE in four other series. (-:1. 0 Diphtheroid species caused 17% of our cases of PYE, compared to 0% to 5% in these other institutions. I-a. 0 In contrast, streptococci accounted for only 15% of our total PYE cases, compared to 32% to 51 % in other reports. 1-:1. 0 This difference is attributable to our low incidence of late streptococcal PYE (18%), compared to a mean incidence of 48% in other hospitals. I-a Factors which might contribute to this institutional variation, especially the high frequency of S. epidermidis and diphtheroid PYE in this series, could not be identified. There were no common source outbreaks and no clustering of PYE cases in our series or in the other reports. S. epidermidis and diphtheroid species are ubiquitous microorganisms and have been the bacteria most commonly recovered from intraoperative blood samples and extracorporeal pump equipment. 14-16 Peri operative portals of entry could be responsible for the high incidence of these microorganisms in early PYE, but it is difficult to relate this source to the many cases of late PYE caused by these microorganisms. We rarely were able to identify potential portals of entry or invasive procedures predisposing to late PYE regardless of the causative microorganisms. The S. epidermidis strains isolated from patients with PYE were usually resistant to both the penicillinaseresistant penicil1lns and the cephalosporins, as determined by in vitro tube dilution sensitivity testing. Only 9% were judged to be sensitive to methicillin or nafcillin and only 43% were sensitive to cephalothin by our bactericidal criteria. Disc sensitivity testing was frequently unreliable, particularly with cephalothin. 17 The S. epidermidis and diphtheroid isolates were uniformly sensitive to vancomycin by all criteria, and this antibiotic is now included in our initial therapeutic regimen.!" We are reluctant to depend on either a penicillin or cephalosporin for therapy unless the microorganism has been subjected to the most stringent sensitivity testing methods. These would include testing with inocula ranging from 105 to 108 bacteria per milliliter in a broth assay and determining minimum bactericidal antibiotic concentrations after 48 hours of incubation. The overall mortality rate of PYE in this series was 69%, and that in other reports ranges from 35% to 60% .1-3. 6. 7 The mortality rate of early PYE (75%) did not differ significantly from that of late PYE (67%). Other reports have emphasized the improved prognosis in late PYE and attributed it largely to a predominance
The Journal of Thoracic and Cardiovascular Surgery
of patients with streptococcal infections in this group. 3. 4, 6 Indeed, in the present series, the mortality rate was 29% in streptococcal PYE and 76% in nonstreptococcal PYE. However, the number of streptococcal cases was too few to influence significantly the overall mortality statistics. Factors other than a nonstreptococcal infection which were associated with a high mortality rate were infection of the aortic valve (p < 0.01), the development of a new or increased regurgitant murmur (p < 0.025), and the presence of moderate or severe CHF (p < 0.001). The mortality rate was 76% to 84% if any of these conditions were present. The results of medical therapy were comparable to those of combined medical and surgical therapy in this series and in several recent reports.v :' This is not surprising, since the criteria for valve replacement have seen very stringent. Most of our patients (68%) had their valves replaced only when there was unequivocal evidence for prosthesis dysfunction and, even then, there were delays between recognition of the dysfunction and operation. The resultant mortality rate of 87% in patients undergoing valve replacement for prosthesis dysfunction might be anticipated under these conditions. Of the 33 deaths in this series, 25 were attributed to cardiac causes and eight to central nervous system events. Modification or new advances in medical therapyare not likely to prevent these deaths, so it is appropriate to re-examine our criteria for valve replacement. The accumulated experience at this and other institutions indicates that all patients with PYE should be candidates for early valve replacement except those with uncomplicated streptococcal PYE.4-6, II. 19 The recognition that the mortality rate exceeds 75% in