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Candida Osteomyelitis
Candida osteomyelitis is one of the less frequent manifestations of invasive candidiasis. However, this condition carries significant morbidity, particularly when its diagnosis is delayed by lack of recognition of Candida spp. as potential bone pathogens.
Osteomyelitis due to Candida species can occur following either hematogenous dissemination or direct traumatic inoculation.
Limited data are available regarding the incidence of candidal osteomyelitis. Gathe et al. reviewed all reports through to 1986, and found 53 cases, 21 of which were pediatric cases [814]. A decade later, Hennequin et al. reviewed the world literature up to 1995 for cases of Candidal spondylodiskitis, which is the most common type of Candida osteomyelitis, and found 52 cases [1026]. Since then, only five more cases have been published in the English literature [130, 476, 1478, 2028, 2267].
Risk factors
The classic risk factors for invasive candidiasis are usually present in cases of presumed or documented hematogenous bone seeding. Among all the well known groups at risk to develop disseminated candidiasis, neonates and intravenous heroin drug addicts seem to be especially at risk to have bone involvement [814, 1128].
About one third of neonates with neonatal candidiasis have bone and/or joint involvement [1128].
With respect to intravenous drug addicts of brown heroin, these patients seem to often present with involvement of the costochondral joints [247, 250, 623, 719, 1281, 1368, 1813, 2467].
When candidal osteomyelitis is related to direct inoculation, the classic risk factors are often absent. Instead, a previous surgical procedure or trauma has taken place [814]. Sternal osteomyelitis is the most frequent type of candidal osteomyelitis where this mechanism operates [814]. This condition can be occasionally associated with candidal mediastinitis.
Candida species and Candida Osteomyelitis
Candida albicans is responsible for the majority of cases of Candida osteomyelitis [814]. However, essentially any other species may be seen [476, 727, 814, 1158, 1478, 1686, 2073, 2207].
Candidal bone seeding may manifest either simultaneously or several months after an episode of documented or presumed candidemia. Neonates seem to more often develop osteomyelitis close to the time of fungemia, or even as the only manifestation of disseminated candidiasis [767]. Conversely, adults with candidal osteomyelitis often present several months after the proven or suspected episode of candidemia. A range of 2 to 15 months has been described [814].
Candida bone infection in infants usually presents with concomitant arthritis [1807]. A free communication between the arterial supplies and venous channels of the metaphysis with the epiphyseal vessels explains the simultaneous seeding of bones and joints in cases of hematogenous dissemination.
Interestingly and unfortunately, an antifungal regimen enough to "clear" the episode of fungemia may not prevent the occurrence of this late complication [720, 727, 814, 2186].
Candida osteomyelitis may involve any bone, however, the long bones are the most frequently affected in infants, while in adults the axial skeleton is most commonly involved. In order of frequency, the following sites are classically affected:
- The spine (vertebral osteomyelitis). The lumbar spine is the most frequently affected site [814].
- Long bones. Usual sites are humerus, femur, fibula and tibia [814].
- Sternum. The involvement of this bone has been reported both in association with candidemia and with direct inoculation related with sternotomy [508, 693, 814, 2234].
Most cases of Candida osteomyelitis related to hematogenous dissemination involve a single bone. If two bones are affected they usually will be two contiguous vertebral bodies [814].
Candidal osteomyelitis presents with classic signs and symptoms including:
- Localized pain. Vertebral osteomyelitis usually presents with back pain as the single complaint [1026]. Any bone pain in a patient with a previously known episode of candidemia should be carefully evaluated and a high index of suspicion should be maintained.
- Soft-tissue swelling or drainage. Sinus tracts are classically described in cases of sternal osteomyelitis [814].
- Fever. This sign is described in less than half of the cases [814].
- Contiguous palpable abscess.
The diagnosis of candidal osteomyelitis should be based on isolation of Candida spp. from the bone. An adequate sample is very important. Even though percutaneous needle aspiration may be helpful, many cases remain undiagnosed until a good sample is obtained by open surgery [1026].
An adequate bone sample will also permit histopathologic confirmation of osteomyelitis [814].
Ancillary diagnostic studies such as plain X-rays and bone scans will show the classic findings of osteomyelitis.
