Non-pyogenic infections of the spine

International Journal of Antimicrobial Agents 36 (2010) 99–105

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International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag

Review

Non-pyogenic infections of the spine Ghassan S. Skaf a , Zeina A. Kanafani b , George F. Araj c , Souha S. Kanj b,∗ a

Division of Neurosurgery, Department of Surgery, American University of Beirut Medical Center, Beirut, Lebanon Division of Infectious Diseases, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon c Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon b

a r t i c l e Keywords: Spine Spondylodiscitis Tuberculosis Brucellosis Fungal infection

i n f o

a b s t r a c t Subacute and chronic spondylodiscitis can be caused by a wide spectrum of infectious aetiologies including Mycobacterium tuberculosis, Brucella spp. and a variety of fungi including Aspergillus spp., Candida spp. and Cryptococcus neoformans. Knowledge of the local epidemiology and prior exposure might suggest the aetiology. Non-invasive diagnostic approaches, such as blood culture or antibody titres in the case of Brucella or antigen detection in the case of fungal infections, can be helpful in reaching the diagnosis. However, direct aspiration or tissue biopsy is usually necessary to identify the causative organism. Specimens are usually sent for pathology, special stains, cultures and, when indicated, molecular analysis. To minimise morbidity and mortality, antibiotic treatment should be initiated promptly directed against the suspected organism, and later adjusted according to the confirmed aetiology. Surgical treatment is reserved for recurrent infection, unstable spinal segment or marked kyphosis in the face of any neurological deficits and uncontrollable pain. Surgical approaches are dictated by the anatomic location of the offending lesion. Once medical treatment fails and surgery becomes warranted, we advocate the use of a two-stage surgical treatment for non-fixed kyphosis and a three-stage operation for fixed kyphosis. © 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Introduction

2. Epidemiology

Subacute and chronic spinal infections are characterised by a gradual onset of symptoms and an indolent clinical course compared with spondylodiscitis caused by pyogenic organisms such as Staphylococcus aureus and Gram-negative enteric organisms. Subacute and chronic spondylodiscitis is usually caused by a wide spectrum of pathogens, of which Mycobacterium tuberculosis is considered the most common [1]. Other organisms include Brucella spp. in endemic areas [2] and a variety of fungi including Aspergillus spp., Candida spp. and Cryptococcus neoformans [3]. In addition to these non-pyogenic infections, some bacterial infections typically have a protracted course of illness, such as coagulase-negative staphylococci (CoNS), viridans group streptococci and propionibacteria [4]. In this paper, we review the most common offending organisms in non-pyogenic subacute and chronic spine infections and discuss the clinical presentation, diagnosis, complications and treatment. We highlight the importance of establishing a microbiological diagnosis. Appropriate medical and surgical management can then be undertaken accordingly.

The incidence of non-pyogenic chronic spondylodiscitis is difficult to determine as it is closely related to the epidemiology of each of the incriminated organisms in different parts of the world. Spinal tuberculosis, or Pott’s disease, can occur at any age. In general, patient age varies with the prevalence of tuberculosis in the general population. In areas of high endemicity such as Africa and the Indian subcontinent, infection is common in the paediatric age group, whereas in North America and Europe, where the prevalence of the disease is lower, tuberculous spondylodiscitis is more commonly seen in adult patients with a mean age of 40 years [5]. In the last two decades there has been a resurgence of tuberculosis in developed countries as a result of several contributing factors, including the human immunodeficiency virus (HIV) pandemic, the emergence of drug-resistant mycobacterial strains and extensive immigration from countries where tuberculosis is endemic [6,7]. This might lead in the near future to a changing epidemiology of Pott’s disease in these countries. In contrast to tuberculosis, brucellosis is an infection endemic both to industrialised and developing countries [8]. Brucella melitensis is relatively prevalent in the Mediterranean basin [9,10], the Middle East [11,12] and Latin America [13]. Whilst in the USA only 200 cases of brucellosis are reported every year, it is the most frequent zoonosis in Spain [14]. In a recent study from Greece, 11 of 33 patients admitted with spinal infections to a teaching hospital had brucellosis [15].

