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Candida endocarditis with femoral emboli
Candida endocarditis with femoral emboli Treatment with surgery and 5-fluorocytosine A case of primary Candida endocarditis with massive embolization of mycotic material to the vessels of the legs is presented. Treatment by bilateral femoral embolectomies, early aortic valve replacement by a fresh-frozen stented homograft, and intensive medical therapy with 5-fluorocytosine was successful. Despite an early perivalvular leak requiring valve replacement with another homograft, the patient survived. The Candida growth was controlled with initial treatment. The successful outcome in this patient would seem to strengthen further the case for an early aggressive surgical approach in combination with antifungal therapy.
Norton T. Montague, M.D., and W. L. Sugg, M.D., Dallas, Texas
Candida endocarditis is a highly lethal disease. Kay and associates,' in reviewing the English literature, found that 6 of 52 patients have survived, for a mortality rate of 89 per cent. He reported the first success with surgery after failure with antibiotic therapy in 1961" and then reported 3 operative cases with two additional cures.' Grehl" recently reported on a patient who survived after an aggressive surgical approach was used; he also mentioned a second operative survivor and a third patient who died after surgery. Because of the rather unusual presentation and successful outcome in our patient, the following case is reported. Case report C. H., a 49-year-old Caucasian man, was admitted to the Dallas Veterans Administration Hospital for the third time on Sept. 18, 1971. His chief complaint was pain in the legs of 3 hours' duration associated with coolness, discoloration, and diminished muscle strength. Three days prior to admission he had had chills and fever for 2 days and developed a very sore right From the Division of Thoracic and Cardiovascular Surgery, Department of Surgery, The University of Texas Health Science Center, 5323 Harry Hines Blvd., Dallas, Texas 75235, and the Veterans Administration Hospital, 4500 S. Lancaster Road, Dallas, Texas 75216. Received for publication July 20, 1973.
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second finger tip which subsided after 1 day. The day before admission he developed sore wrists without, swelling or redness, that spontaneously subsided. He had noted increasing weakness, lassitude, and frequent headaches the previous week. On admission he appeared pale and acutely ill. Blood pressure was 160170 mm. Hg, pulse 90 beats per minute and regular, temperature 100° F., respiration 16 breaths per minute, weight 68 kilograms, and height 72 inches. Examination of the right eyelid showed two small petechiae. Results of fundoscopy were normal. The chest and lung fields, except for scattered basilar rales, were normal. There was a Grade 3/6 blowing holodiastolic murmur heard best along the left sternal border radiating to the apex. The first heart sound was crisp. There was no gallop, rub, or thrill. Examination of the abdomen was unremarkable. Both legs were blanched and mottled below the knee with poor capillary filling on the right and none on the left. Sensation and range of motion were satisfactory, but strength in the feet and toes was diminished. Femoral pulses were present, but none below this level was palpable. Laboratory examination showed a white blood count of 14,100 with 63 segments, 2 metamyelocytes, 27 band cells, and 8 lymphocytes. The hemoglobin value was 9.8 mg. per cent, hematocrit 32 volumes per cent, platelet count 175,000, and prothrombin time 14 seconds (12 second control); urinalysis yielded normal findings. Serum sodium, potassium, bicarbonate, chloride, blood urea nitrogen, glucose, creatinine, total bilirubin, serum glutamic oxaloacetic transaminase, alkaline
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phosphatase, total protein, albumin, and cholesterol were within normal limits. Serum calcium was 8.2 mg. per cent and later became normal. The electrocardiogram showed varying first and second degree heart block. The chest x-ray film (Fig. 1) was normal except for slight enlargement in the cardiac shadow. Past history disclosed neither rheumatic fever nor heart disease. One admission in January, 1971, after prolonged alcohol abuse , resulted in a laparotomy at which time evidence of pancreatitis and an immature pancreatic pseudocyst was found . He received rather extensive medication with Keflin, tetracycline, and kanamycin during this hospitalization and was hyperalimented intravenously with a subclavian catheter. On February 25, during a febrile episode, blood , urine, and the central venous catheter were cultured and grew Candida spp. No specific antifungal treatment was given, but the central venou s catheter was removed and all antibiotics were discontinued when the culture reports were received . Repeat blood, urine, and sternal marrow cultures were negative. He recovered from the pancreatitis, having no further septic episodes, and was discharged on March 16. The patient was readmitted on April 21, 1971, for elective decompression of a chronic pancreatic pseudocyst by Roux-en-Y cyst jejunostomy. He developed a staphylococcal wound infection which was managed by local wound care and methicillin. Cultures of blood, urine, and sputum were negative for Candida. He was discharged on May 14 and remained well until the present illness. Soon after this admission, bilateral femoral embolectomies with local anesthesia and regional hepar inization were done via a balloon catheter. The left common femoral artery was filled with clot and a crumbly gray-white embolic material. Large amounts of fresh clot and embolus were recovered from the profunda and superficial femoral vessels. There was a smaller amount on the right side but similar in distribution. Postoperatively, the peripheral pulses were excellent, but the left calf became extremely tense and required fasciotomy of the anterior and posterior compartments. However, persistent foot drop resulted. Antibiotic coverage with methicillin was used initially. Amphotericin B, 20 mg. intravenously, was begun after smears of the embolic material revealed budding yeast with hyphae (Fig . 2). Cultures grew Candida tropicalis as did blood cultures. Urine and sputum cultures were sterile. Postoperatively, he developed cardiac failure, requiring digitalis. He developed petechiae over the dorsum of both hands and a splinter hemorrhage under the left fourth nail. Further deterioration ensued with development of a systolic murmur, arrh ythmas, and clinically decreasing cardiac output that could not be med ically managed. On the second hospital day the aortic valve was re-
....._ -9-18-7/ - - -_ ... Fig. 1. Admission chest x-ray film, Sept. 18, 1971, shows slight cardiomegaly. The pat ient had femor emboli and endocarditis on admission.