Unfortunately, a delay no less than 30 days from the onset of symptoms to diagnosis occurs in most cases [814]. Factors that can explain this include the insidious course of the disease, the lack of a specific diagnostic test, and as mentioned before, the reluctance of clinicians to see Candida spp. as true pathogens.
Data on therapeutic options for the treatment of Candida bone infection are limited to case reports. For adults, it is recommended to combine bed rest, surgery, and antifungal therapy.
Neonates with Candida osteomyelitis should be treated using principles for the management of neonatal candidiasis. Most cases will resolve without surgery.
Surgery
Surgery can be a helpful adjunct in the management of candidal osteomyelitis. It allows the physician to:
- obtain good material for histopathologic and microbiologic examination
- perform extensive debridement
- decompress the spinal canal and provide stability in cases of vertebral osteomyelitis with significant neurologic deficits
Antifungal therapy
The chronic nature of candidal ostemyelitis makes difficult the eradication of this
infection. Long-term antifungal therapy is usually necessary [1600].
- Amphotericin B
Amphotericin B is the standard therapy for neonates and neutropenic patients with any form of deep organ candidal infection. Precise doses and length of therapy have not been studied and because of the rarity of this condition it is unlikely they ever will. Therefore, by extrapolation from the management of other candidal deep organ infections and the published cases, a dose of 0.5-1 mg/kg/day for a period enough to complete 1 to 1.5 gr is recommended [51, 130, 814, 979, 1279]. Following such a regimen with a course of an azole for another 6 to 12 months is not unreasonable.
- Ketoconazole
In one case, ketoconazole was successfully used after treatement with 1.5 gram IV amphotericin B [51]. In two other cases, ketoconazole was used for 3 to 7 months as a single antifungal agent also with satisfactory results [169, 594].
- Fluconazole
Because of its favorable toxicity profile, there has been a trend to substitute the use of ketoconazole with fluconazole. Pharmacological studies on fluconazole have shown poor penetration to bone tissue [736]. However, several cases have been successfully treated with this convenient antifungal agent either as the single therapy or after a course of amphotericin B [520, 1026, 1279, 1596, 2186, 2222, 2267]. One case of Candida lusitaniae osteomyelitis in a premature infant was successfully treated with 5-fluorocytosine and fluconazole [1686]. Dosage of 200 to 400 mg/day for periods of 3-7 months have been used. Failures when using this agent have also been reported [508, 979].
Finally, cases not responding to standard therapy or related to unusual Candida species may benefit from the currently growing knowledge on susceptibility testing for antifungal agents and specially for azoles [1911]. For this reason, it is recommended to keep the isolate for a certain time and if necessary request MIC testing from a laboratory familiar with the NCCLS M27 procedure [1623].
Candida Mediastinitis
Overview. Candida mediastinitis is a serious condition, closely related to sternal osteomyelitis, but associated with a higher mortality, especially when diagnosis is delayed due to lack of adequate samples for diagnosis or when cultures positive for Candida are disregarded as contaminants [448].
Epidemiology. Precise data on the occurrence of this condition are not available, but an indirect estimation made from the number of reports in the English literature. In a recent review by Clancy et al., two thirds of cases were diagnosed during the last 2 years [448]. This suggests either an increased appreciation of the role of Candida in this condition or an increase in its incidence [670].
Risk factors. Direct inoculation is considered the most important portal of entry. Not surprisingly, thoracic surgery has been recognized as the most important risk factor.
Clinical Manifestations. A distinction should be made between actual mediastinitis and the spectrum that generally precedes this severe condition which includes sternal wound infection, sternum and/or costal cartilage osteomyelitis, pericarditis and pleuritis. Clinical manifestations are identical to those seen with bacterial mediastinitis, and include chest wall drainage, erythema, sternal instability, fever and shock. Consequently a high level of suspicion should be maintained for cases that do not respond to antibacterial agents and surgical debridement.
Therapies. Aggressive surgical debridement in combination with prolonged antifungal therapy is recommended for all cases [448]. Fluconazole is a good alternative, especially for the outpatient phase of treatment. Several case reports have stressed a good cure rate when using this agent in the chronic phase of the disease. A course of amphotericin B is warranted for a total dose of no less than 1gr/kg [448].
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References
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2267. Turner, D. L., S. A. Johnson, and S. A. Rule. 1999. Successful treatment of candidal osteomyelitis with fluconazole following failure with liposomal amphotericin B. J Infection. 38:51-53.
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