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Candida spondylodiscitis and epidural abscess: management with shorter courses of anti-fungal therapy in combination with surgical debridement
Journal of Infection (2005) 51, 17–23
www.elsevierhealth.com/journals/jinf
Candida spondylodiscitis and epidural abscess: management with shorter courses of anti-fungal therapy in combination with surgical debridement S.L. Chiaa,*, B.H. Tanb, C.T. Tana, S.B. Tana a
Department of Orthopaedic Surgery, Singapore General Hospital, Singapore Department of Internal Medicine, Singapore General Hospital, Singapore
b
Accepted 17 August 2004 Available online 29 September 2004
KEYWORDS Fungal infection; Spine; Candida; Epidural abscess; Management; Fluconazole
Abstract Epidural abscess associated with candidal spondylodiscitis is rarely seen, particularly when it involves the cervical and thoracic spine. We report two such cases that were successfully managed with early surgical debridement, as well as medical therapy with intravenous amphotericin followed by oral fluconazole. The literature related to candidal spinal infection is reviewed, and a rational approach to the management of this uncommon condition is proposed. A good outcome may generally be expected with early diagnosis as well as appropriate surgical and pharmacological treatment. Oral fluconazole appears to be useful in the management of candida spondylodiscitis complicated by epidural abscess formation. Treatment until a normal ESR is attained is ideal, and this may be as short as 3 months when surgical drainage has been adequately performed. Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
Introduction Although Candida is known to affect virtually any tissue or organ system within the body,1 infection of bone, or cartilage, or both is uncommon in clinical practice and in the literature.2–5 In particular, Candida infection involving the cervical and thoracic spine has been rarely reported over the past 30 years, and epidural abscess associated with Candida spondylodiscitis has been virtually unreported.6 We report one case each of cervical and thoracic
spondylodiscitis (both associated with epidural abscess) due to candida that were successfully treated with surgery followed by a 3-month course of fluconazole, and discuss their risk profiles, management and subsequent outcome in relation to the available literature on fungal infections of the spine.
Reports Case 1
* Corresponding author. Tel.: C65 6321 4047; fax: C65 6224 8100. E-mail address: [email protected] (S.L. Chia).
A 63-year-old man with a history of hypertension and poorly-controlled Type II diabetes mellitus had
0163-4453/$30.00 Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2004.08.020
18 been hospitalised 7 months earlier for acute haemorrhagic pancreatitis that was associated with chronic calculous cholecystitis. During this hospitalisation, he received a variety of broadspectrum antibiotics (imipenem, ceftazidime and ciprofloxacin, at different times), and was also on total parenteral nutrition (TPN). Towards the end of his stay he developed a febrile episode and cultures of the blood and the tip of a central venous catheter were positive for methicillin-resistant Staphylococcus aureus (MRSA). He received intravenous vancomycin and was discharged after that. However, he continued to complain of episodic abdominal discomfort. Computed tomography (CT) of the abdomen 6 weeks after discharge revealed a pancreatic abscess. He was re-admitted and intravenous antibiotics (cefepime and metronidazole) commenced. Pancreatic necrosectomy and cholecystectomy was performed; cultures of the pus were positive for MRSA and Klebsiella sp. Postoperative blood cultures were also positive for MRSA and vancomycin was added to the antibiotic regimen. TPN was commenced after the first postoperative week. The patient developed another febrile episode a few days later and cultures of the blood, urine and the tip of the removed central venous catheter were all positive for Candida albicans. A total of 180 mg of amphotericin was given over 14 days. Bladder irrigation with amphotericin was also carried out over three days. Repeat blood and urine cultures performed several days after the institution of amphotericin were negative for candida. He was discharged after 5 weeks in hospital. Two months later, he was re-admitted for neck pain that had been worsening over the preceding three weeks. He was afebrile, and appeared fairly comfortable although neck movements were limited in all directions due to pain. Examination of the circulatory and respiratory systems, and of the abdomen, was unremarkable. No neurological deficit was detected. The haemoglobin (Hb) was 10.4 g/dl, white cell count (WCC) was 8.5!109 lK1 (polymorphs 73%) and the platelet (plt) count was 352!109 lK1. The erythrocyte sedimentation rate (ESR) was 110 mm/h. The chest radiograph (CXR) showed clear lung fields. Blood and urine cultures performed on the day of admission were negative. Plain X-rays of the cervical spine (Fig. 1) revealed diminution of the intervertebral space between C5 and C6, associated with a destructive process involving the corresponding vertebral bodies. Magnetic resonance imaging (MRI) of the cervical spine (Fig. 2) was compatible with a diagnosis of infective discitis at C5/6 with associated vertebral osteomyelitis and epidural abscess.
S.L. Chia et al.
Figure 1 Lateral plain X-ray of the cervical spine of Case 1, showing destruction and collapse of the C5/C6 disc space.
Intravenous vancomycin, ceftazidime and amphotericin were commenced empirically based on his previous microbiological history. Anterior cervical decompression comprising C5/6 discectomy with limited adjacent vertebral corpectomy,
Figure 2 Saggital T1-weighted MRI images of the cervical spine of Case 1. Note the destruction of the C5/C6 interspace as well as involvement of the adjacent vertebral bodies. There is an associated epidural abscess (arrow).