∗ Corresponding author. Present address: American University of Beirut Medical Center, P.O. Box 11-0236 Cairo Street, Riad El-Solh 1107 2020, Beirut, Lebanon. Tel.: +961 1 350 000; fax: +961 1 370 814. E-mail address: [email protected] (S.S. Kanj).

0924-8579/$ – see front matter © 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2010.03.023

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The most common fungal organisms causing spondylodiscitis include Aspergillus spp., Candida spp. and C. neoformans [3]. Fungal infections of the spine are rare and occur primarily as opportunistic infections in relatively immunocompromised patients. Whereas Cryptococcus, Candida and Aspergillus have a worldwide distribution, other fungi such as Coccidioides immitis and Blastomyces dermatitidis are limited to specific geographical areas. Therefore, residence in or travel to endemic areas should be taken into consideration when evaluating patients with chronic spondylodiscitis. The common denominator in many cases appears to be an incompetent host defence mechanism secondary to conditions such as diabetes mellitus, corticosteroid use, chemotherapy, malnutrition or intravenous (i.v.) drug use. 3. Pathogenesis Spinal infections can occur through one of two routes. The first is through haematogenous spread from a distant focus, of which tuberculosis and brucellosis are important examples. Patients with fungaemia may also have seeding of the vertebral spine [16]. Since the intervertebral disc does not have a direct blood supply in adults, most haematogenous infections of the disc space are the result of dissemination from the adjacent bone. In tuberculous discitis, the organism reaches the metaphysis of the vertebral body via a haematogenous route. In a significant percentage of tuberculous osteomyelitis, the primary infection is not evident. For example, ca. 80% of patients with vertebral tuberculosis do not have evidence of concomitant pulmonary infection [17]. However, in the majority of cases spinal infection results from arterial haematogenous seeding of the mycobacterium, starting from a quiescent pulmonary focus [18]. Spread from an initial pulmonary source has also been described with fungal pathogens [3]. The second route of transmission is through contiguous spread from a soft-tissue infection or by direct inoculation of the organism at the time of a surgical intervention, such as with Candida and Aspergillus [3]. 4. Clinical manifestations The hallmark of subacute and chronic spinal infections is the insidious onset of back pain, with or without the presence of other systemic symptoms. Specific clinical manifestations might suggest the infecting pathogen.

dysphagia or inspiratory stridor [5,21]. Occasionally, a soft-tissue swelling or mass is evident, and in late stages a draining sinus may be seen. Kyphotic deformity of the spine occurs as a consequence of collapse in the anterior spinal elements. Lesions in the thoracic spine have a greater tendency to cause kyphosis than those in the thoracolumbar or lumbar spine [22]. There is an average increase of 15◦ deformity in all patients with spinal tuberculosis who are treated conservatively [23]. Neurological involvement has been reported in 10–61% of patients with tuberculous discitis [20]. Ischaemia of the spine through either direct pressure or thrombosis has been hypothesised as a mechanism of neurological compromise [20]. Bony deformity alone is thought to be an infrequent cause of neurological deficits unless a pathological dislocation or subluxation occurs [20]. The risk of myelopathy or neurological deficit is highest when the infection involves the cervicothoracic region [24]. Vertebral tuberculosis may be complicated by paraplegia due to the presence of radiculomyelitis or arachnoiditis. Tuberculous arachnoiditis of the spine frequently involves the spinal cord as well as the meninges and the nerve roots and is mostly seen in patients with antecedent or coexisting meningitis [21]. Since it can occur despite appropriate treatment, early diagnosis and treatment are mandatory to prevent neurological sequelae [25]. Irreversible paraplegia usually starts late during the active stage of the disease but can occasionally present several years after the infection has been deemed cured. In the latter case it is associated with degeneration of the spinal cord and rarely with vascular changes [26]. Atypical presentations of tuberculous discitis have been reported and include the absence of disc involvement, localisation to a single vertebral body and the exclusive involvement of posterior elements [27]. However, such presentations are unusual and are reported in only 3.7% of all cases [28]. 4.2. Brucellosis Patients with Brucella spondylodiscitis usually present with prominent musculoskeletal complaints (especially back pain) accompanied by constitutional symptoms such as fever, malaise and weight loss [29]. When compared with spondylodiscitis due to pyogenic organisms or tuberculosis, high-grade fever is seen more frequently in patients with Brucella spondylodiscitis [30]. Patients may initially present with sciatica and may be misdiagnosed with lumbar disc herniation owing to non-specific neurological and radiological findings. The delay in diagnosis may lead to rapid progression of the disease and complications [31,32].

