Candida endocarditis after cardiac surgery

Candida endocarditis after cardiac surgery Clues to earlier detection Mildred S. Seelig," C. Peter Speth, ** Philip J. Kozinn,*** Evelyne F. Toni,**** and Claire L. Taschdiian, ***** Union City, N. J.

Most of the increasing numbers of cases of Candida endocarditis have developed after cardiac surgery. The purpose of this paper is twofold: to consider factors in the vulnerability of the open-heart surgery patient to this form of endocarditis and to discuss factors in the recent improvement in prognosis of a disease that has been almost invariably fatal. Early diagnosis is usually difficult, since the usual physical signs and laboratory indices of endocarditis are unreliable when the infecting organism is Candida. Serologic tests for rising titers of Candida antibodies provide a better indication of the presence of deep Candida infection; falling titers have been associated with its cure. In the high-risk cardiac surgery patient, positive Candida serology should alert the physician to the possibility that Candida endocarditis may be developing. Present eviReceived for publication Nov. 13, 1973. • Adjunct Associate Professor of Pharmacology. New York Medical College; Research Associate, Maimonides Research Center. "Resident in Pathology, Albert Einstein Medical Center. •• 'Clinical Professor of Pediatrics, Downstate Medical Center, State University of New York, Brooklyn, N. Y. ····Department of Pathology, Downstate Medical Center, State University of New York. Brooklyn, N. Y.

*• • . . . . Research Associate, Maimonides Research Center;

Professor of Biology, SI. Francis College, Brooklyn, N. Y.

dence suggests that such patients should be monitored serologically. Although every effort should be made to verify the diagnosis by culture, it must be kept in mind that blood cultures have been persistently negative or only transiently positive until late in the course of this disease. Candida precipitins develop and agglutinins rise to high titers as the patient reacts immunologically to Candida within his tissues. When the cardiac surgery patient develops such reactions, the endocardium is a likely focus of infection. If antifungal therapy is instituted early enough, it may be possible to arrest or even to eliminate early nidation of Candida without having to resort to further surgery. Once vegetations become established, it is essential to remove them surgically in addition to instituting full-course antifungal therapy. Factors in vulnerability of cardiac surgery patients to Candida infection

Analysis of the postoperative courses and outcomes of 87 published and unpublished cases of Candida endocarditis' reveals this complication in 16 patients after valvulotomies.v-" in 19 after implantation of valvular homografts (including 2 unpublished cases from Dismukes), 13-22 in 2 after hetero-

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Table I. Outcome of Candida endocarditis by cardiac surgical procedure

Surgical procedure

Valvulotomy Implantation of valve homograft Implantation of valve heterograft Implantation of valve prosthesis Miscellaneous Total

No. of cases

Recovery on observation

<

1 yr.

I>

1 yr.

o

Time of death (mo. after operation)

<

1-3

I >

3-6

I>

6-12

I >

12 INo data

16

0

19

5

2

0

o

2

o

o

o

41 9

5

2 3

14 2

6 2

3 1

7

1

o

o

87

11

6

30

16

6

12

6

grafts (unpublished cases from Harris), in 40 after valvular prostheses.v" * and in 10 after miscellaneous procedures (Table I). There are many possible sources of this ubiquitous organism, which may gain access to the heart during and after the operation (Fig. 1). Rarely, suture or implant materials may be contaminated, or air-borne spores may reach the exposed endocardium. Other possible sources of candidemia in the open-heart surgery patient are- oral or tracheal trauma as a result of intratracheal intubation for anesthesia, spread from an infected tracheostomy wound, or spread from a postoperative bronchopulmonary infection. However, it is probable that Candida most commonly invades postoperatively via indwelling intravenous catheters.

Operative procedure The surgically traumatized endocardium and foreign intracardiac materials provide suitable loci for the deposition of circulating pathogens. There are insufficient data to indicate whether the risk of development of Candida endocarditis is greater with one type of cardiac surgery than with another. Candida endocarditis is known to progress rapidly after digital valvulotomy (by the bare finger technique) and after heterograft valve replacements, except in Louria "This includes 9 unpublished cases' (from Curtis, Fekety, Harris, Kloth, Muchmore, Roberts. Spencer, Speth, and Young) and additional data from 2 cases (from Bowman" and Dexter").

4

7

3

8

2

o 4

and Dineen's- patient, who was intensively and repeatedly treated early at each recurrence. Temple and Malloy" reported that, in contrast to the frequency (20 per cent) of Candida endocarditis among 33 recipients of valvular homografts, none of their 54 patients who had had insertion of Starr-Edwards prostheses during the same period by the same technique developed Candida endocarditis. Conway and colleagues':' have considered the possibility that homografts or suture materials might be contaminated by Candida. Beginning rejection of the graft may provide a favorable medium for its growth. However, before accepting the premise that homografts are necessarily more susceptible to Candida infection, one must consider that very low rates of fungal complication of this type of implant have been reported by others."",,,6 It is possible that the source of the homografts and the means of their sterilization'<" may influence the risk of infective complications. The high incidence of Candida endocarditis after insertion of mechanical prostheses may merely reflect the popularity of this procedure. When Candida-infected valves are replaced, there is considerable risk that the new valves will be infected by Candida, and it may then prove exceedingly difficult, if not im4The method proposed by Lo Grippo's group," which involves sterilizing arterial homografts with betapropiolactone, has been shown to kill fungi, as well as bacteria and viruses, and is also applicable to the preparation of valvular hornografts. It has been found to be more effective than

ultraviolet irradiation, and than

many cytotoxic agents, in producing sterile homografts.

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Candida endocarditis after cardiac surgery

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~

' ORA L -

TRACHEA

1

CANDIDA!-

Trauma to Mucosa: Anesthesia Intubation; Aspiration

J _- - ., J

L I

DIRECT CONTAMINATION OF OPERATIVE SITE CANDIDA IN GRAFT MATERIALS? ( CANDIDA SPORES IN AIR?

41NTESTINAL CANDIDA I

I Pericarditis, Myocarditis

LUNGS ---------~ Pulmonary, Pleural __- - - - - - - ~ Candida INDWELLING INTRAVENOUS CATHETER

L-

--1

ANTIBACTERIAL I ANTIBIOTICS - Esophageal Candida (Candidatceration I

t

TRACHEOSTOMY

!

r--_

---::....-

\.

~===

L.= -= -= - r C H E S T

WOUND _ - - - - ' \'INFECTION: CANDIDA

CANDIDA {IN FIBRIN PLUG AT INOCULATION SITE flnduration IN MURAL THROMBI LCellulitis IN INFUSION FLUID CANDIDA ON S K I N - - - - - - - - - - . . . . . . J

Fig. 1. Pathways of infection by Candida in the cardiac surgery patient.

possible, to remove all of the infected cardiac tissue. The procedures involved in open-heart surgery also influence host defenses adversely. Hairston and Lee." have suggested that use of a pump oxygenator during cardiac surgery may depress humoral defenses.r,R, "" They have shown that perfusion through such devices depresses the bactericidal activity and immunoproteins of serum from cardiac surgery patients, possibly because of protein denaturation.": G1 Alexander's group" has demonstrated that surgical trauma depresses the bactericidal activity of phagocytes. In this context it is of interest that, thus far, we know of no cases of fungal infection after the Vineberg and saphenous vein bypass procedures. The effect of open-heart surgery on cellular immunology and on soluble mediators thereof, which supply the major protection against fungi, should be explored, as is being done for chronic mucocutaneous candidiasis. G3-G" Intratracheal intubation during anesthesia: Tracheostomy Evidence of early tracheobronchial and/or pulmonary infection was seen in 11 of the 87 cardiac surgery patients (including 1 from Spencer) who developed Candida endocarditis.": ~:!, 29, 31, 33, 34 Intratracheal in-

tubation during anesthesia is liable to introduce oral Candida into the lower respiratory tract and may contribute both to transitory candidemia and to postoperative respiratory infection that may be the avenue of sustained access of Candida to the circulation. Indwelling intravenous catheters Candidemia subsequent to indwelling intravenous catheters has caused fatal disseminated candidiasisv''" and has even been associated with Candida endocarditis.'" ~:!, G7, GS, 74, ," Candida contamination of the perfusion fluid and of needle thrombi and Candida infection at the injection site may well contribute to the development of the disease and to its rapid progression, possibly as a result of repeated reintroduction of Candida. Concomitant bacterial and candidal infection In 17 of 25 patients with Candida endocarditis who had concomitant bacterial infections, staphylococci were found in the blood and/or in endocardial lesions.' Eight had Staphylococcus aureus and 5 had Staphylococcus albus (in one instance in association with Staphylococcus aureus); five staphylococcal infections were not speciated. Eight had gram-negative infections, associated in two instances with staphylo-

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Table II. Influence of time and type of therapy on outcome of Candida endocarditis after cardiac surgery Candida injection cured Total

No.

