Candida osteoarticular infections

INTRODUCTION — Invasive Candida infections tend to occur in selected patients, including those who are immunocompromised (eg, neutropenia, glucocorticoid therapy), have indwelling central venous catheters, have received broad-spectrum antibiotics, or who inject drugs [1,2]. Candida albicans is the most common pathogen, but other species, such as Candida glabrata, Candida parapsilosis, and Candida tropicalis, can be involved [2-8].

Clinical issues related to Candida osteomyelitis and arthritis will be reviewed here. An overview of Candida infections is presented separately. (See "Overview of Candida infections".)

MECHANISMS AND SITES OF INFECTION — Candida osteoarticular infections are most often due to hematogenous seeding of the joint or bone in patients who have been candidemic [1,2,8-12]. The areas most often seeded during an episode of candidemia in adults are intervertebral discs and knee joints [2,10,11].

Exogenous inoculation also can lead to infection in the following settings:

●After trauma or at the time of intraarticular injection (most often the knee) or prosthesis implantation [9,13,14]. (See "Osteomyelitis associated with open fractures in adults".)

●After surgical procedures, such as median sternotomy for heart surgery [15]. (See "Candida infections of the abdomen and thorax", section on 'Mediastinitis'.)

●In people who inject drugs, especially those who use brown heroin [16]. These patients may develop a unique syndrome consisting of septic arthritis (usually costochondral or sternoclavicular), endophthalmitis, and folliculitis involving the face, scalp, and chest.

Among patients with osteomyelitis, the site of involvement varies with age. The vertebrae are most commonly involved in adults [2,8,11,17-20], whereas the long bones of the extremities are more likely to be involved in children [8,21]. Of 207 cases of Candida osteomyelitis in adults and children, the most common sites of infection were the vertebra (in 51 percent), the femur (in 14 percent), the ribs (in 13 percent), and the sternum (in 11 percent) [8].

Among patients with septic arthritis, most infections have been described in native joints, but prosthetic joints can also be involved [13,22]. In a review of 112 patients (of whom 31 percent were children) with non-prosthetic joint Candida arthritis, the knee was involved in 75 percent of cases [23]. Approximately one-third of cases involved more than one joint, and another third were associated with adjacent osteomyelitis. Most were related to hematogenous dissemination, but 19 percent were thought to be due to direct inoculation.

CLINICAL MANIFESTATIONS — Osteoarticular infections often become symptomatic weeks or months after an episode of candidemia or a surgical procedure, and the manifestations are generally more subtle than bacterial infections at the same sites. Both of these factors contribute to long delays in diagnosis, especially in patients with vertebral osteomyelitis [1,2,8-11].

The most common symptom of Candida osteomyelitis is local pain [2,8,10], and some patients also have tenderness, erythema, and edema [8]. Fever is present in less than one-third of patients [2,8]. Limitation of function and movement occurs in nearly one-third of patients [8]. Sinus tracts and purulent drainage occur in 32 percent of patients with non-vertebral osteomyelitis but in only 1 percent of patients with vertebral osteomyelitis.

In a literature review of 59 patients with Candida vertebral osteomyelitis, most patients (83 percent) had back pain for more than one month, and 29 percent had back pain for more than three months [2]. The primary site of involvement was the lower thoracic or lumbar spine in almost all patients. Approximately 20 percent had neurologic deficits.

Similar findings were noted in another review of 65 patients with Candida vertebral osteomyelitis [11]. Among the 40 patients with documented candidemia before the onset of osteomyelitis, the delay between the detection of candidemia and the onset of symptoms was 2 to 12 months in 70 percent and more than one year in 10 percent.

When a joint is infected, the major symptoms are pain, swelling, erythema, and decreased range of motion. (See "Septic arthritis in adults", section on 'Clinical manifestations' and "Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

DIAGNOSIS — A high index of suspicion is required to establish the diagnosis of Candida osteoarticular infections [2,11]. Two clinical clues are a history of or current or recent detection of candidemia and the presence of risk factors for Candida infection [2,8,11]. Among 207 patients with Candida osteomyelitis, 57 (28 percent) had preceding candidemia, and 31 (15 percent) had candidemia at the time of diagnosis with Candida osteomyelitis [8]. Among 112 patients with Candida arthritis, 63 percent had candidemia or other forms of candidiasis; however, only 11 percent were candidemic at the time the diagnosis of septic arthritis was made [23].