Candida spondylodiscitis and epidural abscess followed by fusion with autogenous iliac bone grafting was performed a few days later. No plating/instrumentation was employed. The findings at surgery correlated well with the MRI study. Cultures of the necrotic intervertebral disc grew C. albicans. Histology confirmed the presence of osteomyelitis of the adjacent vertebrae. Intravenous vancomycin and ceftazidime was continued for one week following surgery, and intravenous amphotericin for 29 days (a total of 725 mg). There was no clinical nor biochemical evidence of nephrotoxicity during this period of antifungal therapy. Blood cultures taken just prior to cessation of amphotericin therapy were negative for fungal pathogens. Oral fluconazole 200 mg daily was then continued until the ESR was normal (a total of 3 months). This was well tolerated by the patient. Blood cultures taken following discontinuation of fluconazole were negative. At his most recent review at one year after surgery, he was ambulant with functionally adequate and pain-free neck movements.
Case 2 A 50-year-old man was admitted with left-sided chest pain that was accompanied by fever and rigors. His other complaint was that of pain in the upper back in the preceding week. He had an allergy to penicillin. His prior medical history was as follows: he was a chronic Hepatitis B carrier, and had been diagnosed with Stage IIb non-Hodgkin’s lymphoma 4 years before admission. He had received a course of chemotherapy, and was in clinical remission. Six months before the current admission, he suffered a relapse. He was scheduled for stem cell transplantation and received high-dose cyclophosphamide with a view to peripheral blood stem cell mobilisation. The harvested stem cells were culturepositive for C. tropicalis. He was started on amphotericin and received 1 g of it. The patient was then started on fluconazole 200 mg daily (this was continued until the time of his present admission). He was also on low dose steroid therapy (prednisolone 5 mg daily) during this period. One month before admission he was admitted for pyrexia. A CT scan of the abdomen and pelvis was negative, but a CT scan of the thorax revealed bilateral subpleural nodules and prominent scars, thought to be granulomata, in the right upper lobe. Histology of the latter lesions (obtained via thoracoscopic biopsy) was consistent with pneumonia with marked granulomatous inflammation. Culture of the biopsy specimens, as well as fungal and
19 mycobacterial acid-fast bacteria (AFB) stains were all negative. Upper respiratory cultures grew Enterobacter on subculture. Bone marrow aspiration biopsy was negative for lymphoma, and bacterial and mycobacterial cultures of marrow aspirate grew no organisms. Repeated blood cultures were likewise negative. He was discharged after 10 days in hospital and the fluconazole was continued without interruption. At the current admission he was noted to be febrile and tachypnoeic, and appeared pale. Auscultation of the lungs revealed bi-basal crackles with reduced air entry over the lower left chest. Neurological examination was unremarkable. The Hb was 6.6 g/dl, WCC was 2.65!109 lK1 (neutrophils 49%, lymphocytes 21%, monocytes 24%) and the plt count was 49!109 lK1. Serum creatinine was 356 mmol/l. CXR showed infiltrates in the left lung field. Plain X-rays of the thoracic spine revealed reduction of the disc space height between T7 and T8 as well as erosion of the endplates of the adjacent vertebral bodies (Fig. 3). An MRI of the thoracic spine was ordered, and this revealed changes consistent with spondylodisciitis at T7/T8 associated with osteomyelitis of T7 and T8 vertebrae. There was also an epidural abscess
Figure 3 Lateral plain X-ray of the thoracic spine of Case 2. The T7/T8 interspace is markedly diminished and there is erosion of the adjacent end-plates.
20 causing significant narrowing of the spinal canal at that level (Fig. 4). Blood and sputum cultures at admission were negative. The patient was started on intravenous clindamycin, ciprofloxacin and vancomycin for pneumonia. Empiric anti-tuberculous therapy was also initiated (isoniazid, rifampicin, ethambutol). Surgery was advised towards the end of the first week of hospitalisation on the basis of the MRI findings and the development of extensor plantar reflexes. Anterior decompression through a right lateral thoracotomy was performed. At surgery, the T7/8 intervertebral disc and adjacent vertebral bodies were found to be destroyed and replaced by a large mass of granulation tissue. No pus or caseation was found. The T7/T8 necrotic disc together with the affected halves of the adjacent vertebral bodies were resected, and the resulting gap was bridged with autogenous rib graft. No instrumentation was employed. Histology of the removed necrotic bone was consistent with osteomyelitis, and cultures grew C. tropicalis. Intravenous amphotericin was started and in all 630 mg was administered over a period of 21 days. During this period no deterioration in renal function was noted. Blood fungal cultures taken just prior to discharge from hospital were negative. Oral fluconazole 400 mg twice a day was then prescribed for a further 3 months on an outpatient basis while monitoring the ESR. Two sets of blood cultures taken at an interval of two weeks, following cessation of fluconazole therapy, were both negative. More than a year has since elapsed and the patient has remained well, with no residual neurological deficit.
Figure 4 Saggital T2-weighted MRI images of the thoracic spine of Case 2. There is significant T7/T8 disciitis and osteomyelitis of the adjacent vertebrae, and there is an epidural abscess (arrow) causing cord compression.
S.L. Chia et al.