placed with a No . 10 fresh-frozen stented homograft valve. At operation there was almost complete destruction of the right and noncoronary cusps by the fungus. The infection had extended into the annulus at the midportion of the non coronary cusp. This could not be completely excised, but as much of the vegetation was removed as possible. Local application of amphotericin B was not used. His operative and postoperative courses were uneventful except for a wound seroma. Staphcillin was continued for 7 days postoperatively. The day after the operation, 5fluorocytosine, I Gm. orally every 6 hours , was begun and continued for 3 months. Amphotericin B was stopped. During the remainder of his hospital course, numerous cultures were taken from various sites and none grew Candida after the aortic valve repl acement. Microscopic examination of the resected aortic valve showed destruction by colonies of yeast with hyphae (F ig. 3). The pat ient was discharged on November 8, without evidence of cardiac failure, taking Lanoxin 0.25 mg. daily and 5-fiuorocytosine. There was a Grade 3/6 aortic systolic murmur but no diastolic murmur. Ten days later a Grade 3/6 holodiastolic murmur of aortic insufficiency was noted, and he was admitted for evaluation of valvular function and possible recurrence of Candida endocarditis. There was no change in the patient's functional tolerance, and he was asymptomatic. Vital signs were unchanged. All cultures were negat ive for Candida, and bactericidal levels of 5-fiuorocytosine were adequate. Electronmyography revealed return of left peroneal nerve function. He was discharged on November 24.
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Fig. 2. Smear of embolic material to the femoral arteries shows budding yeast with hyphae .
Fig. JA. Low-power photomicrograph of Candida-infected aortic valve leaflet, removed Sept. 20, 1971, shows valve invasion and destruction (Giemsa stains). On March 14, 1972, he was admitted for congestive heart failure with pedal edema, severe orthopnea, nocturnal dyspnea, hepatomegaly, rales, and the previously described murmurs (Fig. 4) . Cultures remained sterile . As he responded to diuretics, a diuret ic with potas sium chloride supplementation was added to Lanox in as an outpatient medication. He was again admitted for congestive heart failure and right pleur al effusion in August , 1972, responding to thoracocentesis and diuretics. Again, cultures for Candida were sterile. His sixth admission on Sept. 27, 1972, was for dysuria and hematuria caused by cystitis and prostatitis. Escherichia coli was cultured from the urine, but Candida could not be cultured. He responded to ampicillin and was discharged on Oct. 4, 1972. Because of increasing symptoms of cardiac failure, despite add itional outpatient diuretic therapy, he was readmitted for a seventh time on Oct. 27, 1972. Increasing his diuretic therapy and fur-
ther restricting salt intake resulted in some improvement in symptoms. On October 31, cardiac catheterization showed a large degree of aortic insufficiency. Pressures measured are seen in Table I. On Nov. 6, 1972, the aortic homograft valve was replaced with another No. to stented homograft valve. At operation there was an extensive perivalvular leak in the area of the noncoronary cusp, as well as partial destruction of the left coronary cusp of the homograft. There was no evidence of fungal vegetations, and cultures of the -valve were sterile for fungi and bacteria . His postoperative course was complicated by bleeding from several areas in the aortic suture line, necessitating reoperation and resulting in slow recovery. He was discharged on December 2, taking only digoxin .25 mg. daily, with no symptoms of cardiac failure. Since discharge , he has done well without symptoms of failure. His cardiac silhouette on roentgenography has diminished in size, and he no longer has a pleural effusion (Fig.
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5). He has no significant murmur of aortic insufficiency.