4.1. Tuberculosis 4.3. Fungal infections Two distinct patterns of vertebral tuberculosis may be seen: (i) spondylodiscitis characterised by destruction of two or more contiguous vertebrae and opposed end plates, with disc infection and commonly a paraspinal mass or collection; and (ii) an increasingly recognised atypical form of spondylitis without disc involvement [19]. The clinical manifestations are reflective of the systemic illness, the osseous lesion, as well as any neurological complications [20]. Weight loss, fever and malaise may be associated with the chronic illness that often precedes identification of the spinal lesion. Symptoms related to the involvement of other organ systems, including the urinary, pulmonary and lymphatic systems, can be elicited. As noted above, only 20% of patients may have evidence of active pulmonary infection. Although tuberculin skin testing (PPD test) is usually positive, a negative PPD should not exclude the diagnosis. Progressive backache is the predominant clinical feature, associated with spine stiffness and spasm of the paravertebral muscles. Most patients complain of mechanical spinal pain [21]. Cervical involvement may present with torticollis, neck pain and stiffness,

Bone or joint symptoms in patients with fungaemia should raise the suspicion for a focal complication at the time of presentation. In fungal spondylodiscitis, back pain is the most frequent complaint, whilst neurological impairment appears to be relatively infrequent [3]. Kyphosis is also uncommon due to the indolent nature of the infection. Involvement of the vertebral bodies can lead to vertebral compression fractures and deformity of the spine. In addition, spread of infection along the anterior longitudinal ligament can lead to psoas muscle or paravertebral abscesses. 5. Differential diagnosis Pyogenic infections of the spine usually have a more acute presentation and may be accompanied by symptoms of overt sepsis. The differential diagnosis of subacute and chronic spondylodiscitis includes infectious and non-infectious aetiologies. In addition to M. tuberculosis, Brucella and fungal pathogens, organisms that may present with an indolent course include CoNS [33], viridans

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group streptococci [34], Actinomyces [35], Nocardia [36], atypical mycobacteria [37] and Echinococcus [38]. Metastatic disease is usually seen in elderly patients but may be difficult to differentiate from infection without a biopsy. Autoimmune disorders such as sarcoidosis may also involve the spine and mimic infectious spondylodiscitis. 6. Diagnosis Computed tomography (CT)-guided needle aspiration and biopsy is presently the most effective method of establishing the diagnosis in chronic spondylodiscitis [39]. It is an important tool in the evaluation of spinal lesions and a positive result may obviate the need for open surgical intervention [40]. Upon negative results, the diagnosis should be confirmed with core biopsy or clinical evolution [41]. 6.1. Routine blood studies Routine laboratory investigation is usually non-specific in patients with chronic spondylodiscitis, with a normal white blood cell (WBC) count and an elevated erythrocyte sedimentation rate (ESR). The WBC count and ESR tend to be lower in Brucella spondylodiscitis compared with tuberculous or pyogenic spondylitis [9]. However, focal infection in brucellosis can be associated with leukocytosis [2]. 6.2. Microbiological analysis Specimens obtained by CT-guided aspiration or biopsy should be processed for bacterial, fungal and mycobacterial stains and cultures. Microbiological analysis enables definitive diagnosis and may further define treatment via susceptibility testing [42]. Although the growth of M. tuberculosis may take 6 weeks to appear on routine solid media, the availability of the BACTEC® culture system has shortened the detection time by at least 25% in many cases [43]. With brucellosis, blood and tissue cultures are usually positive [44]. A recent study from Turkey showed that 9 of 22 patients had positive blood cultures [45]. The culture yield is higher with the automated systems. When blood cultures are negative, a bone marrow culture can be entertained since it has a 15–20% higher yield [46]. As for fungal infections, early recognition of the disease requires a high index of suspicion. Patients with suspected fungal spondylodiscitis should have blood sent specifically for fungal cultures, especially when Candida or Cryptococcus spp. are suspected. Furthermore, specimens obtained by CT-guided fine needle aspiration should be cultured on Sabouraud media. Unfortunately, fungal stains and culture have been found to be neither sensitive nor specific [42]. 6.3. Serology and antigen detection assays Serological tests are the most relied upon diagnostic tools in cases of suspected brucellosis, and negative serological tests are unusual in Brucella spondylitis [44]. These tests include the standard serum agglutination test (SAT), Coomb’s tests and enzyme-linked immunosorbent assay (ELISA) [46,47]. Coomb’s test is used as an extension of SAT to detect ‘incomplete’, ‘blocking’ or ‘non-agglutinating’ anti-Brucella antibodies such as immunoglobulin G (IgG). This methodology is reliable for the diagnosis of human brucellosis [47,48]. In one study, all patients with Brucella discitis had serum antibody titres of ≥1/160 [45]. However, ELISA proved to be superior to other serological assays in diagnosing chronic and complicated cases of brucellosis. Notwithstanding the utility of serum Brucella antibody detection, caution should be exercised when interpreting serological test findings, especially in endemic

