CASE REPORTS
Hematogenous Candida Osteomyelitis Report of Three Cases and Review of the Literature
JOHN E. EDWARDS, SUSAN
Jr., M.D.*
B. TURKEL, M.D.
Torrance, California HARVEY
A. ELDER, MD
Loma Linda. Californri, ROBERT W. RAND, Ph.D., M.D. LUCIEN B. GUZE, M.D. Los Angeles, California
Candida osteomyelitis of the spine and intervertebral disc developed in three patlents without evidence of back trauma or overlying cutaneous infection. Two patlents were prone to the development of disseminated candidiasis by the use of multiple antlbiotits and other predisposing modallties following abdominal surgery. One patient had no identifiable cause for development of the infection. The diagnosis was estabtished in all three cases by x-ray evideirce of osteomyelitis and culture from needle aspirate. Two patients had bone scans consistent with infection. Each patient received different therapy. One was treated with amphoteritin 6, one with spinal fusion and 5fluorocytosine, and one with no antifungal therapy. All patients had complete healing of the involved vertebrae. Candida organisms have the potential to cause destructive bone infection following hematogenous dissemination. The presence of Candida osteomyelitis may be helpful in diagnosing disseminated candidiasis. During recent years, organisms belonging to Candida species have emerged as clinically important pathogens [l-8]. The incidence of localized Candida infections, candidemia and systemic candidiasis has increased. Accompanying the increased incidence of candidemia has been an increased recognition of the peripheral manifestations, such as hematogenous Candida chorioretinitis [ 9- 111 and hematogenous skin infection [ 131. The three cases we report illustrate Candida osteomyelitis, a complication of candidemia which is now rare, but which should be of increasing importance if current trends continue.
From the Departments of Medicine and Pathology, Harbor General Hospital, Torrance, California 90509; the Research and Medical Service, Wadsworth Hospital, Veterans Administration Center and UCLA School of Medicine, Los Angeles, California 90073; and the Department of Medicine, Loma Linda University School of Medicine, Loma Linda, California 92354. This study was supported by U.S. Public Health Service Grant A102257. Requests for reprints should be addressed to Division of Infectious Disease, Department of Medicine. Harbor General Hospital, 1000 West Carson Street, Torrance, California 90509. Manuscript accepted May 10, 1974. Present address: Box 52, Naval Hospital, Camp Pendleton, California 92055. l
CASE REPORTS Case 1.
A 74 year old Mexican-American woman (CR.) was well until May 1971, when she underwent vagotomy and pyloroplasty for bleeding esophageal varices. A liver biopsy revealed cirrhosis which was responsible for portal hypertension and the accompanying varices. Three weeks after surgery a gastrojejunostomy was performed for partial obstruction of the pyloroplasty. Because of unexplained postoperative fever, the patient was treated with penicillin, cephaloridine, cephalexin, gentamicin and nitrofurantoin; she was subsequently discharged on the latter drug for a urinary tract infection. Hyperalimentation was not administered postoperatively. Two months later the patient complained of low back pain. Culture of needle aspirate from a lytic vertebral lesion (10th to the 1 lth thoracic vertebrae level), which involved both the intervertebral disc space and the
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Figure I. Lateral views of the spines of Case 1 (A), Case 2 (6) and Case 3 (C) showing destruction of the vertebrae and narrowing of the intervertebral disc spaces.
adjacent vertebral bodies, grew Candii albicans. Figure 1A is a roentgenogram of the spine. Simultaneous urine and sputum cultures also grew C. aibicans. Four cultures of blood taken after the spinal osteomyelitis was diagnosed were negative. On September 24, 1971, culture of a repeat needle aspirate (under fluoroscopy) and open biopsy specimen of the spine again grew pure C. albicans. Histologically, the specimen showed fibrous tissue and scarring but no Candiia organisms on staining either with periodic acid-Schiff or methenamine silver stains. Funduscopic examination on October 27 showed several foci of chorioretinitis. Intravenous amphotericin B therapy was begun on October 28, 1971, for the spine lesion and continued until January 25, 1972, for a total dose of 1.0 g. Coincident with this amphotericin B therapy, the patient’s back pain diminished. Therapy was complicated only by two episodes of transient elevation of the serum creatinine and blood urea nitrogen levels. Sixteen days after termination of amphotericin B therapy, low back pain recurred. The patient was hospitalized on February 11, 1972, because of temperature elevations to 102*F, and group A beta-hemolytic streptococci were cultured from her blood. Prior to the return of the positive cultures, the patient was treated with penicillin, Choloromycetine and gentamicin. The source for this septicemia was inapparent. Three days after admission, she experienced shock and muttiple arrhythmias, and she died. After the autopsy, the presumptive cause of death was septic shock.
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Postmortem examination of the spine showed an extensive fibrotic and sclerotic process replacing the 19th to the 1 Ith thoracic and first to the second lumbar vertebral bodies (Figure 2). The extensive fibrosis and scarring were confirmed on microscopic examination (Figure 3). No active infection or Candida organisms were found on multiple sections stained with periodic acid-Schiff reagent. Cultures of postmortem bone biopsy specimens were all negative. Both eyes contained multiple areas of chorioretinitis. These lesions were large; some lesions had overlying vitreous involvement. Microscopically, they showed granulomatous inflammation with moderate scarring. No organisms were seen.