Discussion Candidiasis in this patient most likely originated during the first admission, when he had a septic episode while being parenterally alimented by a subclavian central venous catheter. This cannot be definitely proved, because the species of Candida was not determined during the first hospitalization. Candida sepsis, as a complication of parenteral alimentation catheters, is well recognized. Certain predisposing factors are generally present, such as Candida infections elsewhere, use of broad-spectrum antibiotics, steroid therapy, antimetabolites, and lymphoproliferative diseases.':" This man had been given long-term antibiotics (Keflin, Kantrex, and tetracycline) prior to development of candidemia. The management of Candida septicemia secondary to catheters is removal of the central venous catheter. Whether antifungal chemotherapy is necessary is debatable as there have been several reports in which the infection cleared after removal of the catheter.r-" Ellis" encouraged removal of indwelling venous and urinary catheters when candidemia is found, as well as discontinuance of antibiotics, steroids , and antimetabolites whenever possible. He suggested that no specific antifungal therapy be started so long as the patient's clinical condition is improving and a careful search gives no evidence of tissue infection. However, if his condition is deteriorating at the time positive blood cultures are reported, then antifungal therapy should be considered promptly in addition to the above nonspecific measures. It appears that our patient had no more than a transient candidemia on his first admission, responding to withdrawal of both the catheter and antibiotics, as there was no evidence of Candida on subsequent cultures during his first and second admissions. Large emboli to major vessels are a common complication in patients with Candida endocarditis. The incidence of embolization to specific vessels seems to parallel that of
Fig. 3B. High-power view. For legend, see Fig. 3A.
Table I. Cardiac catheterization data (Oct. 31 , 1972) Pressure Site
Right atrium (mean) Pulmonary artery (mean) Pulmonary capillary wedge Left ventricle LVEDP (mean)
(mm. Hg)
7 40
22
160/40 40
Legend: Left ventricular end-diastolic pressure.
emboli from the left side of the heart, being most common in the vessels of the iliofemoral region, brain , and kidneys and also involving the arterial supply of the arms, abdominal viscera, and even the pulmonary artery from tricuspid and right ventricular endocarditis ." Large vessel embolization reflects the large size and friability of the mycotic vegetations. Prior attempts at embolectomy for mycotic emboli have generally been unsuccessful. However, in most cases the procedure had not been done early.' Early embolectomy, as the present case
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3-8-72 Fig. 4. Chest x-ray film approximately 6 months after aortic valve replacement for endocarditis, taken just prior to admission for congestive heart failure.
demonstrates, can result in patent vessels and viable extremities. Seelig,l1 in reviewing Candida endocarditis after cardiac surgery, found no survivors in patients developing early major emboli. The treatment of our patient for endocarditis was a combination of intensive medical management with an aggressive surgical approach. Initial coverage with amphotericin B was changed to 5-fluorocytosine because of fear of the toxic effects of amphotericin B, especially on renal function. The dosage of 5-fluorocytosine in this patient was approximately 60 mg. per kilogram. The decision to replace the aortic valve early in the course was based on two facts: ( 1) the rapid deterioration of the cardiovascular hemodynamics due to aortic valve disruption primarily' > and (2) our belief that nothing short of removal of the mycotic vegetations would prevent further emboli. Selection of the fresh-frozen stented homograft valve avoided anticoagulation in the postoperative period. The perivalvular leak occurred early in the patient's postoperative course and later proved to be in the area where the mycotic process involved the annulus. This was hemodynamically insignificant initially but later required valve replacement. On
Fig. 5. Chest x-ray film, taken approximately 3 months after aortic homograft replacement for perivalvular leak, shows marked reduction in the heart size.