patients who have nonstreptococcal PYE, aortic valve infection, significant CHF, or a new or increased regurgitant murmur identifies the group most likely to benefit from early valve replacement. Bacterial PYE which relapses or persists despite appropriate antibiotic therapy and any type of fungal PYE should also be managed by combined medical-surgical therapy. REFERENCES Slaughter L, Morris JE, Starr A: Prosthetic valve endocarditis. A 12 year review. Circulation 47:1319,1973 2 DismukesWE, KarchmerAW, Buckley MJ, Austen WG, Swartz MN: Prosthetic valve endocarditis. Analysisof 38 cases. Circulation 48:365, 1973 3 Wilson WR, Jaumin PM, Danielson GK, Giuliani ER, Washington JA, Geraci JE: Prosthetic valve endocarditis. Ann Intern Med 82:751, 1975 4 KarchmerAW, DismukesWE, BuckleyMJ, AustenWG:
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Prosthetic valve endocarditis
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Late prosthetic valve endocarditis. Clinical features influencing therapy. Am J Med 64:199, 1978 5 Duma RJ (ed): Infections of Prosthetic Heart Valves and Vascular Grafts, Baltimore, 1977, University Park Press 6 Rossiter SG, Stinson EB, Oyer PE, Miller DC, Schapira IN, Martin RP, Shumway NE: Prosthetic valve endocarditis. Comparison of heterograft tissue valves and mechanical valves. J THoRAc CARDIOVASC SURG 76:795, 1978 7 Richardson JV, Karp RB, Kirklin JW, Dismukes WE: Treatment of infective endocarditis. A 10 year comparative analysis. Circulation 58:589, 1978 8 Werner AS, Cobbs CG, Kaye D, Hook EW: Studies on the bacteremia of bacterial endocarditis. JAM A 202: 199, 1967 9 Rubinstein E, Noriega ER, Simberkoff MS, Holzman R, Rahal J1: Fungal endocarditis. Medicine 54:331, 1975 10 Madison J, Wang K, Gobel FL, Edwards JE: Prosthetic aortic valvular endocarditis. Circulation 51:940, 1975 II Arnett EN, Roberts WC: 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 12 Anderson DJ, Bulkley BH, Hutchins GM: A clinicopatho-
13 14
15
16
17
18 19
logic study of prosthetic valve endocarditis in 22 patients. Morphologic basis for diagnosis and therapy. Am Heart J 94:325, 1977 Silver MD: Late complications of prosthetic heart valves. Arch Pathol Lab Med 102:281, 1978 Ankeney JL, Parker RF: Staphylococcal endocarditis following open heart surgery related to positive intraoperative blood cultures, Prosthetic Heart Valves, LA Brewer, ed., Springfield, Ill. 1969, Charles C Thomas, Publisher, pp 719-728 Blakemore WS, McGarrity GJ, Thurer RJ, Wallace HW, Mac Vaugh H, Coriell LL: Infection by airborne bacteria with cardiopulmonary bypass. Surgery 70:830, 1971 Kluge RM, Calia FM, McLaughlin JS, Hornick RB: Sources of contamination in open heart surgery. JAMA 230:1415, 1974 Laverdiere M, Peterson PK, Verhoef J, Williams DN, Sabath LD: In vitro activity of cephalosporins against methicillin-resistant coagulase-negative staphylococci. J Infect Dis 137:245, 1978 Hook EW III, Johnson WD Jr: Vancomycin therapy of bacterial endocarditis. Am J Med 65:411, 1978 Saffle JR, Gardner P, Schoenbaum SC, Wild W: Prosthetic valve endocarditis. The case for prompt valve replacement. J THORAC CARDIOVASC SURG 73:416, 1977
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THoRAc CARDIOVASC SURG
80:31-37, 1980
Prosthetic valve endocarditis The diagnosis, therapy, and complications of prosthetic valve endocarditis (PVE) in 48 patients seen between 1962 and 1978 are reviewed. Staphylococcus epidermidis and diphtheroids were the most common causes of both early and late PVE. These microorganisms were frequently resistant 10 the penicillins and cephalosporins but were uniformly sensitive to vancomycin. The mortality rate in this series was 69%, with 20% of the deaths attributed to central nervous system emboli and the remainder to cardiac causes. The mortality rate exceeded 75% in patients with any of the following findings: aortic valve infection, nonstreptococcal infecting microorganism, new or increased regurgitant murmurs, or significant congestive heart failure (CHF). The mortality rate was lowest in streptococcal PVE (29%) and in mitral valve PVE (47%). The unacceptably high mortality rate suggests that early replacement of infected prostheses should be considered in all patients except those with uncomplicated streptococcal or mitral valve PVE.
Henry Masur, M.D.,* and Warren D. Johnson, Jr., M.D., New York, N. Y.