Comment: This elderly woman
underwent two gastrointestinal tract surgeries, had an unexplained postoperative fever and received five antibiotics before resolution of the fever. Two months later spinal osteomyelitis with disc involvement developed; needle
aspirate grew C. albicans on culture. The patient was treated with 1.0 g of amphotericin 6. Death from unrelated causes occurred 2 weeks after completion of her therapy: there was no evidence of active spine infection at autopsy. Case 2.
The patient (J.S.) was a male Caucasian in his iate seventies when he was first admitted to the University of California Center for the Health Sciences in November 1969 for revision of a colostomy. Partiil resection of his
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Figure 2. Case 1. Gross specimen of spine removed at autopsy showing healing of the destroyed vertebrae and fusion at the /eve/of the 10th and 7 7th thoracic vertebrae.
colon had been performed 11 years earlier for carcinoma. Following tha revision, he had two episodes of bowel obstruction necessitating lysis of adhesions and further bowel resection. Postoperatively a wound infection developed which communicated with a small bowel fistula. On the 19th day after his last surgery, culture of material from his subclavian catheter grew C. albicans. Cultures of blood taken after removal of the intravenous catheter were positive for C. albicans as were cultures of sputum, wound and urine. In addition to receiving multiple antibiotics and subclavian catheters during his prolonged postoperative course, the patient received a series of hyperalimentation fluids. Following the development of blood cultures positive for Candida, 27 mg of amphotericin B were given over 5 days. However, because of azotemia, administration of the drug was discontinued. One subsequent blood culture, 2 weeks after termination of the amphotericin B therapy, was positive for CandMa. Eighty days after admission, the patient was discharged somewhat improved. He remained well for
the next 4 months, and then lumbar pain recurred. Roent genograms showed an infective process in the second and third lumbar intervertebral disc space with erosion of the adjacent vertebral bodies (Figure 1B) and a small erosion of the right first metacarpal. A bone scan of the spine area was consistent with infection. Aspirate from the second and third lumbar disc space and of the right hand were positive for C. albicans. Therapy consisted of bed rest alone. Both the spine and hand lesions healed successfully. In 1972 the patient again had bowel surgery, but there was no further evidence of systemic or local Candida infections. The antibiotic therapy during the course of these prolonged hospitalizations included 11 drugs: cephalothin and phthalylsulfathiazole in 1969, neomycin (cream), ampicillin, cephalothin, gentamicin, tetracycline, methicillin, chloramphenicol, cloxacillin and polymyxin B-bacitracin-neomycin ointment. A single dose of isoniazid was also given when spinal osteomyelitis was diagnosed. After the positive Candida cultures and multiple negative mycobacteria cultures
Figure 3. Case 1. Microscopic appearance of the intervertebral region showing dense fibrosk and scarring. No organisms were seen. Microscopic section was taken at autopsy.
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bicans. Treatment with 8 g/day of 5fluorocytosine for 3 months resulted in healing of the infected area. There were no apparent predisposing factors responsible for this Candida infection.
were obtained, the administration of isonfazid was discontinued. The patient also received topical steroid creams but no systemic steroids.
Comment: This man in his late seventies had multiple gastrointestinal tract surgeries complicated by wound infections and gastrocutaneous fistulas. During his prolonged hospitalization he was treated with multiple antibiotics, hyperalimentation fluids and the insertion of intravenous catheters with eventual clearing of the fistulas and wound infections. Four months later osteomyelitis of the spine and wrist developed; culture of aspirate from each location grew C. albicans. Treatment with bed rest alone resulted in complete healing of the involved bones.
COMMENTS
The factors responsible for the increased incidence of Candida infections include widespread use of antibiotics [ 14,151, immunosuppressives [5], abdominal surgery [ 161, cardiac valvular surgery [ 17,181, and glucose infusions and intravenous catheters [ 19,201. Our first two patients were predisposed to disseminated candidiasis because of a number of these factors. Specifically, they were abdominal surgery, use of multiple antibiotics and, in one (Case 2), use of hyperalimentation fluids and central venous catheters. However, our third patient is of interest because there were no identifiable predisposing factors, and the reasons for the development of spinal Candida osteomyelitis remain speculative. It is known that Candida organisms can disseminate widely following candidemia [ 161. Involvement in almost all organs including the eye [lo] and skin [ 131 has been reported. Bone infection, however, is rare. Reports of disseminated candidiasis in over 130 cases [ 1,3,12] mention bone involvement in only two: the details are not described. Several comprehensive reviews of osteomyelitis [21-241 do not list Candida as a cause. Connor [ 251, in 1928, described osteomyelitis of the hip from Monilia. In this case the osteomyelitis probably resulted from direct extension of a cutaneous abscess. Keating [26], in 1932, published 15 cases of Candida osteomyelitis, only 5 of which were proved by culture of material from the infected site. In the remaining cases, the diagnosis was based on the presence of osteomyelitis with Candida cultured from