none of the numerous cultures after the first valve replacement, as well as examination microscopically and culture of the replaced homograft valve, were Candida organisms demonstrated. The use of 5-fluorocytosine in Candida infections has been reported recently. Record' > reported its use in 3 patients with Candida infections of prosthetic valves and in 1 with aortic insufficiency and candidemia who was suspected of having Candida endocarditis. Two patients died. One of them had resistant Candida albicans on a prosthetic aortic valve. In another, who died ]9 days after removal of an infected mitral prosthetic valve, no viable organisms were recovered at autopsy. The third patient survived without surgical intervention. Greenberg> described ]4 patients with systemic candidiasis who were treated with 5-fluorocytosine; 9 had unequivocably favorable responses and 5 had improvement. Five of these patients had been refractory to amphotericin B. Fass'" reported the combined use of amphotericin Band 5-fluorocytosine with surgery in a surviving patient who had an infected Starr-Edwards valve. Logan' ? reported on a patient with Candida endocarditis following Streptococcus viridans en-
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docarditis who was treated for 6 months with 5-fluorocytosine in therapeutic doses. At 6 months the Candida organism became resistant to the drug, and the patient soon died of aortic valve rupture. Adverse reactions ascribed to 5-fluorocytosine are apparently not severe and include rash, anemia, leukopenia, and alteration of liver en-
zymes.'":" The mortality rate for patients with Candida endocarditis treated only by antifungal agents is greater than 80 per cent. There are 4 survivors who were treated with amphotericin B alone and I who was treated with parenteral Mycostatin, which is no longer commercially available." The choice of valve replacement does not seem to influence survival. Two prior survivors of primary Candida endocarditis had aortic valves replacement with Magovern ball valves, usually with the silicone rubber or Ivalon cuff removed. 1 Patients with prosthetic valves infected by Candida have had valves replaced with the Magovern-Cromie valve with the cuff removed" as well as with Starr-Edwards valves." 15. IS Suture material has been reported in only two instances,': H in which monofilament wire was used. In the present case, Ti-Cron suture material was used to affix the valve and fine silk to repair the aortotomy. The importance of removing as much of the vegetative process as possible, even if it cannot be excised completely, has been stressed. Hairston" reported I case in which the infected prosthetic valve was left in place and only debridement of the mycotic vegetations was carried out, resulting in apparent cure with concomitant amphotericin B therapy.
REFERENCES 1 Kay, I. H., Bernstein, S., Tsuji, H. K., Redington, I. V., Milgram, M., and Beam, T.: Surgical Treatment of Candida Endocarditis, I. A. M. A 203: 105, 1968. 2 Kay, I. H., Bernstein, S., Feinstein, D., and Biddle, M.: Surgical Cure of Candida albicans Endocarditis With Open-Heart Surgery, N. Engl. I. Med. 264: 907, 1961. 3 Grehl, T. M., Cohn, L. H., and Angell, W.
W.: Management of Candida Endocarditis, I. THORAC. CARDOVASC. SURG. 63: 118, 1972. 4 Andriole, V. T., Krauetz, H. M., Roberts, W. C., and Utz, I. P.: Candida Endocarditis: Clinical and Pathologic Studies, Am. I. Med. 32: 251, 1962. 5 Harrel, E. R., and Thompson, G. R.: Systemic Candidiasis (Moniliasis) Complicating Treatment of Bacterial Endocarditis, With Review of Literature and Report of Apparent Cure of One Case With Parenteral Mycostatin, Ann. Intern. Med. 49: 207, 1958. 6 Ellis, C. A, and Spivak, M. L.: The Significance of Candidemia, Ann. Intern. Med. 67: 511, 1967. 7 Groff, D. B.: Complication of Intravenous Hyperalimentation in Newborn and Infants, I. Pediatr. Surg. 4: 460, 1969. 8 Das, I. B., Filler, A M., Rubin, V. G., et al.: Intravenous Amino Acid-Dextrose Feeding: The Metabolic Response in the Surgical Neonate, I. Pediat. Surg. To be published. 9 Boeckman, C. R., and Krill, C. E.: Bacterial and Fungal Infections Complicating Parenteral Alimentation in Infants and Children, I. Pediatr. Surg. 5: 117, 1970. 10 Ashcraft, K. W., and Leape, L. L.: Candida Sepsis Complicating Parenteral Feeding, I. A M. A. 212: 454, 1970. 11 Seelig, M. S., Speth, C. P., Kozinn, P. I., Toni, E. F., and Taschdjian, C. L.: Candida Endocarditis After Cardiac Surgery, J. THORAC. CARDIOVASC. SURG. 65: 583, 1973. 12 Wilson, L. C., Wilcox, B. R., Sugg, W. L., and Peters, R. M.: Valvar Regurgitation in Acute Infective Endocarditis: Early Replacement, Arch. Surg. 101: 756, 1970. 13 Record, C. 0., Skinner, I. M., Sleight, P., and Speller, D. C. E.: Candida Endocarditis Treated With 5-Fluorocytosine, Br. Med. I. 1: 262, 1971. 14 Greenberg, E., Prince, H. N., and Utz, I. P.: Observation on the Activity of Two Newer Anti-fungal Agents: Saramycetin (X-5079C) and 5-Fluorocytosine. Fifth International Congress of Chemotherapy, Vienna, Austria, June 26 to July 1, 1967, p. 69. 15 Fass, R. I., and Perkins, R. L.: 5-Fluorocytosine in the Treatment of Cryptococcal and Candida Mycoses, Ann. Intern. Med. 74: 535, 1971. 16 Logan, R. L.: C. albicans Resistance to 5Fluorocytosine, Br. Med. I. 3: 531, 1972. 17 Utz, I. P., Tynes, B. S., Shadony, H. I., et al.: 5-Fluorocytosine in Human Cryptococcosis, Antimicrob. Agents Chemother. 9: 344, 1968. 18 Hairston, P., and Lee, W. H., Jr.: Management of Infected Prosthetic Heart Valves, Ann. Thorac. Surg. 9: 229, 1970.