Discussion Although infections of the spine were described as early as the 4th century BC in the writings of Hippocrates, spinal infections are uncommon and comprise only about 1% of all skeletal infections.7 Most of these infections are pyogenic or tuberculous in nature, and fungal infections, while increasing in recent years, are still extremely rare, with most occurring as opportunistic infections in immunocompromised patients.8 In spite of the increasing frequency of candidaemia, Candida is still a relatively uncommon cause of spinal infection,9 with fewer than 60 cases reported over the past 30 years in our review of the world literature—this is corroborated by a recent review which found only 59 cases, including their series of six.10 The usual risk factors for candidaemia include receipt of prolonged periods of broad-spectrum antibiotics, intensive care unit hospitalisation, prolonged use of indwelling vascular catheters, steroid therapy, transplantation and chemotherapy.2–5,7,11 Intra-venous drug abusers also appear to be at risk.8,12,13 The extended administration of wide-spectrum antimicrobial pharmacotherapy alters the normal muco-cutaneous microbial flora leading to overgrowth of Candida species, while vascular access procedures provide portals of entry leading to haematogenous dissemination. Candida spondylodiscitis is a recognised late complication of candidaemia,3,5 and has been reported to occur more than a year following the initial episode of fungaemia,10,14 the range being 2–15 months. Any bone or joint symptom in a patient with a recent history of candidaemia should be evaluated for an infective aetiology of fungal origin. Both of our patients had a history of candidaemia, although in both of them, it appeared to have been adequately treated. It is possible that the dose of fluconazole in Case 2 prior to the development of back symptoms was somewhat low. Nevertheless it has been reported that a course of amphotericin adequate to control the acute episode of disseminated candidiasis may not prevent osteomyelitis.2 We postulate that the vertebral body and, in particular, the intervertebral disc with its unique blood supply and tissue composition may represent privileged sites that can harbour fungal pathogens from complete pharmacologic and immunologic clearance, particularly in the immunocompromised patient. This may have been the case in patient 2, who developed an epidural abscess with concomitant upper motor neuron signs while on oral fluconazole. The most common location of Candida spondylodiscitis is the lumbar spine, and pain appears to be
Candida spondylodiscitis and epidural abscess the most frequent presenting complaint, while neurological impairment seems to be relatively infrequent.8 In contrast to pyogenic and tuberculous spinal infections, the formation of epidural abscesses is distinctly uncommon. In a 10-year review of epidural abscesses encompassing 40 patients, Hlavin et al. did not find a single case in which Candida was the causative agent.15 Indeed, Derkinderen et al. reported as late as 2000 what they believed to be the first documented case of epidural involvement in a case of candidal dorsal spondylodiscitis in a young female intravenous drug abuser.6 Bonomo et al. reported two patients with epidural abscess due to Candida (Torulopsis glabrata), but in both their patients the T. glabrata was isolated as part of a polymicrobial flora.16 In their series of six patients with candida spondylodiscitis, Hendrickx et al. described one patient in whom ‘extension of the infection into the vertebral canal’ occurred while the patient was on fluconazole.10 In one other recent report of Candida tropicalis osteomyelitis of the thoracic vertebra, Eisen et al. described a ‘thin rim contrast enhancing extradural tissue consistent with granulation tissue’.17 The optimal management of candidal infections of the spine remains uncertain, no doubt related in part to the paucity of cases managed by any one institution. However, several observations may be made based on our review of the relevant literature and our experience with these cases. Surgery does not appear to be mandatory in the management of candidal vertebral osteomyelitis.2,3,5,11,18,19 Nevertheless, Hendrickx et al. found that in their series of six patients, all did poorly on medical therapy alone.10 It would therefore appear that in minimally symptomatic patients with no signs of cord or root compression and no radiological evidence of significant spinal instability, immobilisation of the affected spinal segment and pharmacotherapy with an appropriate anti-fungal agent may be advocated as the initial treatment of choice. This has been shown by several authors to achieve good short to medium term results.2,3,5,11,12,18–21 Obviously, the development of progressive neurological impairment, and worsening symptoms, particularly in the presence of corroborative imaging studies, are indications for surgical spinal decompression and stabilisation. The management of epidural abscess, on the other hand, typically involves surgical drainage, particularly in the cervical spine where the canal is narrow and cord damage from the combination of compression and ischaemia is more likely and the consequences potentially more devastating.15 Nonetheless, Derkinderen et al. reported successful non-operative management of a patient with a