No treatment* Antifungal drugs alone Therapy started < 1 mo. postop. Therapy started 1 to 2Y2 mo. postop. Therapy started 3 mo. or more postop. Surgical removal plus antifungal therapy Replacement of prosthesis or homograft Removal of infected cardiac tissue

40

0

0

7 13

4

57

3

1

23

7

17

9 0

53

3

Total

87

17

20

Therapy

Per cent

14 0

'Includes those whose treatment was grossly inadequate (oral amphotericin B) or else begun shortly before death, as well as those for whom we have no data.

cocci and in one instance with streptococci. There were two additional coinfections with streptococci. Possibly, such coinfections may be more common than is realized. It is unlikely that Candida, which grows out more slowly, is routinely sought when a bacterial pathogen is cultured from the blood. It seems plausible that some of the patients who died of unresponsive bacterial endocarditis may have had a contributing Candida infection as well. Candida can readily be missed on routine stains. Therefore, this contribution of Candida to endocarditis, particularly when the lesions are early and bacteria are also present, may not be noted. Antibiotic administration

The risk of bacterial endocarditis in cardiotomy patients has made the use of prophylactic and postoperative antibacterial agents common. Cooper," Utz," and their associates demonstrated that antibacterial drugs were essential to the production of Candida endocarditis in their experimental model. Intravenous injection of Candida guilliermondi in dogs, in which aortic regurgitation had been induced surgically, caused Candida endocarditis only in animals also given tetracycline (3 of 4 animals) or penicillin plus streptomycin (4 of 5). Evidence has been reviewed elsewhere that antibiotics, in addition to increasing the outgrowth of Candida" ,8 may impair the host's resistance."

Prognosis and manifestations of Candida endocarditis after cardiac surgery Recovery rate. The recoveries of 17 of the 87 patients analyzed! (20 per cent) reflects the improvement of prognosis of a disease that had, until recently, been considered almost uniformly fatal.': 80-R2 Further evaluation of these patients for the relationship of their treatment to the ultimate outcome (Table II) reveals that 4 of 7 patients who were promptly treated on detection of a candidal infection, within 3 weeks after operation, recovered after receiving antifungal drugs alone. Delay beyond that period, even for as little as 1 to 2 \/z months, seems to diminish markedly the patient's chances for survival, unless his valvular homograft or prosthesis is replaced, as Kay and coworkers:" R3 first described. Amputation of the infected suture line, without removal of the infected prosthesis or homograft, has been insufficient in the 2 patients so treated in this series,' I of whom was reported upon previously by Harris' group." Among the 17 patients in this series who received full courses of antifungal therapy in addition to replacement of their postoperatively infected valves,": 17, 21, ~2, 41-H, 47-01* there were 4 whose operation to remove the focus of infection was undertaken after its widespread dissemination as a result of major emboliza'This includes I additional case each from Dismukes, Curtis, and Fekety and further details on 1 case from Bowman.w

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Table III. Early complications after cardiac surgery (other than fever) Time of death after surgery Complications Severe chest pain; postcardiotomy syndrome; fibrillation Postoperative emboli; hemolysis; icterus Tracheal, bronchial, and pulmonary pathology Candida infection of chest wall and pleura Renal failure Major mycotic emboli

>

Total

First 3 mo.

12

7

2

2

8

6

o

2

11

8

5 5 2

2 5 2

I

3-6

mo.

I'> 6 mo.

No. who recovered

No data

o o

o

o I

o

I

o

I

o

o o

Legend: There was a total of 27 patients, not including those whose therapy started just before death. Seventeen patients are entered in the table once, 7 are entered twice, 2 are entered three times, and I is entered five times, for a total of 42 entries.

tion. At that stage, infarctions in major organs and overwhelming infection make the outlook very bleak regardless of the therapeutic regimen employed. Despite inclusion of such patients, over half of the patients so treated survived. It is likely that earlier corrective surgery would further improve the recovery rate. Although the number of patients whose antifungal therapy was begun within a month after operation is meager, the recovery of over half of this group on antifungal drugs alone suggests that very early treatment may prevent the development of the classic form of Candida endocarditis. Admittedly, the absence of surgical or autopsy evidence of Candida vegetations in patients who had no further surgery and who recovered permits the original diagnosis of Candida endocarditis to be questioned. The cases presented here had been diagnosed by the reporting physicians as endocarditis on the basis of clinical signs and laboratory evidence: culture" 14, IS, 20-22, 38, 41-44, 52* and/or Candida serology. IS, 34, 53t In several instances, tissues taken surgically-'- 20, 52 or at autopsy"- 11, 34, 38 (following death from other causes) indicated cure of the Candida infection. In a third of this collection of 87 cases, 'This group includes 1 case each from Curtis, Dismukes, and Muchmore. tThis group includes 1 case each from Curtis and Dismukes.

the postoperative courses were complicated' (other than by fever) (Table III). Of 12 with severe postoperative chest pain, fibrillation, or postcardiotomy syndrome, 7 died of Candida endocarditis within 3 months of operation, 4 died in over 3 months, and I recovered. Death occurred before 6 months in all 8 patients who had postoperative emboli, hemolysis, and/or icterus, Early findings (Table IV). Hemorrhage: Aneurysm. Data from patients who were not treated and who died early indicate the speed with which Candida can implant itself in the endocardium after operation. Seven patients (all of whom had persistent fever and 3 of whom had otherwise complicated postoperative courses) died of disruption of suture lines or of aneurysms at the operation site. They had very small or no vegetations.tv-"- 24, 29, 32 Ratcliffe and Pryce's" patient had candidemia four times before dying of a dissecting hemorrhage into a coronary artery 2 weeks after receiving a valve homograft. There were candidal yeast and mycelial forms (detectable only by special stain) in a fibrinous deposit over the homograft. Marsten and colleagues" reported disruption of a suture line and fatal internal hemorrhage a month after insertion of a valvular prosthesis in a patient who had persistent fever but repeatedly negative blood cultures, even when splinter hemorrhages developed the week be-

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Table IV. Early manifestations of Candida endocarditis after cardiac surgery Immediate postop. course Early manijestation oj injection Atypical Early hemorrhage at infected suture line Aneurysm Renal failure (microabcesses) Bronchopulmonary infection; infected tracheostomy Classical Petechiae and/or hepatosplenomegaly (within first month postop.) Large emboli « 1-2 mo. postop.)

No.

Fever

2*

2

5 5 6

5 5 6

7

7

6

6

Stormy or course

Candida ill blood

1 3 5

o

I other

2t

2

5

o

3t

• Another suture line disruption was associated with Candida serology; no autopsy. tSeveral additionaJ cases became positive late. after being negative repeatedly for Candida; 2 of the patients had bacteremia. tTwo each with valve replacement.

fore death. Candida stellatoidea was cultured from small endocardial vegetations found at autopsy. Another patient who died of disruption of the suture line was mentioned briefly by Murray and associates" in their paper on the development of Candida precipitins within 1 month after cardiac surgery. Unfortunately, as there was no autopsy report in this case and no positive cultures, it has not been tabulated as another case of (early) Candida endocarditis, although the development of precipitins (to Candida parapsilosis) after the operation suggests that the failure of the suture line may have been caused by an early Candida infection. Another patient reported by Murray's group, L' 1 who had postcardiotomy syndrome, had positive Candida serology (first tested 5 weeks postoperatively) and died 2 weeks later. He had had staphylococcemia a week earlier; candidemia did not develop until the week before death. A false aortic aneurysm, associated with Candida vegetations on the homograft, was demonstrable at autopsy. Sicard-" described the course of another patient who died of an aortic aneurysm caused by Candida infection. Her persistent low-grade fever existed in the absence of positive blood cultures until 6 weeks after the Starr-Edwards valve had been inserted, at which time streptococci were isolated. Four weeks after penicillin had been added to a course of tetracycline,

she died in shock following sudden development of severe thoracic pain. Postmortem examination revealed a fresh aneurysm at the site of the aortotomy and very small vegetations around the prosthesis, from which Candida albicans was cultured. Tiny Candida vegetations on a homograft were also seen at autopsy in Chaudhuri's'" patient, who died during attempted repair of a false aneurysm of the aorta in the second postoperative month. This patient had suffered from postoperative chest pain as well as a persistent fever; his blood cultures had been repeatedly negative. Conway and co-workers':' reported upon another patient who had been treated with antibiotics for persistent fever until increasing chest pain (beginning 2 weeks after implantation of a homograft) led to attempted surgical repair of the aneurysm. At autopsy large vegetations were seen on the homograft, extending into an aortic aneurysm, from which Candida albicans and staphylococci were cultured. Still another of Murray's" patients with positive Candida serology was seen at autopsy (3 months after implantation of a homograft) to have a large aortic aneurysm, located at the site of an embolectomy, as well as candidal endocardial vegetations that were the source of the major embolus. This patient had repeatedly had negative blood cultures, even though Candida albicans was cultured from the embolus.