Endocarditis is a serious complication of heart valve replacement despite advances in antimicrobial therapy, diagnostic techniques, and surgical procedures. The mortality rate of prosthetic valve endocarditis (PYE) has been 35% to 60% in recent reports;":" We have reviewed our experience with 48 patients with PVE seen at The New York Hospital-Cornell Medical Center between 1962 and 1978. The clinical and pathological features of PVE in these patients are described and recommendations for management are made. Patients and methods The records of all patients with PVE seen at The New York Hospital-Cornell Medical Center were reviewed. The diagnosis of PVE was established by one or both of the following criteria: (1) histopathological evidence of endocarditis in a surgical or autopsy specimen; (2) at least two positive blood cultures for the same organism in a patient with a compatible clinical syndrome and no other potential source for the bacteremia. PYE was considered to be "early" if clinical or From the Division of Infectious Diseases, Department of Medicine, The New York Hospital-Cornell Medical Center, New York, N. Y. 10021. Received for publication Sept. 6, 1979. Accepted for publication Dec. 18, 1979. Address for reprints: Warren D. Johnson, Jr., M.D., Department of Medicine, Division of Infectious Diseases, Cornell University Medical College, 1300 York Ave., New York, N. Y. 10021. ·Supported in part by National Institutes of Health Grant AI 00465.
bacteriologic evidence of onset occurred within 60 days of prosthesis implantation. A patient was considered to be a "survivor" if he completed his course of therapy and had no clinical or bacteriologic evidence of PVE upon discharge from the hospital. A "relapse" was defined as the redevelopment of the clinical syndrome of endocarditis plus blood culture or Gram stain evidence implicating the original microorganism. Blood cultures were obtained by inoculating 5 cc of blood into each of the following media: 90 cc of trypticase soy broth (Scott Laboratories, Fiskeville, R. I.), 90 cc of thioglycollate broth (Scott Laboratories), and 90 cc of heart infusion broth (The New York Hospital Microbiology Laboratory). Blood cultures were incubated at 37° C with 5% carbon dioxide for 21 days. Antimicrobial disc susceptibility tests were done by the Kirby-Bauer method. Minimum bactericidal antibiotic concentrations were determined by the tube dilution method, and the results were expressed as the lowest concentration of antibiotic that killed 99.9% of the inoculum (5 x 105 organisms) after 48 hours' incubation at 37° C. Peak bactericidal serum titers were drawn 45 to 90 minutes after antibiotic administration. The result was expressed as the highest dilution of serum which killed 99.9% of the inoculum after 48 hours. Statistical analyses were performed by means of the chi square test. Results Forty-eight patients were hospitalized at The New York Hospital with PYE between 1962 and 1978. Dur-
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The Journal of Thoracic and Cardiovascular Surgery
Masur and Johnson
Table I. Microbial causes of PVE in 48 patients No. ofpatients
Early PVE*
Microorganism
LatePVE
Micrococcaceae
Staphylococcus epidermidis Staphylococcus aureus Micrococcus species Streptococci Yiridans Streptococcus Group D Streptococcus Pediococcus Diphtheroid species Gram-negative bacteria
8 I I
IS 2
o 4 2
I
5
3
Haemophilus aphrophilus Neisseria sicca Serratia marscescens Fungi
Candida albicuns Aspergillus species
Scopulariopsis brevicaulis
18t
Totals
32
Legend: PYE, Prosthetic valve endocarditis.
'Endocarditis occurring within 60 days of valve replacement. tTwo patients had early PYE caused by both a fungus and a bacterium.
Table II. Survival related to therapy, valve infected, and time of PVE onset Therapeutic regimen Onset of PVE and valve infected
Medical
Medical and surgical
Totals
Early PYE Aortic Mitral
III
0/7 2/3
1/12 3/4
Late PYE Aortic Mitral
6/14 3/9
1/7 1/2
7/21 4/11
Totals
1/5*
11/29
4/19t
15/48
Legend: PYE, Prosthetic valve endocarditis. *The numerator is survivors and the denominator is total number of patients.
tThree additional patients successfully had their valves replaced for PYE relapses after medical therapy.
ing this period, 1,390 prosthetic valves were implanted in 1,282 patients; 90% of implanted valves were Starr-Edwards types. There were no infections of homograft valves. The overall incidence of PYE was 3.7%. The number of PYE cases per year was quite constant, and there were no common source outbreaks or clustering of cases. There were 32 cases of PYE (12 early and 20 late) among the 695 patients with prosthetic aortic valves (4.6%) 16 cases of PYE (four early and
Table III. Indications for valve replacement and outcome of operation * Indication
No. ofpatients
Persistent sepsis Fungal PYE Relapse of PYE Prosthesis dysfunction
2/2t 0/2 3/3 2/15
Totals
7/22
Legend: PYE, Prosthetic valve endocarditis.