21 dorsal epidural abscess due to C. albicans.6 We propose that the indications for surgery in cases of epidural abscess due to Candida should be similar to the decision processes for the management of pyogenic epidural abscesses. Surgery is generally indicated in the presence of neurological abnormality (particularly when it is progressive) and when the abscess is large. As epidural abscesses occurring in the cervical spine are known to present an increased risk to the spinal cord,15 the threshold for operative intervention in such situations should be lower. Amphotericin B, 5-flucytosine and ketoconazole are some of the traditional anti-fungal agents that have been used in the management of deep candidal infections. Amphotericin B has been described as the gold standard for the treatment of candidal osteomyelitis and arthritis.9 There is little data on the penetration of amphotericin B into bone. There is also no consensus on the duration of therapy. A six- to 10-week course of amphotericin B at 0.5–0.6 mg/kg/day has been advocated by some authorities.22 Fluconazole is a relatively new tri-azole that has been shown in controlled trials to be at least as effective as amphotericin in the management of candidaemia while having a better safety and tolerability profile.23–26 The concentration of fluconazole in joint fluid in one patient with Candida albicans septic arthritis was measured by O’Meeghan et al. This patient, who was successfully treated with a combination of joint washout and 12 weeks of fluconazole, had joint fluid levels approximating those in plasma.27 Data on the bone penetration of fluconazole, however, is less encouraging. In a study that used positron emission tomography, the penetration of fluconazole into bone was about a third of corresponding blood levels.28 The authors concluded that the standard dose of 400 mg a day, while adequate for urinary tract and hepato-splenic candidiasis, might be ‘problematic’ in the treatment of candidal osteomyelitis. Nevertheless, several groups have reported the successful use of fluconazole in the treatment of candidal osteoarticular infections, including spondylodiscitis.5,19,29,30 Previous case reports have used regimens of up to 6 months’ of oral fluconazole.5,19,24,29,30 Our experience with these two patients suggests that surgery, in combination with initial treatment with intravenous amphotericin followed by oral fluconazole, may be a reasonable approach. This is in line with the recommendations of an expert committee on the management of serious candidal infections.22 Continuing drug therapy until the ESR becomes
22 normal may be advisable. This may be achieved in three months after adequate surgical debridement. Several studies have documented that a delay in diagnosis is common where fungal spine infections are concerned.7,31,32 This has been attributed to the rarity of the condition, and to the difficulty in culturing the organisms. It has also been suggested that a delay in initiation of anti-fungal therapy is associated with a poorer outcome, particularly in terms of neurological recovery.32 We suggest that the favourable outcome experienced by both of our patients was due in large part to the close attention paid to microbiologic details. In case 1, anti-fungal therapy was initiated from the first day, based on previous microbiology results. In case 2, the thorough sending of specimens to the appropriate laboratories permitted anti-fungal therapy to be started fairly rapidly, since the granulomata and the pneumonia had led the attending doctors to treat him for tuberculosis (instead of candidiasis) initially.
Conclusion Patients who present with evidence of spinal infection should be evaluated for candidiasis, especially when they have a previous history of candidaemia. We emphasize the importance of a careful clinical review (including review of microbiological data) and the sending of all operative specimens for a complete set of cultures in all patients presenting with spinal infections when risk factors are present. A good outcome may generally be expected in candidal osteomyelitis with early diagnosis and appropriate surgical and pharmacological treatment. Oral fluconazole following a period of intravenous amphotericin appears to be effective in the management of candidal spondylodiscitis complicated by epidural abscess formation, after adequate surgical drainage. Treatment until a normal ESR is attained is ideal, and this may be as short as three months when surgical drainage has been adequately performed.
References 1. Edwards Jr JE, Lehrer RI, Stiehm ER, Fischer TJ, Young LS. Severe candidal infections: clinical perspective, immune defense mechanisms, and current concepts of therapy. Ann Intern Med 1978;89(1):91–106. 2. Gathe JC, Harris RL, Garland B, Bradshaw MW, Williams TW. Candida osteomyelitis: report of five cases and review of the literature. Am J Med 1987;82:927–37.
S.L. Chia et al. 3. Almekinders LC, Greene WB. Vertebral candida infections: a case report and review of the literature. Clin Orthop Rel Res 1991;267:174–8. 4. Kashimoto T, Kitagawa H, Kachi H. Candida tropicalis vertebral osteomyelitis and discitis. Spine 1986;11(1):57–61. 5. Hennequin C, Bouree P, Hiesse C, Dupont B, Charpentier B. Spondylodiskitis due to Candida albicans: report of two patients who were successfully treated with fluconazole and review of the literature. Clin Infect Dis 1996;23:176–8. 6. Derkinderen P, Bruneel F, Bouchard O, Regnier B. Spondylodiscitis and epidural abscess due to Candida albicans. Eur Spine J 2000;9(1):72–4. 7. Ghanayem AJ, Zdeblick TA. Cervical spine infections. Orthop Clin North Am 1996;27(1):53–67. 8. Broner FA, Garland DE, Zigler JE. Spinal infections in the immunocompromised host. Orthop Clin North Am 1996; 27(1):37–46. 9. Johnson MD, Perfect JR. Fungal infections of the bones and joints. Curr Infect Dis Rep 2001;3:450–60. 