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Death

Candida serology No. tested 0* 2

o

o

o

I

I

No, positive

Treatment

Cure

Early

0*

o

o

2

o

1

o

o o

o

5 5 6

o o

o

7:1:

2

2

3

3:1:

o

5

2

o o

o

o

Renal failure. Five patients who did not not exhibit clinical signs of endocarditis developed early renal failure. In I (described by Young), hemodialysis prevented death from renal failure. Although that patient developed signs of endocarditis shortly thereafter, his blood cultures were persistently negative even after intensive search for fungi, aruerobes, and wall-defective variants. At autopsy, Candida albicans was cultured from endocardial vegetations. Two heterograft valve recipients (described by Harris) died of renal shutdown 10 days and 6 weeks postoperatively, Candida albicans was cultured from the kidneys and endocardial vegetations. Chaudhuri's" patient had persistent fever that led to suspicion of endocarditis, but repeated blood cultures were negative, The patient died in renal failure, Culture of a large thrombus (adherent to the prosthesis) and of specimens from the tracheostomy, lungs, and kidneys revealed Candida albicans. The renal failure of the fifth patient was one of many postoperative complications. At autopsy it was seen to have been caused by extensive renal candidiasis in association with rather early Candida endocarditis." Respiratory involvement in that patient is considered below. Stormy postoperative course: Tracheobronchial pathology. Six patients (including I unpublished case from Spencer and Speth) who died early of Candida endocardi-

Late

tis had stormy postoperative courses, tracheostomies, and/or bronchopulmonary pathology." "", :l:l.ll Only 2 had exhibited candidemia; 3 were negative for Candida, even on repeated culture. In 1 patient who developed mixed bacteremia and pneumonia, Candida albicans was cultured from the tracheostomy 3 days after the operation and from the wound (chest?) 1 month later." Autopsy 2 months after the operation revealed Candida bronchopneumonia as well as Candida plus gram-negative endocarditis and disseminated candidiasis. Two additional patients exhibited Candida bronchopneumonia and very early dissemination of Candida either from the pulmonary or from seemingly more recent endocardial foci (Speth's patient};" Both had lateonset diabetes, suffered postoperative cerebral emboli, had tracheostomies, and required repeated surgical interventions after the cardiac surgery. One had a Candida infection of her chest wound:"; the other (Speth's patient) had yielded Candida albicans from the sputum before and 1 month after the operation and from the blood in association with gram-negative bacteria before death. Another patient had a very stormy postoperative course that was aggravated by her chronic obstructive pulmonary disease (additional data obtained from Dexter). Only at autopsy was Candida endocarditis diagnosed. Cheng and Yu's" patient,

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who died during reoperation a month after insertion of a valvular prosthesis, had excessive tracheobronchial secretions and pneumonitis during her stormy postoperative course. Candida albicans had been isolated from the blood 2 and 4 weeks after the operation and before her death. At autopsy, cerebral and pulmonary embolization was disclosed, and Candida parapsilosis was isolated from endocardial vegetations. Sicard> described a patient who developed pleural and pneumonic complications after repair of congenital pulmonary stenosis and an interventricular defect. A fever that developed a month later responded to antibacterial therapy. No pathogen was cultured from the blood throughout the course of his illness, and there were no signs of endocarditis before death ensued suddenly in the third month after operation. Candida parapsilosis was cultured from a large vegetation at the site of the interventricular patch, which was partially detached. Another patient, who responded to treatment of early bronchitis, was reported upon by Ostermiller's group." He was discharged only to die of early cerebral embolization a few weeks later (infra vide). Early petechiae: Hepatosplenomegaly. In some instances, the Candida grew so rapidly at the operation site that it caused the development of some of the characteristics of classic Candida endocarditis within 3 months after operation. Six patients (including 1 described by Fekety) developed petechiae within 1 month after operation; only half had candidemia.s- 9, 29, 47 There was 1 child whose candidal infection of the chest wound was accompanied by fever, hepatosplenomegaly, and Candida serology but negative blood cultures. 53 All of the patients received antifungal treatment. Two died after the start of treatment"; 2 children survived on antifungal therapy alone (Ion intravenous amphotericin B9 and the other on Clotrimazole" "). Another patient showed transient improvement after each of two courses ·Clotrimazole is an experimental drug from Delbay Pharmaceuticals, Inc., Bloomfield, N. J.

of intravenous amphotericin B (to a cumulative dose of 5.24 Gm.), but she died of drug toxicity 19 months postoperatively.Pv" A young woman (described by Fekety) had progression of infection with major embolization 2 weeks after starting amphotericin B therapy and experienced recurrent fever and petechiae 5 months postoperatively. Her infected prosthesis was then replaced, but she refused further therapy and died 3 months later. Kay's group" reported on another patient who developed petechiae within a month after insertion of a prosthesis; her survival was prolonged first by antifungal therapy and later by replacement of the prosthesis. This patient's initial surgery had been for removal of a Candida-infected valve. Because a previous Candida endocarditis patient had recovered after surgical removal of the infected valve, with pre- but not postoperative amphotericin B, '3 this patient was similarly given antifungal therapy before but not after the operation. When petechiae developed and fever recurred, fulldosage intravenous amphotericin B therapy was reinstituted, even though multiple blood cultures revealed no pathogen. The patient refused a second operation until 14 months after the initial surgery. She then had fever, splinter hemorrhages, and candidernia, The lesions extended into the ventricular wall so that only incomplete removal of the infected tissue was possible. Despite surgical and antifungal therapy, multiple friable vegetations 'were found at autopsy 5 months later. Early major emboli. Eight of the patients in this series developed major emboli within 1 to 2 months postoperatively. 2, 7, 13, 15-17, 31, 40, 48 (Additional data from 1 case" were obtained from Bowman.) One died of drug toxicity soon thereafter." Already cited under Tracheobronchial involvement is the patient discussed by Ostermiller's group," who had been discharged after successful treatment for postoperative bronchitis. He died suddenly, in the fifth week after operation, from a cerebral embolus that had derived from a fungus ball protruding from the suture line. Although Climie and RachmaninOff 1 3 detected Candida in a femoral embolus

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Candida endocarditis after cardiac surgery

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April,1973

removed 5 weeks after insertion of a homograft, repeated blood cultures were negative until death 2 weeks later. The patient reported upon by Jamshidi and associates' developed fever and chest pain 3 weeks postoperatively and evidence of abdominal and femoral emboli 2 and 4 weeks thereafter; however, he had repeatedly negative blood cultures until just before death, 2 months after valvulotomy. Candidemia appeared only at death in the patient described by Koelle and Pastor" also. This patient had developed embolic phenomena I Yz months earlier (2 months postoperatively). Louria and co-workers':" patient, who was addicted to narcotics, developed hemiparesis 3 weeks after replacement of her Candidainfected aortic valve with a prosthesis. Use of drug therapy alone to clear the infection had failed (data from Bowman). Subsequent to the operation, her blood culture remained negative for 3 weeks. She had temporary remissions after each of two subsequent treatments with drug therapy plus valve replacement, but she died 19 months after the initial operation. This patient, like the woman reported upon by Kay's group," represents early recurrence of infection rather than new infective complication of cardiac surgery. One of 2 patients with serologic evidence of Candida infectionw" has been cited as having had an aortic aneurysm at the bifurcation of the aorta, where a major embolus had been removed 2 months postoperatively. That patient had repeatedly had negative blood cultures. In the second patient with late positive serology whose major embolus stemmed from Candida vegetations on a valve homograft, candidemia appeared in only one of sixteen blood specimens in the month before death." Problems in early diagnosis of Candida endocarditis after cardiac surgery Fever: Unreliable index. Half of the patients who developed Candida endocarditis after cardiac surgery did not appear ill and had no fever in the immediate postoperative period' (Table VA); in half of the other patients, fever was transitory. All but 3 of