'Data from 48 patients with 53 episodes of PYE. tThe numerator is survivors and the denominator is total number of patients.
12 late) among the 673 patients with prosthetic mitral valves (2.4%). PYE developed in three of 94 patients with both mitral and aortic prostheses. The site of infection in these patients was determined to be the aortic valve in two and the mitral valve in one, and they are included in these groups. None of the 22 patients with a prosthetic tricuspid valve alone or in combination with an aortic or mitral valve developed PYE. The interval between prosthetic valve implantation and the onset of PYE in the 32 patients with late infections was 3 to 108 months (median 14 months). The interval between valve insertion and PYE exceeded I year in 15 patients. Clinical characteristics. Fever was the most common clinical finding, and only three of the 48 patients had a rectal temperature of less than 38° C during the first 24 hours of hospitalization. Twenty-six patients had temperatures of 39° C or more during the first week of hospitalization. Other physical findings associated with endocarditis included cutaneous or mucous membrane petechiae (16 patients), Osler nodes and Janeway lesions (one patient), and splenomegaly (five patients). A new or increased regurgitant murmur was noted in 24 patients (aortic 20 and mitral four). The total white blood cell count exceeded 12,000/mm 3 in 26 patients and was greater than 20,000/mm 3 in 10 patients. The magnitude of leukocytosis and temperature elevation did not correlate with outcome of infection. Causative microorganisms. The microbial cause of PYE in these 48 patients is shown in Table 1. The most common causative organism was Staphylococcus epidermidis, followed by diphtheroid species, streptococci, fungi, and gram-negative bacteria. The causative microorganism was identified by blood culture in 43 of the 45 patients with bacterial PYE. Two patients had persistently negative blood cultures (eight and 17 cultures obtained), but both had S. epidermidis cultures from vegetations on their surgically resected valves. The first blood culture obtained was positive in 39 patients (87%), and all blood cul-
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Table IV. Survival related to therapy, causative microorganisms, and time of PVE onset No. of patients Early PVE Microorganism
Medical
I
Late PVE
Medical and surgical
Medical
1/7
3/9
I
Medical and surgical
Micrococcaceae
Staphylococcus epidermidis Staphylococcus aureus Micrococcus species Diphtheroid species Gram-negative bacteria Streptococci Non-group D Group D Fungi Totals
1/1* 0/1
1/6
0/2
O/It
1/3
1/2
1/2
011
1/3 O/It
3/4
O/It
O/It
1/1 0/2
1/1 0/1
2/7
2/11
9/23
2/9
Legend: PVE, Prosthetic valve endocarditis.
'The numerator is survivors and the denominator is total number of patients. tPatients with PYE caused by two microorganisms.
tures were positive in 33 patients (73%). The initial positive blood culture in the other four patients was the second, fifth, seventh, and fourteenth culture obtained. The causative organisms in these latter patients were Neisseria sicca, Micrococcus species and two diphtheroid strains. Twenty of the 45 patients received antibiotics during the 2 week period before blood cultures were obtained. In these patients, 81 % of all blood cultures were positive. In patients who did not receive prior antibiotic therapy, 87% of the blood cultures were positive. Five patients had fungal PVE. The microorganism was identified by blood culture in two patients (Candida albicans), by histologic examination of the resected valve in two patients (Aspergillus species), and by examination of a peripheral embolus in one patient (Scopulariopsis brevicaulis). All patients received peri operative antibiotic prophylaxis at the time of initial valve implantation. In early PVE, only one of 18 causative microorganisms was sensitive to the antibiotics administered. In late PVE, 11 of 32 causative microorganisms were sensitive (p < 0.025). Most patients received either methicillin and ampicillin or else cephalothin alone for 12 hours prior to operation and for 3 to 6 days postoperatively. The 23 S. epidermidis isolates were uniformly sensitive to cephalothin by disc sensitivity testing, but only 10 were killed by :::::;6.25 IA-g/ml of cephalothin. Five isolates were sensitive to methicillin by disc testing, but only two were killed by es 12.5IA-g/ml ofthat antibiotic. Seven of the eight diphtheroid strains were sensitive to