remote sources such as oral pharynx and/or stool, and occasional positive agglutinins. It is unclear whether some of these patients with positive cultures had draining sinuses communicating with the skin. Fourteen patients had infection in the bones of the extremities or hip: one patient had involvement of the dorsal spine. It is not possible from the report to determine whether these patients had hematogenous osteomyelitis or traumatic osteomyelitis. All fiv- patients with positive cultures were treated with 1 tassium iodide and they all showed improvement. eingart et al. [27], in 1942, reported a docum lited case of Candida osteomyelitis of the hip and reviewed the literature prior to that time. They believed that there were only two previously documented cases of Candida bone infection: one was an infected patella [28] and the other involved the vertebrae [29]. However, in the case of the infected patella the diagnosis was made only histologically, and the orga-
Case 3. The patient (J.H.), a 56 year old male Caucasian, was well with the exception of pulmonary emphysema and generalized atherosclerosis until May 1972, when he experienced severe mid-thoracic back pain. Roentgenograms showed only mild osteoarthritis and old juvenile epiphysitis. Since no etiology for the complaint could be identified, he was treated symptomatically. Over the subsequent 4 months, the pain gradually worsened. Roentgenograms obtained in October 1972 showed destruction of the ninth and tenth thoracic interspace and adjacent vertebrae (Figure IC). On October 5, 1972, a needle biipsy of the spine under fluoroscopy yielded both tissue and blood. The tissue grew C. albicans and blood grew Candida species (not albicans). Both specimens also contained diphtheroids. Tissue sections showed granulation tissue containing numerous polymorphonuclear leukocytes, prominent histiocytes and some fibroblasts. Acid-fast, fungal stains, and culture for mycobacteria were negative. The patient was afebrile with normal blood counts and urinalysis. On October 10, isoniazid and streptomycin therapy was begun for the possibility of tuberculous osteomyelitis. Eleven days after the needle biopsy, the patient underwent left thoracotomy for exploration of the involved interspace. Probing of the infected area produced purulent material which grew C. albicans. Tissue sections showed a granulomatous reaction in bone with negative periodic acid-Schiff, methenamine silver, acid-fast and gram stains. A spinal fusion was performed and the patient received an 8 g/day dose of 5fluorocytosine for 3 months (sensitivities to 5-fluorocytosine were not obtained). His symptoms diminished and follow-up films showed healing of the involved area. Investigations to identify a predisposing cause for the Candida infection included blood sugar determinations, myeloperoxidase stain and three serum calcium determinations, which were all normal. There was no history of recent use of antibiotics, drug abuse, hyperalimentation fluids, steroids or central venous catheters. Comment: This 56 year old man had mild pulmonary emphysema and generalized atherosclerosis. He was otherwise well until the development of thoracic osteomyelitis which was surgically explored and treated with spinal fusion. Cultures at surgery produced C. al-
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infection was
healing of both the spine and wrist. It is possible that
probably the result of contiguous spread from a pulmonary abscess, and it is difficult to ascertain whether Candida was the primary pathogen. There have been three recent reports of Candida osteomyelitis [30-321. Two of the patients were neonates with disseminated candidiasis who had Candida arthritis and associated involvement of the metaphyses of the femur, humerus and tibia. Both were successfully treated with amphotericin B. One adult drug addict patient with Candida vertebral osteomyelitis was described by Holzman and Bishko [30]. This patient also had intervertebral disc infection and was similar
in some patients in whom Candida susceptibility factors are removed, such as antibiotics, immunosuppressives and catheters, bone and other Candida lesions may heal spontaneously. 5fluorocytosine should be useful in treating Candida osteomyelitis in patients infected with organisms which are sensitive to the drug. However, caution must be used when treating with 5-fluorocytosine because of the high incidence of resistant Cand,ida and the development of in vivo resistance during treatment [35,36]. Presently, it appears that initial therapy should be directed at the patients’ underlying illness and that subsequently the judicious use of amphotericin B can be included, If a 5-fluorocytosine-sensitive organism is recovered, or if the patient is not able to tolerate amphotericin B, then 5-fluorocytosine may be an acceptable alternative. Hematogenous Candida endophthalmitis has been the subject of recent reports and its importance as a diagnostic aid in disseminated candidiasis has been discussed [ 11,121. Of interest is the eye lesion noted in Case 1. Although no organisms were seen in this lesion, its gross appearance, microscopic characteristics and clinical setting are those of hematogenous Candida endophthalmitis which healed spontaneously or simultaneously with the amphotericin fl therapy. Balandran et al. [ 131 have described hematogenous cutaneous lesions of disseminated infection. Kozinn et al. [37] have emphasized the importance of the bedside evaluation in making a diagnosis of disseminated candidiasis and stressed observing the presence of paronychia, intertrigo, vaginitis and candiduria. Similarly, the discovery of bone pain and osteomyelitis may be another important clinical finding alerting the physician to widespread dissemination.