the 22 patients with persistent or intermittent fevers from the time of operation are known to have died within 3 months of surgery. Seventeen more, who either had fevers responsive to antibacterial therapy or else no recorded fever, also died with Candida endocarditis in 3 months or less. Twenty-nine of those who had no histories of early fever or whose postoperative fevers subsided quickly died of Candida endocarditis more than 3 to 6 months after operation (12 patients) or as long as 6 months to 6 years later (17 patients). Among the 17 cardiotomy patients whose subsequent endocarditis has been reported to be cured or who are clinically well and are being followed, only 1 had persistent fever (until antifungal therapy took effect). Among those patients who did not have postoperative fevers recorded, 6 had elevated temperatures by the fourth day to the third week (Table VB). The first recorded indication of progressing infection was fever, seen within 2 to less than 4 months after surgery in 6 patients, by 4 to under 6 months in 1 patient, and by 6 months to over 2 years in 8. In all but 1 of the patients who first developed fever late or had the first recurrence of fever over 4 months after surgery, the usual signs of advanced Candida endocarditis became manifest at the same time. White blood counts: Unreliable index. Just as fever is an uncertain index of infection in the patient with Candida endocarditis, leukocytosis is also unreliable. Ten of the 87 patients analyzed I had leukocytosis. Twelve had leukopenia, whereas several with low-grade fevers had normal white blood cell counts. Newsom and colleagues," who had repeatedly and unsuccessfully sought a blood-borne pathogen in their patient (who had a postoperative fever that responded to 2 weeks of antibiotics and who developed embolic signs 4 months postoperatively), commented on the patient's surprisingly normal white blood cell counts during the subsequent year before death, 16 months after operation. Candidemia: Unreliable index. Candidemia is only somewhat more reliable than

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Table VA. Fever in Candida endocarditis after cardiac surgery: Fever in immediate postoperative period Time of death after surgery First 3 mo.

Total Fever responsive to antibacterial therapy; transitory Persistent fever* No data on postoperative fever No fever (uneventful) Total

22

5

22 33 10 87

19 11 1 36

I

>

3-6 mo. 4

I

No. who recovered

>

6 mo.

Tentative

IReported

8

0

4

0 4 5 17

0 3 0 3

2t 6 2 14

0 6 2 12

Not reported

1 3 0 5

"One patient had intermittent fever. tOne died later of other causes.

Table VB. Fever in Candida endocarditis after cardiac surgery: Recurrent or later occurrence of first febrile episode.

> I> I

Time of death after surgery Time of first febrile episode

Total

First 3 mo.

In first 3 wk. > 3-8 wk. 2-4 mo. 4- < 6 mo. 6-> 22 mo. Total reported

7 19 7 5 10 49

2 7 0 0 0 11

2 4 5 2 0 13

Table VI. Candida blood cultures in Candida endocarditis after cardiac surgery Negative Time blood drawn postoperatively First month Over 1-4 mo. Late On therapy Time not specified

Total 45 44 19 45* II

Positive

With active disease

21 27 12 11 10

24 17 7 26 1

3-6 mo.

With cure

8*

"There were 5 additional clinical cures, without reported pretherapy and post-therapy cultures.

fever as an index of Candida endocarditis (Table VI). When persistent or recurrent fever existed (in 45 patients), repeated culture of the blood during the month after operation revealed Candida in only 21; 24 had negative cultures despite later proof of Candida endocarditis. Almost two thirds of the 42 tested in the next 3 months had positive blood cultures (including 1 patient de-

No. who recovered 6 mo. 2 5 0 2 7 16

Tentative I Reported 0 0 0 0 2 2

1 2 2 I

1 7

Not reported 0 1 0 0 0 1

scribed by Curtis). Of the 17 with negative findings, 4 had been tested for Candida serology; the tests were positive in all 4.'" 10, 03 In addition to those already cited as having died early of complications of Candida endocarditis, following fevers that were not associated with positive blood cultures, there were 8 who survived for more than 3 to 16 months, even without antifungal therapy." 4-6, 9, 11, 14. 10, 29 In 3 of those cases, the blood cultures became positive only late in the course of the disease.": to, 2" The patient who survived for 16 months was the man, cited above," who had normal white cell counts; cultures of his blood and bone marrow had been negative repeatedly. At autopsy, Candida albicans was cultured from a mycotic aneurysm and from numerous arterial thrombi. Candida serology: Promising index. In the last mentioned patient, whose blood cultures had never been positive, Newsom and colleagues" found a significantly high titer

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of Candida agglutinins in a retained antemortem serum. In retrospect, they considered the clinical signs to have been indicative of Candida endocarditis and suggested the possibility of utilizing Candida serology as an early diagnostic aid. That this theory may have been justified is suggested by the findings reported by Murray and associates, 10 Their patient had had postcardiotomy syndrome but had been well thereafter until death (7 months after a homograft) from an embolus to a coronary artery. This patient exhibited transiently positive Candida serology (II days postoperatively); on antemortem retest, Candida precipitins were again found. Positive blood cultures were not reported. Both Murray's" findings and ours support the contention that Candida serology provides a more reliable early index of the release of Candida antigens in the tissues or circulating blood, to which the host is responding by production of antibodies. The precipitin and agglutinin reactions ,,,, "0, ",;. 73, 84-V" to cytoplasmic Candida antigens (which are released when the Candida cells are disrupted) appear to provide the most reliable index of early Candida infections and give promise of providing means of monitoring response to therapy. The presence of antibodies to cytoplasmic antigens suggests that there has been entry of Candida into the body and that their destruction by phagocytes has taken place. Sustained and rising titers of antibodies to candidal cytoplasmic constituents are pathognomic for systemic candidiasis. Transitory antibodies may reflect the body's immune response to a short-term invasion that the body has controlled. Responses to cell wall antigens are usually heightened concomitantly;" but antibodies to cell wall antigens can also be elevated in subjects with superficial Candida infections; thus they are not useful indicators of deep infection. Cross reactions appear to be limited to Candida species and to Torulopsis glabrata:" Murray's group," who reported the largest series of cardiac surgery patients studied serologically, found that of 47 patients who were serologically negative pre-

operatively, 19 developed positive cytoplasmic precipitins and agglutinins, usually in the postoperative period. An additional 17 had elevated agglutinins only. Two of those in whom precipitins were detected early developed Candida endocarditis and, as noted earlier, another died of disruption of the suture line during the month after operation. We have found Candida precipitins in 5 additional patients who were tested in the first month after operation, in four instances before the blood cultures became positive. Only 1 patient with Candida endocarditis had negative Candida precipitins until tested again antemortem 7 months postoperatively. All but 1 of the remaining patients, who were tested serologically only late in the course of the disease, were found to be positive even when blood cultures remained negative or before they became positive. The patient with repeatedly negative early serology finally showed positive precipitins 2 months after symptoms developed (18 months postoperatively). I" Four patients were successfully treated after serologic diagnosis. Two more of our patients had recurrence of endocarditis more than 6 months after surgical removal of their Candida-infected valves; the diagnoses were substantiated by Candida serology. One never had a positive blood culture with the clinical recurrence; the other developed positive blood and bone marrow cultures 2 weeks after the positive serology was reported. All 7 patients, who died of Candida endocarditis and had been tested serologically before death, had positive serology. Problems in treating postoperative Candida infections and in evaluating therapeutic response Treatment. The earlier the diagnosis and elimination of Candida infection after cardiac surgery, the better the outcome (Table 11). If treatment is started early enough, it may be possible to prevent candidal implantation at the operation site or even to eliminate early nidation, thereby preventing development of vegetations. Prophylactic antifungal therapy. The