cephalothin by disc testing, and six were killed by :::::; 12.5 IA-g/ml. All eight strains were sensitive to vancomycin by disc testing and were killed by :::::; 1.6 IA-g/ml. Therapy and outcome. The overall mortality rate of these 48 patients was 69% (Table II). Four of 16 patients with early PVE and 11 of 32 patients with late PVE were successfully treated. Peak serum bactericidal titers in the 15 survivors ranged from 1: 4 to 1 : 1,024 (median 1: 16). PVE involving the aortic valve was cured in eight of 33 patients (24%), and mitral valve PVE was successfully managed in seven of 15 patients (47%) (p < 0.01). Medical therapy alone was initially employed in 29 patients and 11 survived (38%). The mean duration of parenteral therapy was 6 weeks. Combined medical and surgical initial therapy resulted in the cure of four of 19 patients (21 %). Selection of antimicrobial agents was based on the identification of the microorganism, in vitro susceptibility tests, and the ability to achieve a peak serum bactericidal titer of at least 1: 8. For the entire group of 48 patients, the differences in survival according to time of onset of PVE, medical versus surgical therapy, and the titers of bactericidal activity achieved in serum were not statistically significant. Table III lists the indications for replacement of infected prosthetic valves. Two patients with recurrent or persistent S. epidermidis bacteremia despite 5 to 8 weeks of antimicrobial therapy underwent successful valve replacement. Three patients had a relapse after medical therapy and were cured following valve re-
The Journal of Thoracic and Cardiovascular Surgery
34 Masur and Johnson
Table V. Survival related to microbial cause of PVE and valve infected Valve infected
I
Aortic
Totals
3/3* 4/12
2/4 6/29
5/7* 1O/4U
7/15t
8/33t
15/48
Microbial cause
Mitral
Streptococcal Non-streptococcal Totals
Legend: PVE. Prosthetic valve endocarditis. 'The numerator is survivors and the denominator is total number of patients. tp < 0.01 for the two indicated groups. :j:p < 0.005 for the two indicated groups.
placement. The other two patients (diphtheroid and group D Streptococcus) cured with medical and surgical therapy had prosthetic valve dysfunction. Cultures of valve materials or vegetations obtained at operation were positive in four of the seven patients successfully treated either initially or for relapse after medical therapy. The mean duration of antibiotic therapy after valve replacement in these seven patients was 5.4 weeks. Two of the 22 patients had extensive destruction of the aortic valve anulus and it was not possible to securely implant a new prosthesis. These two patients died despite attempts to secure a prosthesis in the ascending aorta. Table IV relates outcome and type of therapy with causative microorganisms and time of onset of PVE. Six of 27 patients with PVE caused by Micrococcaceae survived and three of eight patients with diphtheroid PVE were successfully treated. Five of seven patients with streptococcal PYE survived. All five patients with fungal PVE died. The worst prognosis was in patients with nonstreptococcal PYE involving the aortic valve, as only six of 29 patients survived (Table V). In contrast, all three patients with streptococcal PYE of the mitral valve survived, and two of four patients with streptococcal infections of the aortic valve survived. Evaluation of prosthetic valve function. Prosthetic valve dysfunction or cardiac failure or both was the primary cause of death in 25 of the 33 patients. A new or increased regurgitant murmur suggesting valve dehiscence and/or paravalvular leak was noted in 24 patients. Only five of these patients (21 %) survived, whereas 10 of the 24 patients (42%) without such murmurs were successfully treated (p < 0.025). Aortic valve PYE associated with a new or increased murmur (20 patients) was cured in only three patients (15%); by comparison, there was a success rate of 38% in 13 patients without new murmurs (p < 0.025). Two of the four patients with mitral PYE and new regurgitant
murmurs and five of II patients without such murmurs were successfully treated. Patients were evaluated for the presence of significant congestive heart failure (CHF) as defined by a requirement for increasing doses of digitalis and/or diuretics to control the CHF. Nineteen of 48 patients had significant CHF by these criteria and three survived (16%). The survival rate was 80% in patients without significant CHF (p < 0.001). The development of CHF was associated with clinical or radiologic evidence of valve dysfunction or dehiscence in 74% of patients with this complication. Prosthetic valve stability was evaluated by cinefluoroscopy in 30 patients. The procedure was performed routinely in some patients, and in other patients it was utilized to document possible valve dehiscence. At least four different views of the prosthetic valve were used. A valve was considered to be unstable and probably dehisced if valve motion had significantly changed when compared with a previous study. If a previous study was not available, valve rocking greater than 7 to 10 degrees was considered abnormal. According to these criteria, one half of the cinefluoroscopic studies were considered to show abnormalities (aortic 12 and mitral