In a review of 65 patients with vertebral osteomyelitis, all but three had at least one risk factor, and the median number of risk factors was three in patients with candidemia [11]. The most frequent risk factors were the use of broad-spectrum antibiotics and central venous catheters.

In Candida osteoarticular infections, the erythrocyte sedimentation rate and C-reactive protein are usually elevated; the white blood cell count is often normal or only mildly elevated [8].

Among imaging studies in patients with osteomyelitis, plain radiography can show erosive and destructive changes, but these changes may not be visible upon presentation and frequently take weeks to be visible on plain radiography. Magnetic resonance imaging (MRI) is the imaging modality of choice, as it is in bacterial osteomyelitis. In a study of 207 patients with Candida osteomyelitis, MRI findings included decreased signal intensity on T1-weighted images, increased signal intensity on contrast-enhanced T1-weighted images, and increased signal intensity on T2-weighted images [8]. (See "Vertebral osteomyelitis and discitis in adults".)

The definitive diagnosis is established by culture of the infected site. Candida arthritis is more easily confirmed than osteomyelitis because synovial fluid can be readily obtained for culture. Candida species usually grow in a few days when plated on standard media, such as sheep's blood agar, or on Sabouraud dextrose agar. It is important to point out that even a single colony of Candida spp recovered from joint fluid, a bone biopsy, or an aspirate should be viewed as significant and pathogenic, and the patient should be treated with antifungal agents as described below.

Culture of Candida species from a chronic draining wound, as often occurs with Candida sternal osteomyelitis or a chronic diabetic foot infection, is frequently disregarded as skin microbiota. However, repeated isolation of Candida and no other pathogen makes it possible that Candida is the causative agent [15]. In these cases, it is imperative to submit tissue for both microbiologic workup and histopathologic workup with appropriate stains.

TREATMENT — Candida septic arthritis in a native joint is easier to treat than osteomyelitis because adequate antifungal drug levels are more easily achieved in synovial fluid than in bone [1,13,21,24,25].

Fungal prosthetic joint infections are difficult to cure with medical therapy alone. Most patients with prosthetic joint infections require prosthesis removal followed by an extended course of antifungal therapy to resolve their infections. (See "Prosthetic joint infection: Treatment".)

Osteomyelitis is difficult to treat because the diagnosis is often delayed for weeks to months [2,11], the infected bone is often poorly perfused (which limits both the host inflammatory response and the delivery of antifungal drugs), and there may be foreign material present, as occurs with median sternotomy. Few data are available on the penetration of antifungal agents into bone [26].

Septic arthritis

Native joint — Adequate drainage and source control is essential for the treatment of all cases of Candida septic arthritis [27]. In one review of a large number of cases, 36 percent were treated with both surgical debridement and antifungal agents, but 62 percent were treated with only antifungal agents.

Antifungal treatment recommendations for septic arthritis caused by fluconazole-susceptible Candida species, such as C. albicans, C. parapsilosis, and C. tropicalis include oral fluconazole (400 mg [6 mg/kg]) daily for at least six weeks or an intravenous (IV) echinocandin daily for at least two weeks, followed by oral fluconazole (400 mg [6 mg/kg]) daily for at least four weeks (table 1) [27]. Since fluconazole is highly bioavailable, oral therapy is appropriate for most patients. IV therapy with either an echinocandin or fluconazole (at the same dose as the oral dose) should be given to patients who are unable to take oral medications, who are not expected to have good gastrointestinal absorption, or who are severely ill. Patients treated initially with IV fluconazole should be transitioned to oral fluconazole when feasible.