10. Hendrickx L, Van Wijngaerden E, Samson I, Peetermans WE. Candidal vertebral osteomyelitis: report of 6 patients, and a review. Clin Infect Dis 2001;32:527–33. 11. Hirschmann JV, Everett ED. Candida vertebral osteomyelitis: case report and review of the literature. J Bone Jt Surg 1976; 58-A(4):573–5. 12. Friedman BC, Simon GL. Candida vertebral osteomyelitis: report of three cases and a review of the literature. Diagn Microbiol Infect Dis 1987;8:31–6. 13. Dupont B, Drouhet E. Cutaneous, ocular and osteoarticular candidiasis in heroin addicts: new clinical and therapeutic aspects in 38 patients. J Infect Dis 1985;152:577–91. 14. Ferra C, Doebbeling BN, Hollis RJ, Pfaller MA, Lee KC, Gingrich RD. Candida tropicalis vertebral osteomyelitis: a late sequela of fungemia. Clin Infect Dis 1994;19(4): 697–703. 15. Hlavin ML, Kaminski HJ, Ross JS, Ganz E. Spinal epidural abscess: a 10-year perspective. Neurosurgery 1990;27(2): 177–84. 16. Bonomo RA, Strauss M, Blinkhorn R, Salata RA. Torulopsis (Candida) glabrata: a new pathogen found in spinal epidural abscess. Clin Infect Dis 1996;22(3):588–9. 17. Eisen DP, MacGinley R, Christensson B, Larsson L, Woods ML. Candida tropicalis vertebral osteomyelitis complicating epidural catheterisation with disease paralleled by elevated D-arabinitol/L-arabinitol ratios. Eur J Clin Microbiol Infect Dis 2000;19:61–3. 18. Pohjola-Sintonen S, Ruutu P, Tallroth K. Hematogenous Candida spondylitis. A case report. Acta Med Scand 1984; 215(1):85–7. 19. Lafont A, Olive A, Gelman M, Roca-Burniols J, Cots R, Carbonell J. Candida albicans spondylodiscitis and vertebral osteomyelitis in patients with intravenous heroin drug addiction. Report of 3 new cases. J Rheumatol 1994;21(5): 953–6. 20. Sugar AM, Saunders C, Diamond RD. Successful treatment of Candida osteomyelitis with fluconazole. A noncomparative study of two patients. Diagn Microbiol Infect Dis 1990;13(6): 517–20. 21. Dijkmans BA, Koolen MI, Mouton RP, Falke TH, van den Broek PJ, van der Meer JW. Hematogenous Candida vertebral osteomyelitis treated with ketoconazole. Infection 1982;10(5):290–2. 22. Rex JH, Walsh TJ, Sobel JD, Filler SG, Pappas PG, Dismukes WE, Edwards JE. Practice guidelines for the treatment of candidiasis. Clin Infect Dis 2000;30:662–78. 23. Anaissie EJ, Darouiche RO, Abi-Said D, Uzun O, Mera J, Gentry LO, Williams T, Kontoyiannis DP, Karl CL, Bodey GP.
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Pharmacokinetics of 18F-labelled fluconazole in healthy human subjects by positron emission tomography. Antimicrob Agents Chemother 1993;37:1270–7. Perez-Gomez A, Prieto A, Torresano M, Diez E, Mulero J, Labiano I, Andreu JL. Role of the new azoles in the treatment of fungal osteoarticular infections. Semin Arthritis Rheum 1998;27(4):226–44. Weers-Pothoff G, Havermans JF, Kamphuis J, Sinnige HA, Meis JF. Candida tropicalis arthritis in a patient with acute myeloid leukaemia successfully treated with fluconazole: case report and review of the literature. Infection 1997; 25(2):109–11. Garvey TA, Eismont FJ. Tuberculous and fungal osteomyelitis of the spine. Semin Spine Surg 1990;2:295–308. Frazier DD, Campbell DR, Garvey TA, Wiesel S, Bohlman HH, Eismont FJ. Fungal infections of the spine: report of eleven patients with long-term follow-up. J Bone Jt Surg (Am) 2001; 83-A(4):560–5.
www.elsevierhealth.com/journals/jinf
Candida spondylodiscitis and epidural abscess: management with shorter courses of anti-fungal therapy in combination with surgical debridement S.L. Chiaa,*, B.H. Tanb, C.T. Tana, S.B. Tana a
Department of Orthopaedic Surgery, Singapore General Hospital, Singapore Department of Internal Medicine, Singapore General Hospital, Singapore
b
Accepted 17 August 2004 Available online 29 September 2004
KEYWORDS Fungal infection; Spine; Candida; Epidural abscess; Management; Fluconazole
Abstract Epidural abscess associated with candidal spondylodiscitis is rarely seen, particularly when it involves the cervical and thoracic spine. We report two such cases that were successfully managed with early surgical debridement, as well as medical therapy with intravenous amphotericin followed by oral fluconazole. The literature related to candidal spinal infection is reviewed, and a rational approach to the management of this uncommon condition is proposed. A good outcome may generally be expected with early diagnosis as well as appropriate surgical and pharmacological treatment. Oral fluconazole appears to be useful in the management of candida spondylodiscitis complicated by epidural abscess formation. Treatment until a normal ESR is attained is ideal, and this may be as short as 3 months when surgical drainage has been adequately performed. Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
Introduction Although Candida is known to affect virtually any tissue or organ system within the body,1 infection of bone, or cartilage, or both is uncommon in clinical practice and in the literature.2–5 In particular, Candida infection involving the cervical and thoracic spine has been rarely reported over the past 30 years, and epidural abscess associated with Candida spondylodiscitis has been virtually unreported.6 We report one case each of cervical and thoracic
spondylodiscitis (both associated with epidural abscess) due to candida that were successfully treated with surgery followed by a 3-month course of fluconazole, and discuss their risk profiles, management and subsequent outcome in relation to the available literature on fungal infections of the spine.
Reports Case 1
* Corresponding author. Tel.: C65 6321 4047; fax: C65 6224 8100. E-mail address: [email protected] (S.L. Chia).