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countries where titres may remain elevated for a long period after an old infection despite treatment and cure [46]. Antigen detection assays are useful in fungal infections where they have a high positive predictive value for the diagnosis of Candida albicans and Aspergillus infections. These tests are based on the detection of circulating cell wall fungal antigens (galactomannan from Aspergillus or mannan from Candida) [49]. With cryptococcal infections, the most reliable method for serodiagnosis is the latex agglutination (LA) test for detection of polysaccharide antigen. It can be used for diagnosis as well as for monitoring of the disease course and response to treatment by serial determination of antigen titres [50]. An ELISA for detection of cryptococcal antigen has been used. It has several potential advantages over LA, including clear and objective discrimination of positive from negative results and the ability to provide quantitative information without endtitre dilution [50]. In addition, ELISA is inherently more sensitive than the LA test in the detection of cryptococcal antigen in body fluid specimens [51]. 6.4. Molecular analysis Application of molecular techniques such as polymerase chain reaction (PCR) has facilitated the early detection and identification of a variety of microorganisms. DNA-based methods are highly sensitive and specific and they can complement standard microbiological methods for identifying the cause of infectious spondylodiscitis in patients with negative blood and disc aspirate cultures [52]. For example, PCR was found to have high sensitivity, specificity and accuracy (95%, 83% and 92%, respectively) in detecting M. tuberculosis from formaldehyde solution-fixed, paraffin-embedded tissue samples from histologically proven tuberculous spondylitis [53]. In addition, a highly sensitive and specific real-time PCR assay for Brucella spp. has recently been described [54]. In one report, quantitative real-time PCR on blood and tissue specimens allowed the diagnosis of brucellar spondylitis within 24 h in a patient with negative results by conventional methods [55]. A study from the American University of Beirut Medical Center aimed to develop a real-time PCR assay for the rapid diagnosis of human brucellosis on clinical specimens [56]. Three assays were developed and compared targeting the 16S–23S internal transcribed spacer (ITS) region and the genes encoding for Omp25 and Omp31. All assays showed 100% analytical sensitivity and 100% specificity when tested on 28 consecutive clinical isolates of Brucella spp. The ITS assay was the most sensitive, with a limit of detection of two genome equivalents per PCR reaction. This assay was then clinically validated prospectively with samples from whole-blood samples and three paraffin-embedded tissues. However, real-time PCR is not being used in routine clinical practice owing to lack of standardisation. Molecular techniques have also been used with fungal infections and have enhanced the sensitivity of conventional methods used in diagnostic mycology [57]. These techniques mainly rely on PCR for the detection of fungal-specific nucleic acids in clinical specimens [49]. 6.5. Pathological examination Although of low sensitivity, demonstration of microorganisms such as acid-fast bacilli (AFB), yeast or fungal hyphae in fluid or tissue obtained by aspiration or biopsy of the infected disc space is very helpful in the setting of chronic infectious discitis. We also rely on the presence of certain pathological findings to assist in the diagnosis.