nism was never cultured. The vertebral
in many respects to our three patients. Positive cultures for Candida stellatoidea were obtained by needle aspiration of the intervertebral disc. Although the patient was treated with amphotericin B, the results of the therapy were not detailed at the time the case was reported. The fact that all three of our patients had osteomyelitis of the spine with no history of back trauma or cutaneous infection is supportive for a hematogenous mechanism of bone seeding. In addition, the second patient had a focus in the hand with no known trauma to that area. The spine involvement is consistent with the observation that the vertebrae are the most common sites for hematogenous osteomyelitis in the adult [24], whereas the bones of the extremities are the most frequent location in the child. The exact reason for the predisposition of the vertebrae in the adult is not clear. Wiley and Trueta [33] have concluded that the vascular supply of the vertebrae in the adult is increased compared to that in the child. They have also speculated on the possibility of spine infection from veins draining the pelvic region. However, on the basis of their own anatomic studies, they concluded that this venous route plays a negligible role in hematogenous spinal infection. It is presumed that the disc infection in all three patients was secondary to spread from the infected adjacent vertebrae. Primary involvement of the disc cannot be ruled out. Amphotericin B has been shown to be effective in the treatment of osteomyelitis caused by fungi [34]. With the exception of the two neonates previously discussed, there is little information regarding the efficacy of its use in bone infections caused by Candida. Each of the patients of this report was treated differently. One patient (Case 1) received a 1 g total dose of amphotericin B before she died of other causes. The involved area was completely healed at autopsy (Figures 2 and 3). The patient who received 5fluorocytosine (Case 3) also had complete resolution of the process. Of interest is the patient who was treated with only bed rest (Case 2) and who had
ADDENDUM Since preparation of this manuscript, O’Connell et al. [38] have described an additional case of candida spinal osteomyelitis at the level of the sixth and seventh cervical vertebrae with complete loss of the disc space. The patient was a 34 year old black, male, heroin addict with sickle cell trait. Candida guilliermondii was recovered from the infected site at the time of anterior exploration. He was treated with 1.8 g of amphotericin B over 42 days and posterior spinal fusion. Roentgenograms obtained 8 months later revealed complete healing. Chmel et al. [39] also reported a case of C. albicans postoperative sternal wound infection with secondary sternal osteomyelitis which was cured by local amphotericin B irrigation and combination amphotericin B and 5fluorocytosine parenteral therapy. Oxacillin and clindamycin were also administered.
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These investigators reviewed an additional case of probable hematogenous scapular osteomyelitis reported by Lehrer and Cline [40]. In this patient, Candida was recovered from mouth, stool, urine and spu-
turn and an abscess of the left forearm. He was treated successfully with 1,200 mg of amphotericin B and was found to have a deficiency of leukocyte myeloperoxidase.
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Louria DB, Stiff DP, Bennett 8: Disseminated moniliasis in the adult. Medicine 41: 307, 1962. Hughes JM, Remington JS: Systemic candidiasis, a diagnostic challenge. Calif f&d 116: 8, 1972. Bodey GP: Fungal infections complicating acute leukemia. J Chronic Dis 19: 667. 1966. Hart PD, Russell E Jr, Remington JS: The compromised host and infection. II. Deep fungal infection. J Infect Dis 120: 169, 1969. Rifkind D, Marchioro TL, Schneck SA, Hill RB: Systemic fungal infections complicating renal transplantation and immunosuppressive therapy. Am J Med 43: 28, 1967. Hill RB Jr, Darhling BE. Starzl TE, Rifkind D: Death after transplantation-an analysis of 60 cases (editorial). Am J Med 42: 327, 1967. Eras P, Goldstein MJ, Sherlock P: Candida infection of the gastrointestinal tract. Medicine 51: 367, 1972. Andriole VT, Kravetz HM, Roberts WC, Utz JP: Candida endocarditis-clinical and pathologic studies. Am J Med 32: 251, 1962. Fishman LS, Griffin JR, Sapico FL, Hecht R: Hematogenous Candida endophthalmitis-a complication of candidemia. N Engl J Med 286: 675. 1972. Michelson PE, Stark W. Resser F, Green WR: Endogenous Candida endophthalmitis. Report of 13 cases and 16 from the literature. Int Ophthalmol Clin 11: 125, 1971. Griffin JR, Pettit TH, Fishman LS, Foos RY: Blood-born Candida endophthalmitis. Arch Ophthalmol 89: 450, 1973. Edwards JE Jr, Foos RY, Montgomerie JZ, Guze LB: Ocular manifestations of Candida septicemia. Medicine 53: 47, 1974. Balandran L, Rothschild H. Pugh N, Seabury J: A cutaneous manifestation of systemic candidiasis. Ann Intern Med 78: 400, 1973. Seelig MS: Mechanisms by which antibiotics increase the incidence and severity of candidiasis and alter the immunological defenses. Bacterial Rev 30: 442, 1966. Toala P, Schroeder SA, Daly AK, Finland M: Candida at Boston City Hospital. Clinical and epidemiological characteristics and susceptibility to eight antimicrobial agents. Arch Intern Med 126: 983, 1970. Bernhardt HE, Orlando JC, Benfield JR, Hirose FM, Foos RY: Disseminated candidiasis in surgical patients. Surg Gynecol Obstet 134: 819, 1972. Chaudhuri MR: Fungal endocarditis after valve replacements. J Thorac Cardiovasc Surg 80: 207, 1970. Hairston P, Lee WH: Management of infected prosthetic heart valves. Ann Thorac Surg 9: 229, 1970. Ashcraft KW, Leape LL: Candida sepsis complicating parenteral feeding. JAMA 212: 454, 1970. Brennan MF, Goldman MH, O’Connell RC, Kundsin RB, Moore FD: Prolonged parenteral alimentation. Candida growth and the prevention of candidemia by amphoteri-