Norton T. Montague, M.D., and W. L. Sugg, M.D., Dallas, Texas
Candida endocarditis is a highly lethal disease. Kay and associates,' in reviewing the English literature, found that 6 of 52 patients have survived, for a mortality rate of 89 per cent. He reported the first success with surgery after failure with antibiotic therapy in 1961" and then reported 3 operative cases with two additional cures.' Grehl" recently reported on a patient who survived after an aggressive surgical approach was used; he also mentioned a second operative survivor and a third patient who died after surgery. Because of the rather unusual presentation and successful outcome in our patient, the following case is reported. Case report C. H., a 49-year-old Caucasian man, was admitted to the Dallas Veterans Administration Hospital for the third time on Sept. 18, 1971. His chief complaint was pain in the legs of 3 hours' duration associated with coolness, discoloration, and diminished muscle strength. Three days prior to admission he had had chills and fever for 2 days and developed a very sore right From the Division of Thoracic and Cardiovascular Surgery, Department of Surgery, The University of Texas Health Science Center, 5323 Harry Hines Blvd., Dallas, Texas 75235, and the Veterans Administration Hospital, 4500 S. Lancaster Road, Dallas, Texas 75216. Received for publication July 20, 1973.
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second finger tip which subsided after 1 day. The day before admission he developed sore wrists without, swelling or redness, that spontaneously subsided. He had noted increasing weakness, lassitude, and frequent headaches the previous week. On admission he appeared pale and acutely ill. Blood pressure was 160170 mm. Hg, pulse 90 beats per minute and regular, temperature 100° F., respiration 16 breaths per minute, weight 68 kilograms, and height 72 inches. Examination of the right eyelid showed two small petechiae. Results of fundoscopy were normal. The chest and lung fields, except for scattered basilar rales, were normal. There was a Grade 3/6 blowing holodiastolic murmur heard best along the left sternal border radiating to the apex. The first heart sound was crisp. There was no gallop, rub, or thrill. Examination of the abdomen was unremarkable. Both legs were blanched and mottled below the knee with poor capillary filling on the right and none on the left. Sensation and range of motion were satisfactory, but strength in the feet and toes was diminished. Femoral pulses were present, but none below this level was palpable. Laboratory examination showed a white blood count of 14,100 with 63 segments, 2 metamyelocytes, 27 band cells, and 8 lymphocytes. The hemoglobin value was 9.8 mg. per cent, hematocrit 32 volumes per cent, platelet count 175,000, and prothrombin time 14 seconds (12 second control); urinalysis yielded normal findings. Serum sodium, potassium, bicarbonate, chloride, blood urea nitrogen, glucose, creatinine, total bilirubin, serum glutamic oxaloacetic transaminase, alkaline
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phosphatase, total protein, albumin, and cholesterol were within normal limits. Serum calcium was 8.2 mg. per cent and later became normal. The electrocardiogram showed varying first and second degree heart block. The chest x-ray film (Fig. 1) was normal except for slight enlargement in the cardiac shadow. Past history disclosed neither rheumatic fever nor heart disease. One admission in January, 1971, after prolonged alcohol abuse , resulted in a laparotomy at which time evidence of pancreatitis and an immature pancreatic pseudocyst was found . He received rather extensive medication with Keflin, tetracycline, and kanamycin during this hospitalization and was hyperalimented intravenously with a subclavian catheter. On February 25, during a febrile episode, blood , urine, and the central venous catheter were cultured and grew Candida spp. No specific antifungal treatment was given, but the central venou s catheter was removed and all antibiotics were discontinued when the culture reports were received . Repeat blood, urine, and sternal marrow cultures were negative. He recovered from the pancreatitis, having no further septic episodes, and was discharged on March 16. The patient was readmitted on April 21, 1971, for elective decompression of a chronic pancreatic pseudocyst by Roux-en-Y cyst jejunostomy. He developed a staphylococcal wound infection which was managed by local wound care and methicillin. Cultures of blood, urine, and sputum were negative for Candida. He was discharged on May 14 and remained well until the present illness. Soon after this admission, bilateral femoral embolectomies with local anesthesia and regional hepar inization were done via a balloon catheter. The left common femoral artery was filled with clot and a crumbly gray-white embolic material. Large amounts of fresh clot and embolus were recovered from the profunda and superficial femoral vessels. There was a smaller amount on the right side but similar in distribution. Postoperatively, the peripheral pulses were excellent, but the left calf became extremely tense and required fasciotomy of the anterior and posterior compartments. However, persistent foot drop resulted. Antibiotic coverage with methicillin was used initially. Amphotericin B, 20 mg. intravenously, was begun after smears of the embolic material revealed budding yeast with hyphae (Fig . 2). Cultures grew Candida tropicalis as did blood cultures. Urine and sputum cultures were sterile. Postoperatively, he developed cardiac failure, requiring digitalis. He developed petechiae over the dorsum of both hands and a splinter hemorrhage under the left fourth nail. Further deterioration ensued with development of a systolic murmur, arrh ythmas, and clinically decreasing cardiac output that could not be med ically managed. On the second hospital day the aortic valve was re-
....._ -9-18-7/ - - -_ ... Fig. 1. Admission chest x-ray film, Sept. 18, 1971, shows slight cardiomegaly. The pat ient had femor emboli and endocarditis on admission.