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In tuberculous discitis, histological findings include the presence of caseating necrosis and giant cell formation with or without a positive Ziehl–Neelsen stain for AFB. In the pre-purulent phase of granulation tissue, the inflammatory reaction spreading throughout the vessels of the vertebral body can be seen, resulting in bony necrosis. As the abscess increases, stripping of the periosteum and avascular necrosis of the vertebral body may be noted. In addition, there may be a pathological fracture with sequestrum formation, compromising the spinal canal. The disc space is usually not involved but the disc itself lies in a pool of exudate. Paraspinal abscess formation is the hallmark of active tuberculosis. The abscess cavity, surrounded by a wall of granulation tissue, may be in contact with the dura. In contrast, Brucella spondylodiscitis is characterised by noncaseating granulomas with negative acid-fast staining and the presence of Gram-negative coccobacilli on Gram stain [46].

6.6. Radiographic findings Imaging studies are essential for diagnosis and evaluation of the extent of spondylodiscitis. They may aid in the differential diagnosis by assessing features that are characteristic of certain infectious aetiologies. Although plain radiographs and CT scans are still widely used [20], magnetic resonance imaging (MRI) has become the imaging modality of choice [45,58,59]. Plain radiographs of the spine may demonstrate advanced bony deformity in tuberculous discitis, although the earliest change is rarefication. Disc space narrowing, anterior vertebral scalloping, vertebrae plana and kyphotic deformity can also be seen [60]. Abscesses may appear as soft-tissue calcification. In the cervical region abscesses cause widening of the space between the pharynx and the vertebral body, whereas upper thoracic abscesses cause a squaring of the superior mediastinal shadow. Below T4 abscesses take up a typical fusiform shape, and below the diaphragm they cause loss of the normal psoas shadow. A draining sinus can be seen in severe cases and can occur in an area not contiguous to the vertebral lesion by dissecting its way to remote areas like the supraclavicular region or the groin. Lesions of the posterior neural arch, including the lamina and pedicle, when present suggest tuberculosis with a higher incidence of neurological complications [24]. MRI with co-administration of gadolinium contrast is useful in distinguishing abscesses (non-enhancing centre) from granulation tissue (diffuse pattern of enhancement) and is helpful in delineating the extent and size of soft-tissue disease as well as the amount of bony involvement and/or destruction. Radiographic features of Brucella discitis include a predilection for the anterior inferior vertebral end-plate, especially at the L4 level. Early osseous reparative processes are characteristic, frequently with only minor destructive lesions. MRI usually shows vertebral body signal changes without morphological changes with increased signal in the intervertebral disc on T2 -weighted and contrast-enhanced sequences. A great majority of patients have involvement at only one vertebra level [45], with only a few patients having multilevel involvement [61]. In some cases of Brucella spondylodiscitis, soft tissue involvement without abscess formation and facet joint signal changes following contrast enhancement can be seen [62,63]. T1 -weighted sequences appear to be more sensitive than T2 -weighted sequences in demonstrating the inflammatory processes in the vertebral bodies. Gadolinium-enhanced T1 -weighted sequences are very sensitive in assessing the extent of inflammatory processes into the spinal canal and in evaluating their persistence. Involvement of epidural spaces, nerve root and cord compression as well as abscess formation can also be seen.