three). The cinefluoroscopic results confirmed the clinical impression of a stable or unstable valve in 20 of the 30 patients. Unexpected results were obtained in 10 patients. Four patients (three aortic valves and one mitral valve) had abnormal cinefluoroscopic studies but did not have new or increased regurgitant murmurs. These patients had their valves replaced because of relapse (one), recurrent bacteremia (one), or suspected prosthesis dysfunction (two). At operation, the infected prostheses were unstable, with I to 3 em dehiscences about the valve anulus. Six additional patients (five aortic valves and one mitral valve) had new or increased regurgitant murmurs but normal cinefluoroscopic results. Five of these six patients either died from neurologic causes or underwent cardiac operation for reasons other than valve dysfunction. In all five patients, the prosthesis was securely sutured to the anulus despite the presence of 0.3 to 2 em paravalvular leaks. The sixth patient (aortic valve) was treated medically and remains well 4 th years after therapy. Twelve of 15 patients (80%) with abnormal cinefluoroscopic results died, whereas only seven of 15 patients (47%) with normal cinefluoroscopic results died (p < 0.025). Angiography was performed in 12 patients who had either a new or changing murmur (seven patients) or an abnormal cinefluoroscopic study (five patients). In each case, angiography correctly identified whether or not the prosthetic valve was securely attached, as con-
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Prosthetic valve endocarditis
Number 1 July, 1980
firmed by operation or autopsy. In three patients, angiography clarified the apparent paradox between a new insufficiency murmur and a normal result of cinefluoroscopy by demonstrating a stable valve with a paravalvular leak. No clinical embolic events or other complications were associated with angiography. Neurologic and cardiac complications. Fifteen patients (31 %) had clinical evidence of neurologic complications related to PVE. Nine of the 15 patients had autopsy confirmation of the findings. The neurologic lesions were consistent with emboli in 14 of the 15 patients. Eight patients (17%) died of their neurologic complications (one early PVE and seven late PVE). In none of these patients was there any evidence that prosthesis instability or cardiac failure contributed to their death. One patient died of a ruptured mycotic aneurysm and the other seven exhibited unilateral hemiparesis, followed by coma and then death. One patient with late PVE survived an embolus to the middle cerebral artery. Clinically silent bland or septic embolic infarcts were noted in three of eight autopsies in early PVE and three of 14 autopsies in late PVE. Eleven of the 15 patients with neurologic complications had bacterial PVE (four fungal), and 11 had infections involving the aortic valve. All patients were receiving warfarin sodium (Coumadin) at the time of their neurologic complication or death. Prothrombin times, usually 1.5 to 2.5 times control values, did not correlate with the amount of hemorrhage associated with embolic lesions. Cardiac disease was assessed in 36 patients at autopsy (14 patients), valve reoperation (14 patients), or from both autopsy and operative reports (eight patients). The prosthetic valve was detached from the anulus in 20 patients (17 aortic and three mitral valves). Valve dehiscence was associated with extension of the infection into the myocardium or aorta in 10 of 11 patients. Two patients had new septal defects complicating the infection. Twenty-seven patients had positive prosthesis cultures (25) or Gram stains (two) at operation or autopsy, despite up to 70 days of prior antimicrobial therapy. Relapse. Five patients who apperared to be cured and were discharged from the hospital had a relapse within 2 to 16 weeks of discontinuing antibiotic therapy. Four had received medical therapy alone and three of them were subsequently cured with a combination medical and surgical therapy (Streptococcus faecalis, Streptococcus mitior, and S. epidermidis). The two other patients having a relapse (S. aureus and S. epidermidis) died while receiving medical therapy. The 15 survivors have been followed for 2lh to 8
35