A 63-year-old man with a history of hypertension and poorly-controlled Type II diabetes mellitus had
0163-4453/$30.00 Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2004.08.020
18 been hospitalised 7 months earlier for acute haemorrhagic pancreatitis that was associated with chronic calculous cholecystitis. During this hospitalisation, he received a variety of broadspectrum antibiotics (imipenem, ceftazidime and ciprofloxacin, at different times), and was also on total parenteral nutrition (TPN). Towards the end of his stay he developed a febrile episode and cultures of the blood and the tip of a central venous catheter were positive for methicillin-resistant Staphylococcus aureus (MRSA). He received intravenous vancomycin and was discharged after that. However, he continued to complain of episodic abdominal discomfort. Computed tomography (CT) of the abdomen 6 weeks after discharge revealed a pancreatic abscess. He was re-admitted and intravenous antibiotics (cefepime and metronidazole) commenced. Pancreatic necrosectomy and cholecystectomy was performed; cultures of the pus were positive for MRSA and Klebsiella sp. Postoperative blood cultures were also positive for MRSA and vancomycin was added to the antibiotic regimen. TPN was commenced after the first postoperative week. The patient developed another febrile episode a few days later and cultures of the blood, urine and the tip of the removed central venous catheter were all positive for Candida albicans. A total of 180 mg of amphotericin was given over 14 days. Bladder irrigation with amphotericin was also carried out over three days. Repeat blood and urine cultures performed several days after the institution of amphotericin were negative for candida. He was discharged after 5 weeks in hospital. Two months later, he was re-admitted for neck pain that had been worsening over the preceding three weeks. He was afebrile, and appeared fairly comfortable although neck movements were limited in all directions due to pain. Examination of the circulatory and respiratory systems, and of the abdomen, was unremarkable. No neurological deficit was detected. The haemoglobin (Hb) was 10.4 g/dl, white cell count (WCC) was 8.5!109 lK1 (polymorphs 73%) and the platelet (plt) count was 352!109 lK1. The erythrocyte sedimentation rate (ESR) was 110 mm/h. The chest radiograph (CXR) showed clear lung fields. Blood and urine cultures performed on the day of admission were negative. Plain X-rays of the cervical spine (Fig. 1) revealed diminution of the intervertebral space between C5 and C6, associated with a destructive process involving the corresponding vertebral bodies. Magnetic resonance imaging (MRI) of the cervical spine (Fig. 2) was compatible with a diagnosis of infective discitis at C5/6 with associated vertebral osteomyelitis and epidural abscess.
S.L. Chia et al.
Figure 1 Lateral plain X-ray of the cervical spine of Case 1, showing destruction and collapse of the C5/C6 disc space.
Intravenous vancomycin, ceftazidime and amphotericin were commenced empirically based on his previous microbiological history. Anterior cervical decompression comprising C5/6 discectomy with limited adjacent vertebral corpectomy,
Figure 2 Saggital T1-weighted MRI images of the cervical spine of Case 1. Note the destruction of the C5/C6 interspace as well as involvement of the adjacent vertebral bodies. There is an associated epidural abscess (arrow).
Candida spondylodiscitis and epidural abscess followed by fusion with autogenous iliac bone grafting was performed a few days later. No plating/instrumentation was employed. The findings at surgery correlated well with the MRI study. Cultures of the necrotic intervertebral disc grew C. albicans. Histology confirmed the presence of osteomyelitis of the adjacent vertebrae. Intravenous vancomycin and ceftazidime was continued for one week following surgery, and intravenous amphotericin for 29 days (a total of 725 mg). There was no clinical nor biochemical evidence of nephrotoxicity during this period of antifungal therapy. Blood cultures taken just prior to cessation of amphotericin therapy were negative for fungal pathogens. Oral fluconazole 200 mg daily was then continued until the ESR was normal (a total of 3 months). This was well tolerated by the patient. Blood cultures taken following discontinuation of fluconazole were negative. At his most recent review at one year after surgery, he was ambulant with functionally adequate and pain-free neck movements.
Case 2 A 50-year-old man was admitted with left-sided chest pain that was accompanied by fever and rigors. His other complaint was that of pain in the upper back in the preceding week. He had an allergy to penicillin. His prior medical history was as follows: he was a chronic Hepatitis B carrier, and had been diagnosed with Stage IIb non-Hodgkin’s lymphoma 4 years before admission. He had received a course of chemotherapy, and was in clinical remission. Six months before the current admission, he suffered a relapse. He was scheduled for stem cell transplantation and received high-dose cyclophosphamide with a view to peripheral blood stem cell mobilisation. The harvested stem cells were culturepositive for C. tropicalis. He was started on amphotericin and received 1 g of it. The patient was then started on fluconazole 200 mg daily (this was continued until the time of his present admission). He was also on low dose steroid therapy (prednisolone 5 mg daily) during this period. One month before admission he was admitted for pyrexia. A CT scan of the abdomen and pelvis was negative, but a CT scan of the thorax revealed bilateral subpleural nodules and prominent scars, thought to be granulomata, in the right upper lobe. Histology of the latter lesions (obtained via thoracoscopic biopsy) was consistent with pneumonia with marked granulomatous inflammation. Culture of the biopsy specimens, as well as fungal and
19 mycobacterial acid-fast bacteria (AFB) stains were all negative. Upper respiratory cultures grew Enterobacter on subculture. Bone marrow aspiration biopsy was negative for lymphoma, and bacterial and mycobacterial cultures of marrow aspirate grew no organisms. Repeated blood cultures were likewise negative. He was discharged after 10 days in hospital and the fluconazole was continued without interruption. At the current admission he was noted to be febrile and tachypnoeic, and appeared pale. Auscultation of the lungs revealed bi-basal crackles with reduced air entry over the lower left chest. Neurological examination was unremarkable. The Hb was 6.6 g/dl, WCC was 2.65!109 lK1 (neutrophils 49%, lymphocytes 21%, monocytes 24%) and the plt count was 49!109 lK1. Serum creatinine was 356 mmol/l. CXR showed infiltrates in the left lung field. Plain X-rays of the thoracic spine revealed reduction of the disc space height between T7 and T8 as well as erosion of the endplates of the adjacent vertebral bodies (Fig. 3). An MRI of the thoracic spine was ordered, and this revealed changes consistent with spondylodisciitis at T7/T8 associated with osteomyelitis of T7 and T8 vertebrae. There was also an epidural abscess
Figure 3 Lateral plain X-ray of the thoracic spine of Case 2. The T7/T8 interspace is markedly diminished and there is erosion of the adjacent end-plates.