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transitory posinve Candida serology in the early weeks after open-heart surgery among some of Murray's!" patients, who did develop Candida endocarditis later, led Murray's group to suggest that mucosal trauma, caused by intratracheal intubation during anesthesia, may permit entry of Candida (present even on normal oral mucosa) into the circulation. This suggests that prophylactic local antifungal treatment may well be justified before inhalation anesthesia is induced. Perhaps relevant are our findings (unpublished) that myasthenia gravis patients with long-standing tracheostomies often have Candida in tissues surrounding the tracheostomy wound and that they have Candida precipitins. On removal of the tracheostomy tube, the Candida in the local wound disappears, and the positive precipitin tests become negative. In view of the success achieved by Wise and colleagues," who eliminated Candida from the urinary bladder of patients with indwelling Foley catheters by irrigation of the bladder with amphotericin B solution (50 mg. per 1,000 ml.) daily for 3 days, it is possible that local but more limited endotracheal irrigation may also prove effective, a possibility that is now under investigation. There are no published reports on the proper concentration of amphotericin B for irrigation of an endotracheal tube, but possibly a concentration of 0.5 to I mg. per cubic centimeter, such as has been reported by Brennan and colleagues" for flushing of indwelling intravenous catheters, may be effective. Amphotericin B aerosol (5 mg. per milliliter in distilled water, given twice daily to a total daily dose of 1 mg. per kilogram) has been used in the treatment of pulmonary mycosis." This may result in absorption of sufficient amphotericin B to have the systemic effect of that dose given intravenously. Possibly, prophylactic low-dosage antifungal therapy may also prove useful in reducing the risk of Candida endocarditis in cardiac surgery patients who develop candidemia in the early postoperative weeks. Cheng and YU 3 3 have commented on the

inadvisability of waiting for the clinical condition of the patient to deteriorate before instituting therapy for candidemia, as has been advised. U9 They mentioned their own experience with a patient whose candidemia 2 weeks after operation had been disregarded; the patient subsequently died of Candida endocarditis 2 weeks later. Commenting on the observation that simple removal of the intravenous catheter is often sufficient to eliminate candidemiaw"?' and that most isolates of Candida are colonizers rather than infective agents.v": 101 Kozinn and associates-'"- 103 have criticized the failure to distinguish adequately between positive blood cultures and positive cultures from material in which Candida is ubiquitous. Furthermore, Candida endocarditis developed in many patients whose candide-mia had cleared. Anderson and Yardley" have demonstrated Candida in cathetersleeve thrombi in the superior vena cava of 2 patients with central vein catheters who had had gastrointestinal surgery. One had a patch of Candida endocarditis on the atrium, and the other had tiny vegetations on the tricuspid valve. They cautioned that removal of an intravenous catheter cannot be relied upon to eliminate this source of Candida. The technique of flushing indwelling intravenous catheters twice weekly with a solution of amphotericin B (I mg. per milliliter), leaving the solution in the cannula for 5 minutes (described by Brennan's group'" as being effective in markedly reducing the incidence of candidemia associated with hyperalimentation), may be advisable also for cardiac surgery patients on intravenous therapy. In view of the toxicity of available antifungal agents, the cardiac surgeon is understandably reluctant to employ them in the doses shown to be necessary for the treatment of Candida endocarditis, unless the diagnosis is beyond question. However, such high doses may not be necessary if treatment is begun early. Positive serology is more likely than candidemia to persist long enough to permit detection. The key to successful medical treatment of Candida endo-

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carditis lies in early diagnosis, preferably before establishment of large vegetations. Medoff and associates'> have reported the efficacy of unusually low dosages of intravenous amphotericin B therapy (10 to 355 mg. over a 4 to 18 day period) in several patients with candidemia or pulmonary Candida infections. The presence of Candida precipitins after cardiac surgery may also justify such treatment. It is possible that such a therapeutic approach may prevent the development of postcardiotomy Candida endocarditis. Treatment of established Candida endocarditis. Immediate and intensive antifungal treatment is necessary once Candida endocarditis is established. It is not enough to treat the underlying disease, to remove the iatrogenic factors, and to wait for a fall in titers of anti-Candida antibodies or for a drop in hypergammaglobulinemia. By the time vegetations have formed within and around the heart valves, use of high doses of toxic drugs in conjunction with surgical removal of the infected tissue as well as the graft or appliance is then necessary. Amphotericin B is the most effective antibiotic for the treatment of systemic mycotic infection, but it is difficult both for the physician to administer and for the patient to tolerate. Administration of 1 mg. per kilogram on alternate days and use of slow rather than rapid infusions" may reduce toxicity. Antihistamines and antipyretics to reduce pyretic reactions" and small amounts of adrenocorticosteroids to reduce toxicity have been advocated.!" Recently, Hellebusch's group':" presented preliminary experimental evidence that concomitant use of intravenous mannitol may protect against amphotericin B nephrotoxicity. The new orally effective antifungal agent, 5-flucytosine, though also toxic and associated with emergence of resistance.':" has been used in therapy of Candida endocarditis. Now that Medoff and co-workers!" have demonstrated that amphotericin B and 5-flucytosine have synergistic activity against Candida in vitro, it may prove possible to combine these drugs in treatment, thereby improving the therapeutic ratio.

Dosages of amphotericin B (0.3 mg. per kilogram intravenously every other day) and 5-flucytosine (60 mg. per kilogram daily in 3 to 4 divided doses) are under investigation. Two of the patients who are being monitored serologically after clinical recovery (described by Curtis and by Kozinn) were treated with Clotrirnazole." At least 3 to 4 weeks of antifungal therapy, and usually considerably more, seem necessary. Persellin and colleagues' speculated early that surgical debridement of the valvular vegetations of patients with Candida endocarditis whose blood had been cleared of Candida by antifungal therapy, might improve the prognosis. This technique, which has improved the survival rate (to 6 of 9) of patients with bacterial endocarditis or narcotic addiction complicated by Candida endocarditis (personal communication from Kay and Bernstein) has been described by Kay and associates." The survival of 9 of the 17 patients (53 per cent) so treated in this series confirms the improved outlook for patients with Candida endocarditis. Therapeutic failures on monitoring response by blood cultures. Candidemia has often disappeared on treatment, or even without treatment, in patients who later presented with Candida endocarditis (Table VI). In fact, only 3 of 20 patients whose serology tests became negative on treatment survived. The sequence of events, in an unpublished case report from Roberts, DeSilvey, and MacKenzie, demonstrates that there can be as long a time lag as 1 year from the time of early diagnosis and treatment of postoperative candidemia (begun a month postoperatively and continued until it cleared) to death from endocarditis. In several cases, repeated courses of amphotericin B, each time until candidemia cleared, only slowed progression of the disease." 4, 24-29, 31 Prognosis-potential of Candida serology. Candida precipitins have been monitored in 6 patients who were treated for Candida endocarditis after cardiac surgery (including 1 case each from Curtis and Dismukes) .15, 34, 51. 53 In all, the precipitins either de-

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clined or became negative in the course of or after therapy. One patient showed rising titers early during treatment, but they subsequently fell; she survived her fungal infection." Another patient, who died of gram-negative sepsis while on antifungal and antibacterial treatment, had both candidemia and positive precipitins." Although the candidemia soon became negative, the precipitins persisted. At autopsy, beady valvular Candida vegetations were found. Of 2 patients whose Candida serology did not revert to negative despite clinical improvement, I died of recurrent disease (personal communication from Harris), and the other is still being observed. The prudent course, at present, would seem to be to search intensively for Candida in bone marrow, in arterial as well as venous blood, and in catheter urine if precipitins appear during the month after operation. Prophylactic use of low-dosage intravenous antifungal antibiotics'v'- 106 or flushing of the catheter with a concentrated solution of amphotericin B,97 such as has been suggested for patients who develop fungal septicemia during intravenous hyperalimentation, may be applicable to cardiac surgery patients who develop candidemia and/or positive Candida serologicaIly after cardiac surgery. Since as many as a third of a series of 47 cardiac surgery patients developed Candida antibodies" (only a few of whom developed Candida endocarditis) , positive serology should be considered a warning signal, rather than a diagnosis. It suggests that Candida has gained access to the internal milieu and that the body is destroying the organism and reacting immunologically to it. What is needed now are controlled serologic studies of many cardiac surgery patients, which would involve testing their serum for Candida antibodies before and I to 4 weeks after the operation. Those who exhibit elevated titers after operation and who have no other signs of infection should be divided into two groups, one to be treated as is customary and the other to be given lowdosage antifungal therapy. (The optimum duration of such therapy also remains to be

determined.) Both test groups should be monitored serologically at monthly intervals thereafter for I to 2 years, to compare the incidence of later development of recurring positive Candida serology and/or signs of developing endocarditis. If a nontoxic antifungal regimen can be proved effective and if such studies as those proposed show a significant difference, it will then be advisable to recommend, without hesitation, that postcardiotomy patients who develop positive Candida serology should always be treated. Portnoy and associates'? have recently commented that a Candida precipitin test may prove useful in both the diagnosis and management of systemic candidiasis. Our data, thus far, indicate that it is advisable to treat the patient either until Candida precipitins are negative or until they are clearly faIling. The patient's titers should be followed once weekly for a month, then monthly for I to 2 years. We have had experience with patients whose precipitin titers did not return to normal for a full year following completion of therapy and clearing of all signs of infection. Such patients should be tested serologically at intervals thereafter. Concluding comments

Evidence presented here indicates that the incidence and mortality rate of Candida endocarditis can be reduced. Prevention of candidal outgrowth in cardiac surgery patients, by prophylactic and/or topical, nonabsorbed, antifungal antibiotics seems a prudent measure. The presence of Candida in a tracheal aspirate at the time of anesthetic intubation may be a clue to the need for added vigilance and for tracheal irrigation with antifungal solution. A patient who develops candidemia and/or rising titers of Candida antibodies after cardiac surgery should be carefully evaluated. Study of the patterns of Candida endocarditis reveals that the usual diagnostic clues of active infection cannot be relied upon for the early detection of Candida endocarditis. Neither fever nor leukocytosis was reported in a majority of the reported cases. Candidemia was detected