The doses of the echinocandins that we suggest for septic arthritis are:

●Caspofungin – 70 mg IV (loading dose), followed by 50 to 70 mg IV daily

●Anidulafungin – 200 mg IV (loading dose), followed by 100 mg IV daily

●Micafungin – 100 mg IV daily

Alternatively, a lipid formulation of amphotericin B, 3 to 5 mg/kg IV daily for two weeks, followed by oral fluconazole (400 mg [6 mg/kg]) for at least four weeks, can also be given if echinocandins are not available. This regimen is a less attractive alternative to the first-line regimens because of the nephrotoxicity of amphotericin B formulations. Case reports have described cures in patients treated with fluconazole, caspofungin, or amphotericin B in combination with adequate source control [27-30].

Instillation of amphotericin B into the joint space has been described. However, it is not recommended because drug levels are adequate with systemic therapy and irritation of synovial tissues is common with intraarticular therapy.

Prosthetic joint infections — In addition to antifungal drugs, the cure of prosthetic joint infections almost always requires removal of all prosthetic material. The preferred approach is a two-stage procedure in which the infected prosthesis is removed, followed by antifungal therapy, and a new prosthesis is implanted three to six months later. Antifungal therapy should be continued for at least 12 weeks after the resection arthroplasty and for at least 6 weeks after the prosthesis has been replaced [22,27,31-33].

Although cures have been described with debridement without removal of the prosthesis [13,14,34,35], this approach is not recommended for most patients with fungal infections. If the prosthetic device cannot be removed, chronic suppression with fluconazole 400 mg (6 mg/kg) orally daily should be given if the isolate is susceptible [27].

Treatment of infections caused by fluconazole-resistant Candida isolates is discussed below. (See 'Candida glabrata' below and 'Other Candida species' below.)

Treatment of prosthetic joint infections is discussed in greater detail separately. (See "Prosthetic joint infection: Treatment".)

Osteomyelitis — Treatment recommendations for osteomyelitis caused by fluconazole-susceptible Candida species, such as C. albicans, include oral fluconazole (400 mg [6 mg/kg]) daily for 6 to 12 months or an IV echinocandin daily for at least 2 weeks followed by oral fluconazole (400 mg [6 mg/kg]) for a total of 6 to 12 months (table 1) [27]. Since fluconazole is highly bioavailable, oral therapy is appropriate for most patients. IV therapy with an echinocandin or fluconazole (at the same dose as the oral dose) should be given to patients who are unable to take oral medications, who are not expected to have good gastrointestinal absorption, or who are severely ill. Patients treated initially with IV fluconazole should be transitioned to oral fluconazole when feasible.

The doses of the echinocandins that we suggest for osteomyelitis are:

●Caspofungin – 70 mg IV (loading dose), followed by 50 to 70 mg IV daily

●Anidulafungin – 200 mg IV (loading dose), followed by 100 mg IV daily

●Micafungin – 100 mg IV daily

Alternatively, a lipid formulation of amphotericin B, 3 to 5 mg/kg IV daily, can be given for at least 2 weeks followed by oral fluconazole (400 mg [6 mg/kg]) for 6 to 12 months. This regimen is a less attractive alternative than the first-line regimens because of the nephrotoxicity of amphotericin B formulations. Treatment of infections caused by fluconazole-resistant Candida isolates is discussed below. (See 'Candida glabrata' below and 'Other Candida species' below.)

There are no formal clinical trials, so treatment recommendations are based upon case reports and case series [27]. Although most case reports and clinical experience have utilized amphotericin B deoxycholate, several reports currently support the use of fluconazole or an echinocandin as the preferred first-line agents [8,15,19,20,36-39].

Surgical debridement plays an important role in the treatment of Candida osteomyelitis involving non-vertebral sites, but the role of surgical debridement for vertebral osteomyelitis is less clear. Most authors note efficacy with antifungal therapy alone [2,10,36,40], although some favor debridement [11]. Surgery is clearly indicated if there is an associated epidural abscess, neurologic compromise, or instability of the spine. (See "Vertebral osteomyelitis and discitis in adults".)