years without evidence of recurrent infection. Two patients died of cerebrovascular accidents and another patient died when replacement of a noninfected, unstable prosthesis was attempted. Therefore, the maximum 5 year survival rate that can be achieved in the original group of 48 patients is now 25%. Discussion Endocarditis continues to be a devastating complication of heart valve replacement. At The New York Hospital, endocarditis developed in 3.7% of patients receiving prosthetic valves, and 69% of these patients died. The diagnosis of PVE was not difficult to establish in most patients. Clinical findings were helpful, although usually not diagnostic. Fever was present in almost all patients. Leukocytosis, hematuria, petechiae, and new or increased regurgitant murmurs were present in one third to one half of the patients. The diagnosis of bacterial PVE was readily confirmed by blood cultures. At least one of the first five blood cultures obtained yielded the causative microorganism in 91 % of patients, and only two patients (4%) had persistently negative blood cultures. The causative microorganisms (S. epidermidis) were cultured from the surgically resected valves of the latter two patients. One of these patients had recently received antibiotics. The administration of antibiotics during the 2 week period before blood cultures were obtained was associated with a modest decrease in the percentage of positive cultures. Eighty-seven percent of blood cultures were positive in patients who did not receive antibiotics and 81% were positive in the group receiving antibiotics. A comparable effect of prior antimicrobial agents on the proportion of positive blood cultures has been reported in patients with endocarditis involving natural heart valves." As noted by others," blood cultures are frequently negative in fungal PVE, and in these patients the diagnosis is often established by histologic examination of the resected heart valve or peripheral emboli. Cinefluoroscopy was useful in assessing the stability of prosthetic valves, and the results were often in disagreement with auscultatory findings. The cinefluoroscopic results in one third of the patients studied indicated either a stable valve in the presence of a new or increased regurgitant murmur, or an unstable valve in the absence of any change in heart murmur. The lack of correlation between auscultation and valve dehiscence in some patients has been attributed to alterations in cardiac output, stable paravalvular leaks, and valve thrombi or vegetations. 10-13 The microbial cause of PVE at this institution differs
36
Masur and Johnson
from that previously reported in most other large series. S. epidermidis was the etiologic agent in 48% of patients and was the most common cause of both early and late PYE. This microorganism was responsible for only 6% to 35% of cases of PYE in four other series. (-:1. 0 Diphtheroid species caused 17% of our cases of PYE, compared to 0% to 5% in these other institutions. I-a. 0 In contrast, streptococci accounted for only 15% of our total PYE cases, compared to 32% to 51 % in other reports. 1-:1. 0 This difference is attributable to our low incidence of late streptococcal PYE (18%), compared to a mean incidence of 48% in other hospitals. I-a Factors which might contribute to this institutional variation, especially the high frequency of S. epidermidis and diphtheroid PYE in this series, could not be identified. There were no common source outbreaks and no clustering of PYE cases in our series or in the other reports. S. epidermidis and diphtheroid species are ubiquitous microorganisms and have been the bacteria most commonly recovered from intraoperative blood samples and extracorporeal pump equipment. 14-16 Peri operative portals of entry could be responsible for the high incidence of these microorganisms in early PYE, but it is difficult to relate this source to the many cases of late PYE caused by these microorganisms. We rarely were able to identify potential portals of entry or invasive procedures predisposing to late PYE regardless of the causative microorganisms. The S. epidermidis strains isolated from patients with PYE were usually resistant to both the penicillinaseresistant penicil1lns and the cephalosporins, as determined by in vitro tube dilution sensitivity testing. Only 9% were judged to be sensitive to methicillin or nafcillin and only 43% were sensitive to cephalothin by our bactericidal criteria. Disc sensitivity testing was frequently unreliable, particularly with cephalothin. 17 The S. epidermidis and diphtheroid isolates were uniformly sensitive to vancomycin by all criteria, and this antibiotic is now included in our initial therapeutic regimen.!" We are reluctant to depend on either a penicillin or cephalosporin for therapy unless the microorganism has been subjected to the most stringent sensitivity testing methods. These would include testing with inocula ranging from 105 to 108 bacteria per milliliter in a broth assay and determining minimum bactericidal antibiotic concentrations after 48 hours of incubation. The overall mortality rate of PYE in this series was 69%, and that in other reports ranges from 35% to 60% .1-3. 6. 7 The mortality rate of early PYE (75%) did not differ significantly from that of late PYE (67%). Other reports have emphasized the improved prognosis in late PYE and attributed it largely to a predominance
The Journal of Thoracic and Cardiovascular Surgery