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tin B instillation. Ann Surg 176: 265, 1972. Golden HE, Parker RH: Mycobacterial and fungal forms of arthritis. Mod Treat 8: 1117, 1969. Rhangos WC, Chick EW: Mycotic infections of bone. South Med J 57: 664, 1964. Altemeier WA, Largen T: Antibiotic and chemotherapeutic agents in infection of the skeletal system. JAMA 150: 1462, 1952. Waldvogel FA, Medoff G, Swartz MN: Osteomyelitis: a review of clinical features, therapeutic considerations and unusual aspects. N Engl J Med 282: 198, 260, 316, 1970. Connor CL: Monilia from osteomyelitis. J Infect Dis 43: 108, 1928. Keating PM: Fungus infection of bone and joint. South Med J 25: 1072, 1932. Weingart JS, Wirtz DC, Irving NW: Monilia osteomyelitis. Report of a case resulting from thrush. Am J Clin Pathol 12: 597, 1942. Murard J: Mycose de la rotule. Rev Orthop 21: 138, 1934. Yvin M: Un cas de mycose vertebrale. Rev Orthop 21: 42, 1934. Holzman RS, Bishko F: Osteomyelitis in heroin addicts. Ann Intern Med 75: 893, 1971. Klein JD, Yamauchi T, Horlick SP: Neonatal candidiasis, meningitis, and arthritis: observations and a review of the literature. J Pediatr 81: 31, 1972. Adler S, Randall J, Plotkin SA: Candidal osteomyelitis and arthritis in a neonate. Am J Dis Child 123: 595, 1972. Wiley AM, Trueta J: The vascular anatomy of the spine and its relationship to pyogenic vertebral osteomyelitis. J Bone Joint Surg (Br) 41: 796, 1959. lgar M, Larson J: Coccidioidal osteomyelitis. Coccidioidomycosis (Ajello L, ed), Tucson, The University of Arizona Press, 1967, p 89. Fass RJ, Perkins RL: 5-fluorocytosine in the treatment of cryptococcal and Candida mycoses. Ann Intern Med 74: 535,1971. Steer PL, Marks MI, Klite PD. Eickoff TC: 5-fluorocytosine: an oral antifungal compound. A report of clinical and laboratory experience. Ann Intern Med 76: 15, 1972. Kozinn PJ. Hasenclever HF, Taschdjian CL, Mackenzie DW, Protzman W: Problems in diagnosis and treatment of systemic candidiasis. J Infect Dis 126: 548, 1973. O’Connell CJ, Cherry AV, Zoll JG: Osteomyelitis of cervical spine: Candida guilliermondii. Ann Intern Med 79: 748, 1973. Chmel H, Grieco MH, Zickel R: Candida osteomyelitis. Report of a case. Am J Med Sci 266: 299, 1974. Lehrer RI, Cline MJ: Leukocyte myeloperoxidase deficiency and disseminated candidiasis: the role of myeloperoxidase in resistance to Candida infection. J Clin Invest 48: 1478, 1969.
Hematogenous Candida Osteomyelitis Report of Three Cases and Review of the Literature
JOHN E. EDWARDS, SUSAN
Jr., M.D.*
B. TURKEL, M.D.
Torrance, California HARVEY
A. ELDER, MD
Loma Linda. Californri, ROBERT W. RAND, Ph.D., M.D. LUCIEN B. GUZE, M.D. Los Angeles, California
Candida osteomyelitis of the spine and intervertebral disc developed in three patlents without evidence of back trauma or overlying cutaneous infection. Two patlents were prone to the development of disseminated candidiasis by the use of multiple antlbiotits and other predisposing modallties following abdominal surgery. One patient had no identifiable cause for development of the infection. The diagnosis was estabtished in all three cases by x-ray evideirce of osteomyelitis and culture from needle aspirate. Two patients had bone scans consistent with infection. Each patient received different therapy. One was treated with amphoteritin 6, one with spinal fusion and 5fluorocytosine, and one with no antifungal therapy. All patients had complete healing of the involved vertebrae. Candida organisms have the potential to cause destructive bone infection following hematogenous dissemination. The presence of Candida osteomyelitis may be helpful in diagnosing disseminated candidiasis. During recent years, organisms belonging to Candida species have emerged as clinically important pathogens [l-8]. The incidence of localized Candida infections, candidemia and systemic candidiasis has increased. Accompanying the increased incidence of candidemia has been an increased recognition of the peripheral manifestations, such as hematogenous Candida chorioretinitis [ 9- 111 and hematogenous skin infection [ 131. The three cases we report illustrate Candida osteomyelitis, a complication of candidemia which is now rare, but which should be of increasing importance if current trends continue.
From the Departments of Medicine and Pathology, Harbor General Hospital, Torrance, California 90509; the Research and Medical Service, Wadsworth Hospital, Veterans Administration Center and UCLA School of Medicine, Los Angeles, California 90073; and the Department of Medicine, Loma Linda University School of Medicine, Loma Linda, California 92354. This study was supported by U.S. Public Health Service Grant A102257. Requests for reprints should be addressed to Division of Infectious Disease, Department of Medicine. Harbor General Hospital, 1000 West Carson Street, Torrance, California 90509. Manuscript accepted May 10, 1974. Present address: Box 52, Naval Hospital, Camp Pendleton, California 92055. l
CASE REPORTS Case 1.