In cases of fungal spinal osteomyelitis, MRI shows hypointense lesions of the vertebral bodies on T1 -weighted sequences with lack of hyperintensity within the discs on T2 -weighted images, and preservation of the intranuclear cleft on T2 -weighted images [64]. 7. Therapy 7.1. Tuberculosis Antibiotic treatment with four antituberculous drugs, isoniazid (5–10 mg/kg/day), rifampicin (10 mg/kg/day), pyrazinamide (25 mg/kg/day) and ethambutol (25 mg/kg/day), should be started promptly pending susceptibility results. Pyridoxine (50 mg/day) should be given together with isoniazid to patients with poor nutrition to avoid the development of peripheral neuropathy. If the organism is susceptible, ethambutol and pyrazinamide are stopped after 8 weeks and isoniazid and rifampicin are continued for the rest of the treatment course. Whilst traditionally this would amount to at least 9–12 months, studies have shown that rifampicin-based regimens can be used for shorter courses (6 months) [65,66]. There is also evidence to suggest that the use of hyperbaric oxygen as adjuvant to antituberculous therapy may result in earlier clinical and radiological improvement, possibly allowing the use of a shorter duration of therapy [67]. Caution should be exercised in areas with high rates of M. tuberculosis resistance, where initiation of treatment with second-line antituberculous agents may be warranted, taking into consideration penetration into musculoskeletal tissue [68]. Surgery is reserved for cold abscesses that are palpable posteriorly as well as for cases with neurological compromise that have failed to improve in response to a 2–3-month course of antituberculous therapy and immobilisation [60]. In selected patients, early surgical intervention with instrumentation, when indicated, minimises neurological deterioration and spinal deformity, allowing early ambulation with excellent neurological outcome [7]. However, preoperative plegia is associated with poor prognosis [69]. Appropriate antibiotic treatment is instituted immediately thereafter. It is our policy to mobilise patients on chemotherapy in a brace or to operate in the setting of spinal instability. 7.2. Brucellosis Treatment of Brucella spondylodiscitis consists of medical therapy with antibiotics active against Brucella spp. The preferred regimen includes doxycycline (100 mg twice daily) with intramuscular streptomycin (1 g daily) or gentamicin (5 mg/kg/day) for the first 2–3 weeks, followed by doxycycline with or without rifampicin or trimethoprim/sulfamethoxazole (SXT) for a period of 6 months [70]. Shorter courses of treatment for spondylodiscitis have been associated with an increased relapse rate [71]. We and others prefer to add rifampicin (600–900 mg daily) after stopping aminoglycosides. SXT can be used where the use of doxycycline is contraindicated, such as in children and pregnant females [72]. Recent studies suggest that quinolones such as ciprofloxacin and ofloxacin can be used in combination with other drugs for the treatment of brucellosis [73]. However, their use as single agents has been associated with a high relapse rate [74,75]. In 2004, Pappas et al. [76] set out to perform a meta-analysis on the treatment of Brucella spondylitis to evaluate different treatment regimens. Although the study was not completed owing to insufficient recorded data in many series, it was noted that 14 different combinations were used and that no antibiotic combination was superior. Pappas et al. recommend the use of doxycycline and ciprofloxacin for 3 months based on a favourable outcome in five patients. Besides antibiotic therapy, bed rest and bracing are important in the successful treatment of Brucella spine infections. Since recurrence is common,

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close follow-up of the patient after completion of therapy is recommended.

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• A non-diagnostic aspirate should prompt an open bone biopsy for cultures and pathological examination. Specimens should be sent for pathology, special stains and cultures.

7.3. Fungal infections 9. Recommendations for surgical treatment Treatment of fungal spondylitis relies on the prompt institution of appropriate antifungal agents. However, therapy is often delayed because of the difficulty in making the diagnosis. Prognosis depends on the pre-morbid state of the patient, the type of fungal organism and the timing of treatment. Delayed diagnosis may therefore lead to poor outcome in terms of neurological recovery [16]. We recommend performing fungal cultures as well as fungal antigen detection and PCR whenever a fungal spinal infection is suspected. The majority of patients are treated with surgical debridement and systemic antifungal agents for a minimum of 6 weeks and up to 3 months [16]. This approach has also been recommended in the management of Candida spondylodiscitis complicated by epidural abscess formation [77]. In cases of cryptococcal or Candida infections, i.v. amphotericin B (AmB) followed by oral fluconazole appears to be the treatment of choice [78]. The dose of fluconazole depends on the various species of Candida. Some are intrinsically resistant to fluconazole (Candida krusei), in which case fluconazole is not an option for treatment, and amphotericin B deoxycholate, liposomal preparations of amphotericin B (L-AmB) or echinocandins can be used [79]. Aspergillus spondylodiscitis is usually treated with AmB. In the setting of intolerance or toxicity, L-AmB or echinocandins (caspofungin, micafungin or anidulafungin) can be used [80]. Of note, data supporting the use of echinocandins are based on individual case reports. Once the patient is stable, treatment with oral agents can be considered. Voriconazole at 200 mg twice daily was recently found to be very effective in the treatment of invasive aspergillosis compared with AmB [81]. However, recurrence rates are common despite appropriate chemotherapy. Therefore, treatment should be continued until a normal ESR is attained. As in other clinical scenarios of invasive fungal infections, e.g. invasive aspergillosis [82,83], combination antifungal therapy might be considered in complicated cases of fungal infections of the spine until clinical stabilisation is achieved. When surgical drainage has been adequately performed, the duration of treatment can be shortened to 3 months [77]. Constant monitoring of clinical progress is important. Resistance to medical therapy, spinal instability and neurological deficits are indications for debridement and stabilisation with spinal fusion. 8. Recommendations for diagnosis In a patient presenting with subacute or chronic low back pain and where spondylodiscitis is suspected, we recommend the following diagnostic approach. • Obtain an MRI of the spine with gadolinium. • If the MRI shows findings consistent with spondylodiscitis, the following tests should be ordered: PPD; blood cultures to be incubated for 3 weeks (to enhance recovery of Brucella and fungi); serological tests including Brucella antibodies; and antigen detection tests for fungi (Cryptococcus and Aspergillus antigens) if fungal infection is suspected. In areas highly endemic for brucellosis, positive blood cultures for Brucella with suggestive findings on MRI can be highly predictive of the diagnosis of Brucella spondylodiscitis and treatment should be initiated accordingly. • A CT-guided fine needle aspiration and bone biopsy should be performed if the preliminary work-up is unrevealing. Specimens should be sent for bacterial culture, AFB smear and culture, KOH smear and fungal culture, Brucella culture and PCR for M. tuberculosis.