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in only about half of those whose blood was cultured not only in the month after surgery but also more frequently later in the course of their endocarditis. In contrast, Candida precipitins have been found at some time in all of the Candida endocarditis patients who were tested serologically. Development of precipitins may signal the presence of Candida in the blood or tissues. It is not known whether it will prove possible to reduce the incidence of postcardiotomy Candida endocarditis by promptly treating patients who have early candidemia (and possibly those who have only positive precipitins) by means of low-dosage antifungal therapy. However, this seems plausible and remains to be proved. Present evidence indicates that the established infection requires surgical removal of the infected valves as well as institution of vigorous antifungal therapy. Monitoring such patients serologically at intervals after cardiac surgery may disclose early recurrence of infection. Early institution of appropriate therapy should improve the prognosis of Candida endocarditis. Addendum Other physical findings. Fishman and colIeaguest!? recently reported blurring of vision and evidence of candidal chorioretinitis in patients with candidemia. In their patients and in 1 of Louria and Dineen's" patients with endocarditis, who also developed candidal endophthalmitis, the condition cleared on therapy. Postmortem evidence of endophthalmic candidiasis has recently been reported by Bernhardt and associatestn in disseminated candidiasis, and it has been seen in patients with Candida-infected catheter sleeve thrombi and early implantation of Candida on the endocardium.ue Serologic testing was done by Walter Protzman (Schering Corporation, Bloomfield, N. J.) and by Phillip Goldberg and William Nouri (Pediatric Research Laboratory, Maimonides Research Center, Brooklyn, N. Y.). We would like to express our appreciation for data on unpublished cases, or for additional data on cases reported in brief, to the following physicians: F. O. Bowman, Presbyterian Hospital, College of Physicians and Surgeons, Columbia University, New York, N. Y.; J. Curtis, Beth Israel Hospital, New York, N. Y.; D. DeSilvey, ~ew York Hospital, Cornell Medical Center,

New York, N. Y.; L. Dexter, Peter Bent Brigham Hospital, Boston, Mass.; W. E. Dismukes, University of Alabama, Tuscaloosa, Ala.; E. Drouhet, Pasteur Institute, Paris, France; A. Garcia, Beth Israel Hospital, New York, N. Y.; P. D. Harris, Roosevelt Hospital, New York, and Presbyterian Hospital, College of Physicians and Surgeons, New York, N. Y.; F. R. Fekety, University Hospital, University of Michigan, Ann Arbor, Mich.; D. W. R. Mackenzie, New York Hospital, Cornell Medical Center, New York, N. Y.; H. G. Muchmore, University of Oklahoma Medical Center, Oklahoma City, Okla.; R. Roberts, New York Hospital, Cornell Medical Center, New York, N. Y.; F. Spencer, University Hospital, New York University Medical Center, New York, N. Y.; E. Tannenbaum, University Hospital, New York University Medical Center, New York, N. Y.; W. P. Young, University of Wisconsin Medical School, Madison, Wis. REFERENCES Seelig, M. S., Speth, C. P., Kozinn, P. 1., Toni, E. F., and Taschdjian, C. L.: Patterns of Candida Endocarditis: After Cardiac Surgery; Importance of Early Diagnosis and Therapy. To be published. 2 Koelle, W. A, and Pastor, B. H.: Candida Albicans Endocarditis After Aortic Valvulotomy, N. Eng\. J. Med. 225: 997, 1956. 3 Louria, D. B., and Dineen, P.: Amphotericin B in Treatment of Disseminated Moniliasis, J. A M. A 174: 273, 1960. 4 Andriole, V. T., Kravetz, H. M., Roberts, W. C., and Utz, J. P.: Candida Endocarditis: Clinical and Pathologic Studies, Am. J. Med. 32: 251, 1962. 5 Cooper, T., Morrow, A. G., Roberts, W. C., and Herman, L. G.: Postoperative Endocarditis Due to Candida: Clinical Observations and the Experimental Production of the Lesion, Surgery 50: 341, 1961. 6 Hyun, B. H., and Collier, F. C.: Mycotic Endocarditis Following Intracardiac Operations, N. Eng!. J. Med. 263: 1339, 1960. 7 Jamshidi, A., Pope, R. H., and Friedman, N. H.: Fungal Endocarditis Complicating Cardiac Surgery, Arch. Intern. Med. 112: 370, 1963. 8 Persellin, R. H., Haring, O. M., and Lewis, J. F.: Fungal Endocarditis Following Cardiac Surgery, Ann. Intern. Med. 54: 127, 1961. 9 Sanger, P. W., Taylor, F. H., Robicsek, F., Gerrnuth, F., Senterfit, L., and McKinnon, G.: Candida Infections as a Complication of Heart Surgery, 1. A M. A 181: 88, 1962. 10 Simmons, N. A., and Turner, P.: Candida Endocarditis After Cardiac Surgery, Br. Med. J. 2: 1041, 1963. 11 Newsom, S. W. B., Lee, W. R., and Reese,

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J. R.: Fatal Fungal Infections Following Open-Heart Surgery, Br. Heart J. 29: 457, 1967. 12 Freis, A.: Das Auftreten Septemischer Candida -Mykosen im Zusammenhang mit Grundkrankheit und Vorbehandlung, Arzneim. Forsch. 21: 320, 1971. 13 Climie, A. R. W., and Rachmaninoff, N.: Fungal (Candida) Endocarditis Following Open-Heart Surgery, J. THoRAc. CARDIOVASC. SURG. 50: 431, 1965. 14 Conway, N., Kothari, E. L., and Yacoub, M. H.: Candida Endocarditis After Heart Surgery, Thorax 23: 353, 1968. IS Murray, I. G., Buckley, H. R., and Turner, G. C.: Serological Evidence of Candida Infection After Open-Heart Surgery, J. Med. Microbio!. 2: 463, 1969. 16 McConnell, E. M., and Roberts, C.: Pathological Findings in Three Cases of Fungal Endocarditis Complicating Open-Heart Surgery, J. Clin. Patho!. 20: 555, 1967. 17 Unsigned: Heart Valve Hornografts Succumb to Candida. World Medicine, March 7, 1968, p. 23 (confirmed by personal communication from Temple). 18 Ratcliffe, J. G., and Pryce, D. M.: Disseminated Candidiasis Following Aortic Valve Homograft Replacement and Tracheotomy, J. Med. Microbio!. 112: 220, 1968. 19 Chaudhuri, M. F.: Fungal Endocarditis After Valve Replacements, J. THoRAc. CARDIOVASC. SURG. 60: 207, 1970. 20 Gonzalez-Lavin, L., Scappatura, E., Lise, M., and Roso, D. N.: Mycotic Aneurysms of the Aortic Root, Ann. Thorac. Surg. 9: 551, 1970. 21 Rothlin, M., Baumann, P. C., Ratti, R., and Senning, A.: Infektios Endokarditis nach Operationen am Herzen, Dtsch. Med. Wochenschr. 94: 750, 1969. 22 Grehl, T. M., Cohn, L. H., and Angell, W. W.: Management of Candida Endocarditis, J. THoRAc. CARDIOVASC. SURG. 63: 118, 1972. 23 Stein, P. D., Harken, D. E., and Dexter, L.: The Nature and Prevention of Prosthetic Valve Endocarditis, Am. Heart J. 71: 393, 1966. 24 Drouhet, E., and Duval, J.: Aspects biologiques des septicemies a candida. Etude mycologique de 55 souches de Candida isolees d'hemocultures, Bull. Soc. Fr. Myco!. Med. 13: 11, 1968. 25 Drouhet, E.: Yeasts Septicemia and Endocarditis. Mycological, Immunological and Therapeutic Aspects, Antonie van Leeuwenhoek 30: E 15, 1969 (Suppl.: Yeast Symposium). 26 Drouhet, E.: Chemotherapie et Immunologie des Candidases et des Aspergilloses Profondes.