A 74 year old Mexican-American woman (CR.) was well until May 1971, when she underwent vagotomy and pyloroplasty for bleeding esophageal varices. A liver biopsy revealed cirrhosis which was responsible for portal hypertension and the accompanying varices. Three weeks after surgery a gastrojejunostomy was performed for partial obstruction of the pyloroplasty. Because of unexplained postoperative fever, the patient was treated with penicillin, cephaloridine, cephalexin, gentamicin and nitrofurantoin; she was subsequently discharged on the latter drug for a urinary tract infection. Hyperalimentation was not administered postoperatively. Two months later the patient complained of low back pain. Culture of needle aspirate from a lytic vertebral lesion (10th to the 1 lth thoracic vertebrae level), which involved both the intervertebral disc space and the
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Figure I. Lateral views of the spines of Case 1 (A), Case 2 (6) and Case 3 (C) showing destruction of the vertebrae and narrowing of the intervertebral disc spaces.
adjacent vertebral bodies, grew Candii albicans. Figure 1A is a roentgenogram of the spine. Simultaneous urine and sputum cultures also grew C. aibicans. Four cultures of blood taken after the spinal osteomyelitis was diagnosed were negative. On September 24, 1971, culture of a repeat needle aspirate (under fluoroscopy) and open biopsy specimen of the spine again grew pure C. albicans. Histologically, the specimen showed fibrous tissue and scarring but no Candiia organisms on staining either with periodic acid-Schiff or methenamine silver stains. Funduscopic examination on October 27 showed several foci of chorioretinitis. Intravenous amphotericin B therapy was begun on October 28, 1971, for the spine lesion and continued until January 25, 1972, for a total dose of 1.0 g. Coincident with this amphotericin B therapy, the patient’s back pain diminished. Therapy was complicated only by two episodes of transient elevation of the serum creatinine and blood urea nitrogen levels. Sixteen days after termination of amphotericin B therapy, low back pain recurred. The patient was hospitalized on February 11, 1972, because of temperature elevations to 102*F, and group A beta-hemolytic streptococci were cultured from her blood. Prior to the return of the positive cultures, the patient was treated with penicillin, Choloromycetine and gentamicin. The source for this septicemia was inapparent. Three days after admission, she experienced shock and muttiple arrhythmias, and she died. After the autopsy, the presumptive cause of death was septic shock.
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Postmortem examination of the spine showed an extensive fibrotic and sclerotic process replacing the 19th to the 1 Ith thoracic and first to the second lumbar vertebral bodies (Figure 2). The extensive fibrosis and scarring were confirmed on microscopic examination (Figure 3). No active infection or Candida organisms were found on multiple sections stained with periodic acid-Schiff reagent. Cultures of postmortem bone biopsy specimens were all negative. Both eyes contained multiple areas of chorioretinitis. These lesions were large; some lesions had overlying vitreous involvement. Microscopically, they showed granulomatous inflammation with moderate scarring. No organisms were seen.
Comment: This elderly woman
underwent two gastrointestinal tract surgeries, had an unexplained postoperative fever and received five antibiotics before resolution of the fever. Two months later spinal osteomyelitis with disc involvement developed; needle
aspirate grew C. albicans on culture. The patient was treated with 1.0 g of amphotericin 6. Death from unrelated causes occurred 2 weeks after completion of her therapy: there was no evidence of active spine infection at autopsy. Case 2.
The patient (J.S.) was a male Caucasian in his iate seventies when he was first admitted to the University of California Center for the Health Sciences in November 1969 for revision of a colostomy. Partiil resection of his
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Figure 2. Case 1. Gross specimen of spine removed at autopsy showing healing of the destroyed vertebrae and fusion at the /eve/of the 10th and 7 7th thoracic vertebrae.
colon had been performed 11 years earlier for carcinoma. Following tha revision, he had two episodes of bowel obstruction necessitating lysis of adhesions and further bowel resection. Postoperatively a wound infection developed which communicated with a small bowel fistula. On the 19th day after his last surgery, culture of material from his subclavian catheter grew C. albicans. Cultures of blood taken after removal of the intravenous catheter were positive for C. albicans as were cultures of sputum, wound and urine. In addition to receiving multiple antibiotics and subclavian catheters during his prolonged postoperative course, the patient received a series of hyperalimentation fluids. Following the development of blood cultures positive for Candida, 27 mg of amphotericin B were given over 5 days. However, because of azotemia, administration of the drug was discontinued. One subsequent blood culture, 2 weeks after termination of the amphotericin B therapy, was positive for CandMa. Eighty days after admission, the patient was discharged somewhat improved. He remained well for
the next 4 months, and then lumbar pain recurred. Roent genograms showed an infective process in the second and third lumbar intervertebral disc space with erosion of the adjacent vertebral bodies (Figure 1B) and a small erosion of the right first metacarpal. A bone scan of the spine area was consistent with infection. Aspirate from the second and third lumbar disc space and of the right hand were positive for C. albicans. Therapy consisted of bed rest alone. Both the spine and hand lesions healed successfully. In 1972 the patient again had bowel surgery, but there was no further evidence of systemic or local Candida infections. The antibiotic therapy during the course of these prolonged hospitalizations included 11 drugs: cephalothin and phthalylsulfathiazole in 1969, neomycin (cream), ampicillin, cephalothin, gentamicin, tetracycline, methicillin, chloramphenicol, cloxacillin and polymyxin B-bacitracin-neomycin ointment. A single dose of isoniazid was also given when spinal osteomyelitis was diagnosed. After the positive Candida cultures and multiple negative mycobacteria cultures
Figure 3. Case 1. Microscopic appearance of the intervertebral region showing dense fibrosk and scarring. No organisms were seen. Microscopic section was taken at autopsy.