placed with a No . 10 fresh-frozen stented homograft valve. At operation there was almost complete destruction of the right and noncoronary cusps by the fungus. The infection had extended into the annulus at the midportion of the non coronary cusp. This could not be completely excised, but as much of the vegetation was removed as possible. Local application of amphotericin B was not used. His operative and postoperative courses were uneventful except for a wound seroma. Staphcillin was continued for 7 days postoperatively. The day after the operation, 5fluorocytosine, I Gm. orally every 6 hours , was begun and continued for 3 months. Amphotericin B was stopped. During the remainder of his hospital course, numerous cultures were taken from various sites and none grew Candida after the aortic valve repl acement. Microscopic examination of the resected aortic valve showed destruction by colonies of yeast with hyphae (F ig. 3). The pat ient was discharged on November 8, without evidence of cardiac failure, taking Lanoxin 0.25 mg. daily and 5-fiuorocytosine. There was a Grade 3/6 aortic systolic murmur but no diastolic murmur. Ten days later a Grade 3/6 holodiastolic murmur of aortic insufficiency was noted, and he was admitted for evaluation of valvular function and possible recurrence of Candida endocarditis. There was no change in the patient's functional tolerance, and he was asymptomatic. Vital signs were unchanged. All cultures were negat ive for Candida, and bactericidal levels of 5-fiuorocytosine were adequate. Electronmyography revealed return of left peroneal nerve function. He was discharged on November 24.
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Fig. 2. Smear of embolic material to the femoral arteries shows budding yeast with hyphae .
Fig. JA. Low-power photomicrograph of Candida-infected aortic valve leaflet, removed Sept. 20, 1971, shows valve invasion and destruction (Giemsa stains). On March 14, 1972, he was admitted for congestive heart failure with pedal edema, severe orthopnea, nocturnal dyspnea, hepatomegaly, rales, and the previously described murmurs (Fig. 4) . Cultures remained sterile . As he responded to diuretics, a diuret ic with potas sium chloride supplementation was added to Lanox in as an outpatient medication. He was again admitted for congestive heart failure and right pleur al effusion in August , 1972, responding to thoracocentesis and diuretics. Again, cultures for Candida were sterile. His sixth admission on Sept. 27, 1972, was for dysuria and hematuria caused by cystitis and prostatitis. Escherichia coli was cultured from the urine, but Candida could not be cultured. He responded to ampicillin and was discharged on Oct. 4, 1972. Because of increasing symptoms of cardiac failure, despite add itional outpatient diuretic therapy, he was readmitted for a seventh time on Oct. 27, 1972. Increasing his diuretic therapy and fur-
ther restricting salt intake resulted in some improvement in symptoms. On October 31, cardiac catheterization showed a large degree of aortic insufficiency. Pressures measured are seen in Table I. On Nov. 6, 1972, the aortic homograft valve was replaced with another No. to stented homograft valve. At operation there was an extensive perivalvular leak in the area of the noncoronary cusp, as well as partial destruction of the left coronary cusp of the homograft. There was no evidence of fungal vegetations, and cultures of the -valve were sterile for fungi and bacteria . His postoperative course was complicated by bleeding from several areas in the aortic suture line, necessitating reoperation and resulting in slow recovery. He was discharged on December 2, taking only digoxin .25 mg. daily, with no symptoms of cardiac failure. Since discharge , he has done well without symptoms of failure. His cardiac silhouette on roentgenography has diminished in size, and he no longer has a pleural effusion (Fig.
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5). He has no significant murmur of aortic insufficiency.