• Once surgical treatment is planned, our strategy should aim at immediate relief of the severe pain and encouraging early ambulation. • Patients presenting with neurological deficits require special management. Those patients with Frankel grade A (complete paralysis) or B (sensory function only below the injury level) lesions should undergo rapid decompression after localisation of the pathology using MRI with gadolinium with immediate administration of appropriate antimicrobial agents. Patients with grade C (incomplete motor function below injury level) or D (fair to good motor function below injury level) lesions are treated with chemotherapy alone but close monitoring is mandatory. • An unstable spinal segment or marked kyphosis in the face of any neurological deficit is treated surgically. Patients without neurological deficit, but with lesions causing the destruction of two or more vertebrae that will predictably collapse into kyphosis, require surgical treatment with anterior and posterior fusion in the active stage of the disease [84]. • Surgical approaches are dictated by the anatomic location of the offending lesion. In the case of marked kyphosis of the cervicothoracic region, we advocate an anterior decompression and strut grafting via a cervicosternotomy. Thoracotomies are favoured for lesions from T4 to T12. In the lumbar spine a retroperitoneal approach is advocated, which allows for psoas abscess drainage if present. To achieve anterior debridement and place posterior instrumentation, combined anterior and posterior procedures may be required. In a series of 10 consecutive patients who had been managed by one-stage surgery with anterior debridement, bone grafting and posterior spinal instrumentation, Safran et al. [85] reported that they encountered no perioperative complications from the invasiveness of one-stage surgery. However, Krodel et al. [86] pointed out that operative morbidity is increased by combined anterior and posterior operation. They reported that the average amount of blood loss in anterior and posterior procedures is >1700 mL, which may be deleterious in patients with poor general condition. • Autogenous iliac crest bone is the preferred graft material, although an allograft (e.g. humerus or fibula) supplemented by autograft may be necessary for strut grafts that bridge more than two vertebrae. Rib graft is only used as a supplementary graft source [87]. • Instrumentation plays a significant role in preventing or limiting any spinal deformity that may occur in the course of healing. It is highly recommended in patients with circumferential involvement who require decompression for neurological deficit. The main concern of using instrumentation in the presence of infection has been disproved by several authors who have not reported persistence or relapse of infection in patients requiring instrumentation [87,88]. • The type of instrumentation relies on individual preference. In our institution we advocate the use of a two-stage surgical treatment: first, posterior instrumentation; and second, anterior debridement and bone graft. A three-stage operation (anterior release, posterior instrumentation and grafting followed by anterior grafting) is only used for fixed kyphosis [53]. Funding: No funding sources. Competing interests: None declared. Ethical approval: Not required.

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