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bicans. Treatment with 8 g/day of 5fluorocytosine for 3 months resulted in healing of the infected area. There were no apparent predisposing factors responsible for this Candida infection.
were obtained, the administration of isonfazid was discontinued. The patient also received topical steroid creams but no systemic steroids.
Comment: This man in his late seventies had multiple gastrointestinal tract surgeries complicated by wound infections and gastrocutaneous fistulas. During his prolonged hospitalization he was treated with multiple antibiotics, hyperalimentation fluids and the insertion of intravenous catheters with eventual clearing of the fistulas and wound infections. Four months later osteomyelitis of the spine and wrist developed; culture of aspirate from each location grew C. albicans. Treatment with bed rest alone resulted in complete healing of the involved bones.
COMMENTS
The factors responsible for the increased incidence of Candida infections include widespread use of antibiotics [ 14,151, immunosuppressives [5], abdominal surgery [ 161, cardiac valvular surgery [ 17,181, and glucose infusions and intravenous catheters [ 19,201. Our first two patients were predisposed to disseminated candidiasis because of a number of these factors. Specifically, they were abdominal surgery, use of multiple antibiotics and, in one (Case 2), use of hyperalimentation fluids and central venous catheters. However, our third patient is of interest because there were no identifiable predisposing factors, and the reasons for the development of spinal Candida osteomyelitis remain speculative. It is known that Candida organisms can disseminate widely following candidemia [ 161. Involvement in almost all organs including the eye [lo] and skin [ 131 has been reported. Bone infection, however, is rare. Reports of disseminated candidiasis in over 130 cases [ 1,3,12] mention bone involvement in only two: the details are not described. Several comprehensive reviews of osteomyelitis [21-241 do not list Candida as a cause. Connor [ 251, in 1928, described osteomyelitis of the hip from Monilia. In this case the osteomyelitis probably resulted from direct extension of a cutaneous abscess. Keating [26], in 1932, published 15 cases of Candida osteomyelitis, only 5 of which were proved by culture of material from the infected site. In the remaining cases, the diagnosis was based on the presence of osteomyelitis with Candida cultured from remote sources such as oral pharynx and/or stool, and occasional positive agglutinins. It is unclear whether some of these patients with positive cultures had draining sinuses communicating with the skin. Fourteen patients had infection in the bones of the extremities or hip: one patient had involvement of the dorsal spine. It is not possible from the report to determine whether these patients had hematogenous osteomyelitis or traumatic osteomyelitis. All fiv- patients with positive cultures were treated with 1 tassium iodide and they all showed improvement. eingart et al. [27], in 1942, reported a docum lited case of Candida osteomyelitis of the hip and reviewed the literature prior to that time. They believed that there were only two previously documented cases of Candida bone infection: one was an infected patella [28] and the other involved the vertebrae [29]. However, in the case of the infected patella the diagnosis was made only histologically, and the orga-
Case 3. The patient (J.H.), a 56 year old male Caucasian, was well with the exception of pulmonary emphysema and generalized atherosclerosis until May 1972, when he experienced severe mid-thoracic back pain. Roentgenograms showed only mild osteoarthritis and old juvenile epiphysitis. Since no etiology for the complaint could be identified, he was treated symptomatically. Over the subsequent 4 months, the pain gradually worsened. Roentgenograms obtained in October 1972 showed destruction of the ninth and tenth thoracic interspace and adjacent vertebrae (Figure IC). On October 5, 1972, a needle biipsy of the spine under fluoroscopy yielded both tissue and blood. The tissue grew C. albicans and blood grew Candida species (not albicans). Both specimens also contained diphtheroids. Tissue sections showed granulation tissue containing numerous polymorphonuclear leukocytes, prominent histiocytes and some fibroblasts. Acid-fast, fungal stains, and culture for mycobacteria were negative. The patient was afebrile with normal blood counts and urinalysis. On October 10, isoniazid and streptomycin therapy was begun for the possibility of tuberculous osteomyelitis. Eleven days after the needle biopsy, the patient underwent left thoracotomy for exploration of the involved interspace. Probing of the infected area produced purulent material which grew C. albicans. Tissue sections showed a granulomatous reaction in bone with negative periodic acid-Schiff, methenamine silver, acid-fast and gram stains. A spinal fusion was performed and the patient received an 8 g/day dose of 5fluorocytosine for 3 months (sensitivities to 5-fluorocytosine were not obtained). His symptoms diminished and follow-up films showed healing of the involved area. Investigations to identify a predisposing cause for the Candida infection included blood sugar determinations, myeloperoxidase stain and three serum calcium determinations, which were all normal. There was no history of recent use of antibiotics, drug abuse, hyperalimentation fluids, steroids or central venous catheters. Comment: This 56 year old man had mild pulmonary emphysema and generalized atherosclerosis. He was otherwise well until the development of thoracic osteomyelitis which was surgically explored and treated with spinal fusion. Cultures at surgery produced C. al-
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healing of both the spine and wrist. It is possible that