Aspects Actuels des Mycoses Iatrogenes, Comptes Rendu Vo Congr. Soc. Internal. Myco!. Humaine et Animale, 1971, p. 297. 27 Drouhet, E.: Adaptation parasitaire des champignons opportunistes en pathologie humaine, Bull. Soc. Fr. Mycol, Med. 19: 3, 1971. 28 Bastin, R., Christol, D., Drouhet, E., DeGeorges, M., and Sicard, D.: Endocardites a Candide. A propos de 7 observations dont six chez des malades porteurs d'une prosthese valvulaire, Bull. Soc. Fr. Mycol, Med. 13: 13, 1968. 29 Sicard, D.: Les endocardites-fungiques. A propos de 8 observations personnelles. M.D. thesis. Faculte de Medecine de Paris, 1968. 30 Fekety, F. R., Cluff, L. E., Sabiston, D. C., Seidl, L. G., Smith, J. W., and Thoburn, R.: A Study of Antibiotic Prophylaxis in Cardiac Surgery, 1. THoRAc. CARDIOVASC. SURG. 57: 757, 1969. 31 Ostermiller, W. E., Dye, W. S., and Weinberg, M.: Fungal Endocarditis Following Cardiovascular Surgery, 1. THoRAc. CARDIOVASCo SURG. 61: 670, 1971. 32 Marsten, J. L., Greenberg, J. J., Piccinini, J. C., and Rywlin, A. M.: Aortitis Due to Candida Stellatoidia Developing in a Supravalvular Suture Line, Ann. Thorac. Surg. 7: 134, 1969. 33 Cheng, S., and Yu, L.: Candida Parapsilosis Endocarditis Following Heart Surgery: Case Report, Hawaii Med. J. 29: 637, 1970. 34 Toni, E. F., Seelig, M. S., Kozinn, P. J., and Taschdjian, C. L.: Candida Endocarditis: Pathology of Early and Atypical Forms With Record of Eight New Cases. To be published. 35 Carey, J. S., and Hughes, R.: Cardiac Valve Replacement for the Narcotic Addict, J. THoRAc. CARDIOVASC. SURG. 53: 663, 1967. 36 Watanakunakorn, c., Carleton, J., Goldberg, L. M., and Hamberger, M.: Candida Endocarditis Surrounding a Starr-Edwards Prosthetic Valve: Recovery of Candida in Hypertonic Medium During Treatment, Arch. Intern. Med. 121: 243, 1968. 37 Hairston, P., and Lee, W. H.: Mycotic (Fungal) Endocarditis After Cardiovascular Surgery, Am. Surg. 35: 135, 1969. 38 Hairston, P., and Lee, W. H.: Management of Infected Prosthetic Heart Valves, Ann. Thorac. Surg. 9: 229, 1970. 39 Vic-Dupont, V., Coulaud, J. P., and Delrieu, F.: Les septicemies a Candida. Aspects etiologiques, cliniques et therapeutiques d'apres 30 observations, Presse Med. 76: 747, 1968. 40 Record, C. 0., Skinner, 1. M., Sleight, P., and Speller, D. C. E.: Candida Endocarditis Treated With 5-Fluorocytosine, Br. Med. J. 1: 262, 1971.

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41 Warner, J. F., McGehee, F. R., Duma, R. J., Shadomy, S., and Utz, J. P.: 5-Fluorocytosine in Human Candidiasis, Antimicrob. Agents Chemother.-1970, 473, 1971. 42 Harrell, W. E.: The Antifungal Activity of 5-Fluorocytosine, Clin. Med. 78: 11, 1971. 43 Utz, J. P., Duma, R. J., McGehee, R. F., and Warner, J. F.: Chemotherapy of the Systemic Mycoses: Recent Clinical Observations. Comptes Rendu Vo Congr. Soc. Internal. Mycol, Humaine et Animala, 1971, pp. 292296. 44 Frater, F. W. M.: Discussion. Urgent OpenHeart Surgery for Endocarditis of Mitral Valve, N. Y. State J. Med. 71: 2651, 1971. 45 Wilson, R. M.: Candida Endocarditis, J. A M. A 177: 332, 1961. 46 Cohn, L. H., Roberts, W. c., Rockoff, S. D., and Morrow, A G.: Bacterial Endocarditis Following Aortic Valve Replacement, Circulation 33: 209, 1966. 47 Kay, J. H., Bernstein, S., Tsuji, H. K., Redington, J. V., Milgram, M., and Brem, T.: Surgical Treatment of Candida Endocarditis, J. A M. A. 203: 621, 1968. 48 Louria, D. B., Hensle, T., and Rose, J.: The Major Medical Complications of Heroin Addiction, Ann. Intern. Med. 67: 1, 1967. 49 Fass, F. J., and Perkins, R. L.: 5-Fluorocytocine in the Treatment of Cryptococcal and Candida Mycoses, Ann. Intern. Med. 74: 535, 1971. 50 Kloth, H., and Reed, G.: In preparation. 51 Harris, P. D., Yeoh, C. B., Breault, 1., Meltzer, J., and Katz, S.: Fungal Endocarditis Secondary to Drug Addiction: Recent Concepts in Diagnosis and Therapy, 1. THoRAc. CARDIOVASC. SURG. 63: 980, 1972. 52 Stanton, R. E., Lindesmith, G. G., and Meyer, B. W.: Escherichia Coli Endocarditis After Repair of Ventricular Septal Defects, N. Eng!. J. Med. 279: 737, 1968. 53 Lynfield, J., and Kozinn, P. J.: Successful Treatment of Candida Endocarditis Following Surgery for Transposition of the Great Arteries. To be published. 54 Davis, J. M., Moss, A J., and Schenk, E. A: Tricuspid Candida Endocarditis Complicating a Permanently Implanted Transvenous Pacemaker, Am. Heart J. 77: 818, 1969. 55 Young, W. P., Kroncke, G. M., Dacumos, G. C., Jr., and Rowe, G. G.: A Follow-up Study of Aortic Valve Homografts for Two to Four and One-half Years, Ann. Thorac. Surg. 12: 154, 1971. 56 Orvald, T. 0.: Discussion of Young et a!.55 57 LoGrippo, G. A., Overhulse, P. R., Szilagyi, E. E., and Hartman, F. W.: Procedure for Sterilization of Arterial Homografts With Betapropiolactone, Lab. Invest. 4: 217, 1955.

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58 Hairston, P., Manos, J. P., Graber, C. D., and Lee, W. H., Jr.: Alteration of Intrinsic Bactericidal Potential of Blood by Pump Oxygenator Perfusion, ill Norman, 1. C., Folkman, J., Hardison, W. G., Rudolf, L. E., and Verth, R. J., editors: Organ Perfusion and Preservation, New York, 1968, AppletonCentury-Crofts, Inc., pp. 911-928. 59 Hairston, P., Manos, J. P., Graber, C. D., and Lee, W. H., Jr.: Depression of Immunologic Surveillance by Pump Oxygenator Perfusion,1. Surg. Res. 9: 587, 1969. 60 Lee, W. H., Jr., Krumhaar, D., Fonkalsrud, E. W., Schjeide, D. A, and Maloney, J. V., Jr.: Denaturation of Plasma Proteins as a Cause of Morbidity and Death After Intracardiac Operations, Surgery 50: 29, 1961. 61 Pruitt, K. M., Stroud, R. M., and Scott, J. W.: Blood Damage in the Heart-Lung Machine, Proc. Soc. Exp. Bio!. Med. 137: 714, 1971. 62 Alexander, J. W., Hegg, M., and Altemeier, W. A.: Neutrophil Function in Selected Surgical Disorders, Ann. Surg. 168: 447, 1968. 63 Chilgren, R. A., Quie, P. G., Meuwissen, H. J., and Hong, R.: Chronic Mucocutaneous Candidiasis, Deficiency of Delayed Hypersensitivity, and Selective Local Antibody Defect, Lancet 2: 688, 1967. 64 Canales, L., Middlemas, R. 0., III, Lauro, J. M., and South, M. A: Immunologic Observations in Chronic Mucocutaneous Candidiasis, Lancet 2: 567, 1969. 65 Kirkpatrick, C. H., Rich, R. R., and Bennett, J. E.: Chronic Mucocutaneous Candidiasis: Model-building in Cellular Immunity, Ann. Intern. Med. 74: 955, 1971. 66 Louria, D. B.: Pathogenesis of Candidiasis, Antimicrob. Agents Chemotherap. 5: 417, 1965. 67 Hart, P. c, Russell, E., Jr., and Remington, J. S.: The Compromised Host and Infection. II. Deep Fungal Infection, J. Infect. Dis. 120: 169, 1969. 68 Anderson, A. 0., and Yardley, J. H.: Demonstration of Candida in Blood Smears, N. Eng!. J. Med. 286: 108, 1972. 69 Connett, M. C.: Fatal Septic Thrombophlebitis Due to Candida Albicans After Prolonged Antibiotic Therapy, Arch. Surg. 81: 726, 1960. 70 Dennis, D., Miller, M. J., and Peterson, C. G.: Candida Septicemia, Surg. Gynecol, Obstet. 119: 520, 1964. 71 Smits, H., and Freemand, L. R.: Prolonged Venous Catheterization as a Cause of Sepsis, N. Eng!. J. Med. 276: 1229, 1967. 72 Louria, D. B., Blevins, A., Armstrong, D., Burdick, R. J., and Lieberman, P.: Fungemia Caused by Non-pathogenic Yeasts, Arch. Intern. Med. 119: 247, 1967.