of patients with streptococcal infections in this group. 3. 4, 6 Indeed, in the present series, the mortality rate was 29% in streptococcal PYE and 76% in nonstreptococcal PYE. However, the number of streptococcal cases was too few to influence significantly the overall mortality statistics. Factors other than a nonstreptococcal infection which were associated with a high mortality rate were infection of the aortic valve (p < 0.01), the development of a new or increased regurgitant murmur (p < 0.025), and the presence of moderate or severe CHF (p < 0.001). The mortality rate was 76% to 84% if any of these conditions were present. The results of medical therapy were comparable to those of combined medical and surgical therapy in this series and in several recent reports.v :' This is not surprising, since the criteria for valve replacement have seen very stringent. Most of our patients (68%) had their valves replaced only when there was unequivocal evidence for prosthesis dysfunction and, even then, there were delays between recognition of the dysfunction and operation. The resultant mortality rate of 87% in patients undergoing valve replacement for prosthesis dysfunction might be anticipated under these conditions. Of the 33 deaths in this series, 25 were attributed to cardiac causes and eight to central nervous system events. Modification or new advances in medical therapyare not likely to prevent these deaths, so it is appropriate to re-examine our criteria for valve replacement. The accumulated experience at this and other institutions indicates that all patients with PYE should be candidates for early valve replacement except those with uncomplicated streptococcal PYE.4-6, II. 19 The recognition that the mortality rate exceeds 75% in patients who have nonstreptococcal PYE, aortic valve infection, significant CHF, or a new or increased regurgitant murmur identifies the group most likely to benefit from early valve replacement. Bacterial PYE which relapses or persists despite appropriate antibiotic therapy and any type of fungal PYE should also be managed by combined medical-surgical therapy. REFERENCES Slaughter L, Morris JE, Starr A: Prosthetic valve endocarditis. A 12 year review. Circulation 47:1319,1973 2 DismukesWE, KarchmerAW, Buckley MJ, Austen WG, Swartz MN: Prosthetic valve endocarditis. Analysisof 38 cases. Circulation 48:365, 1973 3 Wilson WR, Jaumin PM, Danielson GK, Giuliani ER, Washington JA, Geraci JE: Prosthetic valve endocarditis. Ann Intern Med 82:751, 1975 4 KarchmerAW, DismukesWE, BuckleyMJ, AustenWG:
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Late prosthetic valve endocarditis. Clinical features influencing therapy. Am J Med 64:199, 1978 5 Duma RJ (ed): Infections of Prosthetic Heart Valves and Vascular Grafts, Baltimore, 1977, University Park Press 6 Rossiter SG, Stinson EB, Oyer PE, Miller DC, Schapira IN, Martin RP, Shumway NE: Prosthetic valve endocarditis. Comparison of heterograft tissue valves and mechanical valves. J THoRAc CARDIOVASC SURG 76:795, 1978 7 Richardson JV, Karp RB, Kirklin JW, Dismukes WE: Treatment of infective endocarditis. A 10 year comparative analysis. Circulation 58:589, 1978 8 Werner AS, Cobbs CG, Kaye D, Hook EW: Studies on the bacteremia of bacterial endocarditis. JAM A 202: 199, 1967 9 Rubinstein E, Noriega ER, Simberkoff MS, Holzman R, Rahal J1: Fungal endocarditis. Medicine 54:331, 1975 10 Madison J, Wang K, Gobel FL, Edwards JE: Prosthetic aortic valvular endocarditis. Circulation 51:940, 1975 II Arnett EN, Roberts WC: 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 12 Anderson DJ, Bulkley BH, Hutchins GM: A clinicopatho-
13 14
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17
18 19
logic study of prosthetic valve endocarditis in 22 patients. Morphologic basis for diagnosis and therapy. Am Heart J 94:325, 1977 Silver MD: Late complications of prosthetic heart valves. Arch Pathol Lab Med 102:281, 1978 Ankeney JL, Parker RF: Staphylococcal endocarditis following open heart surgery related to positive intraoperative blood cultures, Prosthetic Heart Valves, LA Brewer, ed., Springfield, Ill. 1969, Charles C Thomas, Publisher, pp 719-728 Blakemore WS, McGarrity GJ, Thurer RJ, Wallace HW, Mac Vaugh H, Coriell LL: Infection by airborne bacteria with cardiopulmonary bypass. Surgery 70:830, 1971 Kluge RM, Calia FM, McLaughlin JS, Hornick RB: Sources of contamination in open heart surgery. JAMA 230:1415, 1974 Laverdiere M, Peterson PK, Verhoef J, Williams DN, Sabath LD: In vitro activity of cephalosporins against methicillin-resistant coagulase-negative staphylococci. J Infect Dis 137:245, 1978 Hook EW III, Johnson WD Jr: Vancomycin therapy of bacterial endocarditis. Am J Med 65:411, 1978 Saffle JR, Gardner P, Schoenbaum SC, Wild W: Prosthetic valve endocarditis. The case for prompt valve replacement. J THORAC CARDIOVASC SURG 73:416, 1977
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