probably the result of contiguous spread from a pulmonary abscess, and it is difficult to ascertain whether Candida was the primary pathogen. There have been three recent reports of Candida osteomyelitis [30-321. Two of the patients were neonates with disseminated candidiasis who had Candida arthritis and associated involvement of the metaphyses of the femur, humerus and tibia. Both were successfully treated with amphotericin B. One adult drug addict patient with Candida vertebral osteomyelitis was described by Holzman and Bishko [30]. This patient also had intervertebral disc infection and was similar
in some patients in whom Candida susceptibility factors are removed, such as antibiotics, immunosuppressives and catheters, bone and other Candida lesions may heal spontaneously. 5fluorocytosine should be useful in treating Candida osteomyelitis in patients infected with organisms which are sensitive to the drug. However, caution must be used when treating with 5-fluorocytosine because of the high incidence of resistant Cand,ida and the development of in vivo resistance during treatment [35,36]. Presently, it appears that initial therapy should be directed at the patients’ underlying illness and that subsequently the judicious use of amphotericin B can be included, If a 5-fluorocytosine-sensitive organism is recovered, or if the patient is not able to tolerate amphotericin B, then 5-fluorocytosine may be an acceptable alternative. Hematogenous Candida endophthalmitis has been the subject of recent reports and its importance as a diagnostic aid in disseminated candidiasis has been discussed [ 11,121. Of interest is the eye lesion noted in Case 1. Although no organisms were seen in this lesion, its gross appearance, microscopic characteristics and clinical setting are those of hematogenous Candida endophthalmitis which healed spontaneously or simultaneously with the amphotericin fl therapy. Balandran et al. [ 131 have described hematogenous cutaneous lesions of disseminated infection. Kozinn et al. [37] have emphasized the importance of the bedside evaluation in making a diagnosis of disseminated candidiasis and stressed observing the presence of paronychia, intertrigo, vaginitis and candiduria. Similarly, the discovery of bone pain and osteomyelitis may be another important clinical finding alerting the physician to widespread dissemination.
nism was never cultured. The vertebral
in many respects to our three patients. Positive cultures for Candida stellatoidea were obtained by needle aspiration of the intervertebral disc. Although the patient was treated with amphotericin B, the results of the therapy were not detailed at the time the case was reported. The fact that all three of our patients had osteomyelitis of the spine with no history of back trauma or cutaneous infection is supportive for a hematogenous mechanism of bone seeding. In addition, the second patient had a focus in the hand with no known trauma to that area. The spine involvement is consistent with the observation that the vertebrae are the most common sites for hematogenous osteomyelitis in the adult [24], whereas the bones of the extremities are the most frequent location in the child. The exact reason for the predisposition of the vertebrae in the adult is not clear. Wiley and Trueta [33] have concluded that the vascular supply of the vertebrae in the adult is increased compared to that in the child. They have also speculated on the possibility of spine infection from veins draining the pelvic region. However, on the basis of their own anatomic studies, they concluded that this venous route plays a negligible role in hematogenous spinal infection. It is presumed that the disc infection in all three patients was secondary to spread from the infected adjacent vertebrae. Primary involvement of the disc cannot be ruled out. Amphotericin B has been shown to be effective in the treatment of osteomyelitis caused by fungi [34]. With the exception of the two neonates previously discussed, there is little information regarding the efficacy of its use in bone infections caused by Candida. Each of the patients of this report was treated differently. One patient (Case 1) received a 1 g total dose of amphotericin B before she died of other causes. The involved area was completely healed at autopsy (Figures 2 and 3). The patient who received 5fluorocytosine (Case 3) also had complete resolution of the process. Of interest is the patient who was treated with only bed rest (Case 2) and who had
ADDENDUM Since preparation of this manuscript, O’Connell et al. [38] have described an additional case of candida spinal osteomyelitis at the level of the sixth and seventh cervical vertebrae with complete loss of the disc space. The patient was a 34 year old black, male, heroin addict with sickle cell trait. Candida guilliermondii was recovered from the infected site at the time of anterior exploration. He was treated with 1.8 g of amphotericin B over 42 days and posterior spinal fusion. Roentgenograms obtained 8 months later revealed complete healing. Chmel et al. [39] also reported a case of C. albicans postoperative sternal wound infection with secondary sternal osteomyelitis which was cured by local amphotericin B irrigation and combination amphotericin B and 5fluorocytosine parenteral therapy. Oxacillin and clindamycin were also administered.
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These investigators reviewed an additional case of probable hematogenous scapular osteomyelitis reported by Lehrer and Cline [40]. In this patient, Candida was recovered from mouth, stool, urine and spu-
turn and an abscess of the left forearm. He was treated successfully with 1,200 mg of amphotericin B and was found to have a deficiency of leukocyte myeloperoxidase.
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