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73 Kozinn, P. J., Taschdjian, C. 1.., Seelig, M. S., Caroline, 1.., and Teitler, A: Diagnosis and Therapy of Systemic Candidiasis, Sabouraudia 7: 98, 1969 (Part 2). 74 Louria, D. B., Stiff, D. 1'., and Bennett, B.: Disseminated Moniliasis in the Adult, Medicine 41: 307, 1962. 75 Soler-Bechara, J., Soscia, J. 1.., Kennedy, R. J., and Grace, W. J.: Candida Endocarditis, Am. J. Cardiol. 13: 820, 1964. 76 Utz, J. P., Roberts, W. C., Cooper, 1'., Kravetz, H. M., and Andriole, V. 1'.: Candida Endocarditis: An Emerging Peril in Cardiovascular Surgery, Ann. Intern. Med. 54: 1058, 1961. 77 Seelig, M. S.: The Role of Antibiotics in the Pathogenesis of Candida Infections, Am. J. Med. 40: 887, 1966. 78 Seelig, M. S.: The Rationale for Preventing Antibacterial-induced Fungal Overgrowth, Med. Times 96: 689, 1968. 79 Seelig, M. S.: Mechanisms by Which Antibiotics Increase the Incidence and Severity of Candidiasis and Alter the Immunological Defenses, Bacteriol. Rev. 30: 442, 1966. 80 Lerner, P. I., and Weinstein, 1..: Infective Endocarditis in the Antibiotic Era, N. Engl. J. Med. 274: 199, 1966. 81 Tumulty, P. A: Management of Bacterial Endocarditis, Geriatrics 22: 122, 1967. 82 Merchant, R. K., Louria, D. B., Geisler, Y. H., Edgcomb, J. H., and Utz, J. P.: Fungal Endocarditis and Report of Three Cases, Ann. Intern. Med. 48: 242, 1958. 83 Kay, J. H., Bernstein, S., Feinstein, D., and Biddle, M.: Surgical Cure of Candida Albicans Endocarditis With Open-Heart Surgery, N. Engl. J. Med. 264: 907, 1961. 84 Taschdjian, C. 1.., Dobkin, G. B., Caroline, L., and Kozinn, P. J.: Immune Studies Relating to Candidiasis. II. Experimental and Preliminary Clinical Studies on Antibody Formation in Systemic Candidiasis, Sabouraudia 3: 129, 1964 (Part 2). 85 Taschdjian, C. 1.., Kozinn, P. J., and Caroline, 1..: Immune Studies in Candidiasis. III. Precipitating Antibodies in Systemic Candidiasis, Sabouraudia 3: 312, 1964 (Part 4). 86 Taschdjian, C. 1.., Kozinn, P. J., Okas, A, Caroline, 1.., and Halle, M. A.: Serodiagnosis of Systemic Candidiasis, J. Infect. Dis. 117: 180, 1967. 87 Taschdjian, C. 1.., Cuesta, M. B., Kozinn, P. J., and Caroline, 1..: A Modified Antigen for Serodiagnosis of Systemic Candidiasis, Am. J. Clin. Pathol. 52: 468, 1969. 88 Taschdjian, C. 1.., Kozinn, P. J., Fink, H., Cuesta, M. B., Caroline, 1.., and Kantrowitz, A. B.: Post-mortem Studies of Systemic

Candidiasis. I. Diagnostic Validity of Precipitin Reaction and Probable Origin of Sensitization to Cytoplasmic Candidal Antigens, Sabouraudia 7: 110, 1969 (Part 2). 89 Taschdjian, C. 1.., Toni, E. F., Hsu, K. c., Seelig, M. S., Cuesta, M. B., and Kozinn, P. J.: Immunofluorescence of Candida in Human Reticulo-endothelial Phagocytes. Implications for Immunogenesis and Pathogenesis of Systemic Candidiasis, Am. J. Clin, Pathol. 56: 50, 1971. 90 Taschdjian, C. 1.., Kozinn, P. J., Cuesta, M. B., and Toni, E. F.: Serodiagnosis of Candidal Infection, Am. J. Clin. Pathol. 57: 195, 1972. 91 Stallybrass, F. C.: Candida Precipitins, 1. Pathol. 87: 89, 1964. 92 Murray, I. G., and Buckley, H. R.: Serological Study of Candida Species, in Winner, H. I., and Hurley, R., editors: Symposium on Candida Infection, Edinburgh and London, 1966, E. & S. Livingstone, Ltd., pp. 44-51. 93 Portnoy, J., Wolf, P. 1.., Webb, M., and Remington, J. S.: Candida Blastospores and Pseudohyphae in Blood Smears, N. Engl. J. Med. 285: 1010, 1971. 94 Remington, J. S., Gaines, 1. D., and Gilmer, M. A: Demonstration of Candida Precipitins by Counterimmune-electrophoresis, Lancet 1: 413, 1972. 95 Stickle, D., Kaufman, 1.., Blumer, S. 0., and McLaughlin, D. W.: Comparison of a Newly Developed Latex Agglutination Test and an Immunodiffusion Test in the Diagnosis of Systemic Candidiasis, Appl. Microbiol. 23: 490, 1972. 96 Wise, G. B., Wainstein, S., Goldberg, P., and Kozinn, P. J.: Candida Cystitis: Management by Continuous Bladder Irrigation of Amphotericin B. To be published. 97 Brennan, M. F., Goldman, H. H., O'Connell, R. C., Knudsin, R. B., and Moore, F. D.: Prolonged Parenteral Alimentation: Candida Growth and the Prevention of Candidemia by Amphotericin Instillation, Ann. Surg, 176: 265, 1972. 98 Kilburn, K. H.: The Innocuousness and Possible Therapeutic Use of Aerosol Amphotericin B, Am. Rev. Resp. Dis. 80: 441, 1959. 99 Ellis, C. A, and Spivack, M. 1..: The Significance of Candidemia, Ann. Intern. Med. 67: 511, 1967. tOO Unsigned editorial: Candidiasis: Colonization vs. Infection, J. A M. A. 215: 285, 1971. 101 Toala, P., Schroeder, S. A, Daly, A K., and Finland, H.: Candida at Boston City Hospital, Arch. Intern. Med. 126: 983, 1970. 102 Kozinn, P. J., and Taschdjian, C. 1..: Candida and Candidiasis, J. A M. A 217: 965, 1971.

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103 Kozinn, P. J., and Degenshein, G.: Treatment of Candida Infection, Arch. Intern. Med. 128: 639, 1971. 104 Medoff, G., Dismukes, W. E., Meade, R. H., and Moses, J.: Therapeutic Programs for Candida Infection, Antimicrob. Agents Chemother.-1970, 286, 1971. 105 Seabury, J. H., and Dascomb, H. E.: Experience with Amphotericin B, Ann. N. Y. Acad. Sci. 89: 202, 1960. 106 Hellebush, A. A., Salama, F., and Eadie, E.: The Use of Mannitol to Reduce the Nephrotoxicity of Amphotericin B, Surg. Gynecol. Obstet. 134: 241, 1972. 107 Shadomy, S.: In Vitro Studies With 5-Fluorocytosine, Appl. Microbiol. 17: 871, 1969. 108 Medoff, G., Comfort, M., and Kobayashi, G. S.: Synergistic Action of Amphotericin B and 5-Fiuorocytosine Against Yeast-like

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Organism, Proc. Soc. Exp. BioI. Med. 138: 571, 1971. Unsigned editorial: Fungal Septicemia Complicating Intravenous Hyperalimentation, Lancet 1: 27, 1972. Fishman, L. S., Griffin, J. R., Sapico, F. L., and Hecht, R.: Hematogenous Candida Endophthalmitis: A Complication of Candidemia, N. Engl. J. Med. 286: 675, 1972. Bernhardt, H. E., Orlando, J. C., Benfield, J. R., Hirose, F. M., and Foos, R. Y.: Disseminated Candidiasis in Surgical Patients, Surg. Gynecol. Obstet. 134: 819, 1972. Seelig, M. S., Kozinn, P. J., Anderson, A. 0., Holzman, R. C., Strauss, R. A., Merz, W., and Speth, C. P.: Candida Endocarditis and Acute Candidiasis After Gastrointestinal Surgery. To be published.