20 causing significant narrowing of the spinal canal at that level (Fig. 4). Blood and sputum cultures at admission were negative. The patient was started on intravenous clindamycin, ciprofloxacin and vancomycin for pneumonia. Empiric anti-tuberculous therapy was also initiated (isoniazid, rifampicin, ethambutol). Surgery was advised towards the end of the first week of hospitalisation on the basis of the MRI findings and the development of extensor plantar reflexes. Anterior decompression through a right lateral thoracotomy was performed. At surgery, the T7/8 intervertebral disc and adjacent vertebral bodies were found to be destroyed and replaced by a large mass of granulation tissue. No pus or caseation was found. The T7/T8 necrotic disc together with the affected halves of the adjacent vertebral bodies were resected, and the resulting gap was bridged with autogenous rib graft. No instrumentation was employed. Histology of the removed necrotic bone was consistent with osteomyelitis, and cultures grew C. tropicalis. Intravenous amphotericin was started and in all 630 mg was administered over a period of 21 days. During this period no deterioration in renal function was noted. Blood fungal cultures taken just prior to discharge from hospital were negative. Oral fluconazole 400 mg twice a day was then prescribed for a further 3 months on an outpatient basis while monitoring the ESR. Two sets of blood cultures taken at an interval of two weeks, following cessation of fluconazole therapy, were both negative. More than a year has since elapsed and the patient has remained well, with no residual neurological deficit.
Figure 4 Saggital T2-weighted MRI images of the thoracic spine of Case 2. There is significant T7/T8 disciitis and osteomyelitis of the adjacent vertebrae, and there is an epidural abscess (arrow) causing cord compression.
S.L. Chia et al.
Discussion Although infections of the spine were described as early as the 4th century BC in the writings of Hippocrates, spinal infections are uncommon and comprise only about 1% of all skeletal infections.7 Most of these infections are pyogenic or tuberculous in nature, and fungal infections, while increasing in recent years, are still extremely rare, with most occurring as opportunistic infections in immunocompromised patients.8 In spite of the increasing frequency of candidaemia, Candida is still a relatively uncommon cause of spinal infection,9 with fewer than 60 cases reported over the past 30 years in our review of the world literature—this is corroborated by a recent review which found only 59 cases, including their series of six.10 The usual risk factors for candidaemia include receipt of prolonged periods of broad-spectrum antibiotics, intensive care unit hospitalisation, prolonged use of indwelling vascular catheters, steroid therapy, transplantation and chemotherapy.2–5,7,11 Intra-venous drug abusers also appear to be at risk.8,12,13 The extended administration of wide-spectrum antimicrobial pharmacotherapy alters the normal muco-cutaneous microbial flora leading to overgrowth of Candida species, while vascular access procedures provide portals of entry leading to haematogenous dissemination. Candida spondylodiscitis is a recognised late complication of candidaemia,3,5 and has been reported to occur more than a year following the initial episode of fungaemia,10,14 the range being 2–15 months. Any bone or joint symptom in a patient with a recent history of candidaemia should be evaluated for an infective aetiology of fungal origin. Both of our patients had a history of candidaemia, although in both of them, it appeared to have been adequately treated. It is possible that the dose of fluconazole in Case 2 prior to the development of back symptoms was somewhat low. Nevertheless it has been reported that a course of amphotericin adequate to control the acute episode of disseminated candidiasis may not prevent osteomyelitis.2 We postulate that the vertebral body and, in particular, the intervertebral disc with its unique blood supply and tissue composition may represent privileged sites that can harbour fungal pathogens from complete pharmacologic and immunologic clearance, particularly in the immunocompromised patient. This may have been the case in patient 2, who developed an epidural abscess with concomitant upper motor neuron signs while on oral fluconazole. The most common location of Candida spondylodiscitis is the lumbar spine, and pain appears to be
Candida spondylodiscitis and epidural abscess the most frequent presenting complaint, while neurological impairment seems to be relatively infrequent.8 In contrast to pyogenic and tuberculous spinal infections, the formation of epidural abscesses is distinctly uncommon. In a 10-year review of epidural abscesses encompassing 40 patients, Hlavin et al. did not find a single case in which Candida was the causative agent.15 Indeed, Derkinderen et al. reported as late as 2000 what they believed to be the first documented case of epidural involvement in a case of candidal dorsal spondylodiscitis in a young female intravenous drug abuser.6 Bonomo et al. reported two patients with epidural abscess due to Candida (Torulopsis glabrata), but in both their patients the T. glabrata was isolated as part of a polymicrobial flora.16 In their series of six patients with candida spondylodiscitis, Hendrickx et al. described one patient in whom ‘extension of the infection into the vertebral canal’ occurred while the patient was on fluconazole.10 In one other recent report of Candida tropicalis osteomyelitis of the thoracic vertebra, Eisen et al. described a ‘thin rim contrast enhancing extradural tissue consistent with granulation tissue’.17 The optimal management of candidal infections of the spine remains uncertain, no doubt related in part to the paucity of cases managed by any one institution. However, several observations may be made based on our