Discussion Candidiasis in this patient most likely originated during the first admission, when he had a septic episode while being parenterally alimented by a subclavian central venous catheter. This cannot be definitely proved, because the species of Candida was not determined during the first hospitalization. Candida sepsis, as a complication of parenteral alimentation catheters, is well recognized. Certain predisposing factors are generally present, such as Candida infections elsewhere, use of broad-spectrum antibiotics, steroid therapy, antimetabolites, and lymphoproliferative diseases.':" This man had been given long-term antibiotics (Keflin, Kantrex, and tetracycline) prior to development of candidemia. The management of Candida septicemia secondary to catheters is removal of the central venous catheter. Whether antifungal chemotherapy is necessary is debatable as there have been several reports in which the infection cleared after removal of the catheter.r-" Ellis" encouraged removal of indwelling venous and urinary catheters when candidemia is found, as well as discontinuance of antibiotics, steroids , and antimetabolites whenever possible. He suggested that no specific antifungal therapy be started so long as the patient's clinical condition is improving and a careful search gives no evidence of tissue infection. However, if his condition is deteriorating at the time positive blood cultures are reported, then antifungal therapy should be considered promptly in addition to the above nonspecific measures. It appears that our patient had no more than a transient candidemia on his first admission, responding to withdrawal of both the catheter and antibiotics, as there was no evidence of Candida on subsequent cultures during his first and second admissions. Large emboli to major vessels are a common complication in patients with Candida endocarditis. The incidence of embolization to specific vessels seems to parallel that of
Fig. 3B. High-power view. For legend, see Fig. 3A.
Table I. Cardiac catheterization data (Oct. 31 , 1972) Pressure Site
Right atrium (mean) Pulmonary artery (mean) Pulmonary capillary wedge Left ventricle LVEDP (mean)
(mm. Hg)
7 40
22
160/40 40
Legend: Left ventricular end-diastolic pressure.
emboli from the left side of the heart, being most common in the vessels of the iliofemoral region, brain , and kidneys and also involving the arterial supply of the arms, abdominal viscera, and even the pulmonary artery from tricuspid and right ventricular endocarditis ." Large vessel embolization reflects the large size and friability of the mycotic vegetations. Prior attempts at embolectomy for mycotic emboli have generally been unsuccessful. However, in most cases the procedure had not been done early.' Early embolectomy, as the present case
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3-8-72 Fig. 4. Chest x-ray film approximately 6 months after aortic valve replacement for endocarditis, taken just prior to admission for congestive heart failure.
demonstrates, can result in patent vessels and viable extremities. Seelig,l1 in reviewing Candida endocarditis after cardiac surgery, found no survivors in patients developing early major emboli. The treatment of our patient for endocarditis was a combination of intensive medical management with an aggressive surgical approach. Initial coverage with amphotericin B was changed to 5-fluorocytosine because of fear of the toxic effects of amphotericin B, especially on renal function. The dosage of 5-fluorocytosine in this patient was approximately 60 mg. per kilogram. The decision to replace the aortic valve early in the course was based on two facts: ( 1) the rapid deterioration of the cardiovascular hemodynamics due to aortic valve disruption primarily' > and (2) our belief that nothing short of removal of the mycotic vegetations would prevent further emboli. Selection of the fresh-frozen stented homograft valve avoided anticoagulation in the postoperative period. The perivalvular leak occurred early in the patient's postoperative course and later proved to be in the area where the mycotic process involved the annulus. This was hemodynamically insignificant initially but later required valve replacement. On
Fig. 5. Chest x-ray film, taken approximately 3 months after aortic homograft replacement for perivalvular leak, shows marked reduction in the heart size.
none of the numerous cultures after the first valve replacement, as well as examination microscopically and culture of the replaced homograft valve, were Candida organisms demonstrated. The use of 5-fluorocytosine in Candida infections has been reported recently. Record' > reported its use in 3 patients with Candida infections of prosthetic valves and in 1 with aortic insufficiency and candidemia who was suspected of having Candida endocarditis. Two patients died. One of them had resistant Candida albicans on a prosthetic aortic valve. In another, who died ]9 days after removal of an infected mitral prosthetic valve, no viable organisms were recovered at autopsy. The third patient survived without surgical intervention. Greenberg> described ]4 patients with systemic candidiasis who were treated with 5-fluorocytosine; 9 had unequivocably favorable responses and 5 had improvement. Five of these patients had been refractory to amphotericin B. Fass'" reported the combined use of amphotericin Band 5-fluorocytosine with surgery in a surviving patient who had an infected Starr-Edwards valve. Logan' ? reported on a patient with Candida endocarditis following Streptococcus viridans en-
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Candida endocarditis with femoral emboli
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February, 1974
docarditis who was treated for 6 months with 5-fluorocytosine in therapeutic doses. At 6 months the Candida organism became resistant to the drug, and the patient soon died of aortic valve rupture. Adverse reactions ascribed to 5-fluorocytosine are apparently not severe and include rash, anemia, leukopenia, and alteration of liver en-
zymes.'":" The mortality rate for patients with Candida endocarditis treated only by antifungal agents is greater than 80 per cent. There are 4 survivors who were treated with amphotericin B alone and I who was treated with parenteral Mycostatin, which is no longer commercially available." The choice of valve replacement does not seem to influence survival. Two prior survivors of primary Candida endocarditis had aortic valves replacement with Magovern ball valves, usually with the silicone rubber or Ivalon cuff removed. 1 Patients with prosthetic valves infected by Candida have had valves replaced with the Magovern-Cromie valve with the cuff removed" as well as with Starr-Edwards valves." 15. IS Suture material has been reported in only two instances,': H in which monofilament wire was used. In the present case, Ti-Cron suture material was used to affix the valve and fine silk to repair the aortotomy. The importance of removing as much of the vegetative process as possible, even if it cannot be excised completely, has been stressed. Hairston" reported I case in which the infected prosthetic valve was left in place and only debridement of the mycotic vegetations was carried out, resulting in apparent cure with concomitant amphotericin B therapy.
REFERENCES 1 Kay, I. H., Bernstein, S., Tsuji, H. K., Redington, I. V., Milgram, M., and Beam, T.: Surgical Treatment of Candida Endocarditis, I. A. M. A 203: 105, 1968. 2 Kay, I. H., Bernstein, S., Feinstein, D., and Biddle, M.: Surgical Cure of Candida albicans Endocarditis With Open-Heart Surgery, N. Engl. I. Med. 264: 907, 1961. 3 Grehl, T. M., Cohn, L. H., and Angell, W.
W.: Management of Candida Endocarditis, I. THORAC. CARDOVASC. SURG. 63: 118, 1972. 4 Andriole, V. T., Krauetz, H. M., Roberts, W. C., and Utz, I. P.: Candida Endocarditis: Clinical and Pathologic Studies, Am. I. Med. 32: 251, 1962. 5 Harrel, E. R., and Thompson, G. R.: Systemic Candidiasis (Moniliasis) Complicating Treatment of Bacterial Endocarditis, With Review of Literature and Report of Apparent Cure of One Case With Parenteral Mycostatin, Ann. Intern. Med. 49: 207, 1958. 6 Ellis, C. A, and Spivak, M. L.: The Significance of Candidemia, Ann. Intern. Med. 67: 511, 1967. 7 Groff, D. B.: Complication of Intravenous Hyperalimentation in Newborn and Infants, I. Pediatr. Surg. 4: 460, 1969. 8 Das, I. B., Filler, A M., Rubin, V. G., et al.: Intravenous Amino Acid-Dextrose Feeding: The Metabolic Response in the Surgical Neonate, I. Pediat. Surg. To be published. 9 Boeckman, C. R., and Krill, C. E.: Bacterial and Fungal Infections Complicating Parenteral Alimentation in Infants and Children, I. Pediatr. Surg. 5: 117, 1970. 10 Ashcraft, K. W., and Leape, L. L.: Candida Sepsis Complicating Parenteral Feeding, I. A M. A. 212: 454, 1970. 11 Seelig, M. S., Speth, C. P., Kozinn, P. I., Toni, E. F., and Taschdjian, C. L.: Candida Endocarditis After Cardiac Surgery, J. THORAC. CARDIOVASC. SURG. 65: 583, 1973. 12 Wilson, L. C., Wilcox, B. R., Sugg, W. L., and Peters, R. M.: Valvar Regurgitation in Acute Infective Endocarditis: Early Replacement, Arch. Surg. 101: 756, 1970. 13 Record, C. 0., Skinner, I. M., Sleight, P., and Speller, D. C. E.: Candida Endocarditis Treated With 5-Fluorocytosine, Br. Med. I. 1: 262, 1971. 14 Greenberg, E., Prince, H. N., and Utz, I. P.: Observation on the Activity of Two Newer Anti-fungal Agents: Saramycetin (X-5079C) and 5-Fluorocytosine. Fifth International Congress of Chemotherapy, Vienna, Austria, June 26 to July 1, 1967, p. 69. 15 Fass, R. I., and Perkins, R. L.: 5-Fluorocytosine in the Treatment of Cryptococcal and Candida Mycoses, Ann. Intern. Med. 74: 535, 1971. 16 Logan, R. L.: C. albicans Resistance to 5Fluorocytosine, Br. Med. I. 3: 531, 1972. 17 Utz, I. P., Tynes, B. S., Shadony, H. I., et al.: 5-Fluorocytosine in Human Cryptococcosis, Antimicrob. Agents Chemother. 9: 344, 1968. 18 Hairston, P., and Lee, W. H., Jr.: Management of Infected Prosthetic Heart Valves, Ann. Thorac. Surg. 9: 229, 1970.