review of the relevant literature and our experience with these cases. Surgery does not appear to be mandatory in the management of candidal vertebral osteomyelitis.2,3,5,11,18,19 Nevertheless, Hendrickx et al. found that in their series of six patients, all did poorly on medical therapy alone.10 It would therefore appear that in minimally symptomatic patients with no signs of cord or root compression and no radiological evidence of significant spinal instability, immobilisation of the affected spinal segment and pharmacotherapy with an appropriate anti-fungal agent may be advocated as the initial treatment of choice. This has been shown by several authors to achieve good short to medium term results.2,3,5,11,12,18–21 Obviously, the development of progressive neurological impairment, and worsening symptoms, particularly in the presence of corroborative imaging studies, are indications for surgical spinal decompression and stabilisation. The management of epidural abscess, on the other hand, typically involves surgical drainage, particularly in the cervical spine where the canal is narrow and cord damage from the combination of compression and ischaemia is more likely and the consequences potentially more devastating.15 Nonetheless, Derkinderen et al. reported successful non-operative management of a patient with a
21 dorsal epidural abscess due to C. albicans.6 We propose that the indications for surgery in cases of epidural abscess due to Candida should be similar to the decision processes for the management of pyogenic epidural abscesses. Surgery is generally indicated in the presence of neurological abnormality (particularly when it is progressive) and when the abscess is large. As epidural abscesses occurring in the cervical spine are known to present an increased risk to the spinal cord,15 the threshold for operative intervention in such situations should be lower. Amphotericin B, 5-flucytosine and ketoconazole are some of the traditional anti-fungal agents that have been used in the management of deep candidal infections. Amphotericin B has been described as the gold standard for the treatment of candidal osteomyelitis and arthritis.9 There is little data on the penetration of amphotericin B into bone. There is also no consensus on the duration of therapy. A six- to 10-week course of amphotericin B at 0.5–0.6 mg/kg/day has been advocated by some authorities.22 Fluconazole is a relatively new tri-azole that has been shown in controlled trials to be at least as effective as amphotericin in the management of candidaemia while having a better safety and tolerability profile.23–26 The concentration of fluconazole in joint fluid in one patient with Candida albicans septic arthritis was measured by O’Meeghan et al. This patient, who was successfully treated with a combination of joint washout and 12 weeks of fluconazole, had joint fluid levels approximating those in plasma.27 Data on the bone penetration of fluconazole, however, is less encouraging. In a study that used positron emission tomography, the penetration of fluconazole into bone was about a third of corresponding blood levels.28 The authors concluded that the standard dose of 400 mg a day, while adequate for urinary tract and hepato-splenic candidiasis, might be ‘problematic’ in the treatment of candidal osteomyelitis. Nevertheless, several groups have reported the successful use of fluconazole in the treatment of candidal osteoarticular infections, including spondylodiscitis.5,19,29,30 Previous case reports have used regimens of up to 6 months’ of oral fluconazole.5,19,24,29,30 Our experience with these two patients suggests that surgery, in combination with initial treatment with intravenous amphotericin followed by oral fluconazole, may be a reasonable approach. This is in line with the recommendations of an expert committee on the management of serious candidal infections.22 Continuing drug therapy until the ESR becomes
22 normal may be advisable. This may be achieved in three months after adequate surgical debridement. Several studies have documented that a delay in diagnosis is common where fungal spine infections are concerned.7,31,32 This has been attributed to the rarity of the condition, and to the difficulty in culturing the organisms. It has also been suggested that a delay in initiation of anti-fungal therapy is associated with a poorer outcome, particularly in terms of neurological recovery.32 We suggest that the favourable outcome experienced by both of our patients was due in large part to the close attention paid to microbiologic details. In case 1, anti-fungal therapy was initiated from the first day, based on previous microbiology results. In case 2, the thorough sending of specimens to the appropriate laboratories permitted anti-fungal therapy to be started fairly rapidly, since the granulomata and the pneumonia had led the attending doctors to treat him for tuberculosis (instead of candidiasis) initially.
Conclusion Patients who present with evidence of spinal infection should be evaluated for candidiasis, especially when they have a previous history of candidaemia. We emphasize the importance of a careful clinical review (including review of microbiological data) and the sending of all operative specimens for a complete set of cultures in all patients presenting with spinal infections when risk factors are present. A good outcome may generally be expected in candidal osteomyelitis with early diagnosis and appropriate surgical and pharmacological treatment. Oral fluconazole following a period of intravenous amphotericin appears to be effective in the management of candidal spondylodiscitis complicated by epidural abscess formation, after adequate surgical drainage. Treatment until a normal ESR is attained is ideal, and this may be as short as three months when surgical drainage has been adequately performed.
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