In a review of 207 cases of Candida osteomyelitis that were reported between 1970 and 2011, 44 percent were treated with antifungal therapy alone, 5 percent with surgery alone, and 48 percent with antifungal therapy in combination with surgery [8]. Among the 92 patients treated with antifungal agents alone, 97 percent had a favorable response, but 16 (17 percent) relapsed. Among the 100 patients who had both antifungal treatment and surgery, 90 percent responded, but the relapse rate was 43 percent. However, without detailed information regarding the type of antifungal drug used and the duration of treatment, it is difficult to know why the relapse rates were so high, especially for the group who received combined medical and surgical therapy. The authors suggested that many patients relapsed because the duration of therapy was too short.

ANTIFUNGAL THERAPY BASED ON SPECIES

Candida albicans — The majority of C. albicans isolates are susceptible to fluconazole and the echinocandins. Specific treatment recommendations are presented above. (See 'Treatment' above.)

Candida glabrata — The choice of therapy with C. glabrata osteoarticular infections is more limited than with C. albicans [2-5]:

●Because many isolates of C. glabrata are resistant to fluconazole, this agent should not be used initially for the treatment of C. glabrata osteoarticular infections. It is essential to obtain susceptibilities prior to switching to either fluconazole or voriconazole.

●Echinocandins are the initial agents of choice for osteoarticular infections due to C. glabrata, followed by step-down therapy with oral azoles (fluconazole or voriconazole) if the isolate is susceptible [37,41,42]. It is essential to obtain susceptibilities before using voriconazole because of the common occurrence of cross-resistance with fluconazole. (See "Antifungal susceptibility testing" and "Management of candidemia and invasive candidiasis in adults".)

●The greatest experience in treating C. glabrata osteoarticular infections is with amphotericin B [2-5]. However, echinocandins are less toxic and are preferred as initial therapy. Echinocandins should be given for at least two weeks, followed by an azole (if the isolate is susceptible) for 6 to 12 months. If the isolate is resistant to fluconazole, in vitro susceptibilities to posaconazole and isavuconazole can be obtained. Although clinical data for these two azoles is lacking, they are oral options that may be used as alternatives to the parenteral alternatives of either an echinocandin or amphotericin B. The other option would be to continue with parenteral echinocandin or amphotericin B for the entire treatment period.

Other Candida species — Candida krusei is resistant to fluconazole, but most isolates are susceptible to voriconazole, echinocandins, and amphotericin B. Only a small number of case reports are available showing benefit from voriconazole alone [43] or caspofungin with voriconazole [42] in treating osteoarticular infection due to C. krusei. For most patients, echinocandins or a lipid formulation of amphotericin B are the agents of first choice, followed by step-down therapy to voriconazole after improvement is noted. (See "Management of candidemia and invasive candidiasis in adults".)

C. parapsilosis isolates may be less susceptible to echinocandins than other Candida species. The clinical implications of these higher minimum inhibitory concentration values are not clear, but we prefer fluconazole for the treatment of osteoarticular infections due to this species. (See "Management of candidemia and invasive candidiasis in adults".)

For other Candida species, antifungal susceptibility tests should be performed to help guide appropriate therapy. (See "Antifungal susceptibility testing".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Candidiasis".)

SUMMARY AND RECOMMENDATIONS

●Risk factors – Invasive Candida infections tend to occur in selected patients, including those who are immunocompromised (eg, neutropenia, glucocorticoid therapy), have indwelling central venous catheters, have received broad-spectrum antibiotics, or those who inject drugs. Candida albicans is the most common pathogen, but other species, such as C. glabrata, C. parapsilosis, and C. tropicalis, can be involved. (See 'Introduction' above.)

●Pathogenesis and anatomic sites – Candida osteoarticular infections are most often due to hematogenous seeding of the joint or bone in patients who have been candidemic. The areas most often seeded during an episode of candidemia in adults are intervertebral discs and knee joints. Exogenous inoculation also can lead to infections after trauma, surgical procedures, or intraarticular injections. (See 'Mechanisms and sites of infection' above.)

●Clinical manifestations – Osteoarticular infections often become symptomatic months after an episode of candidemia or a surgical procedure, and the manifestations are generally more subtle than bacterial infections at the same sites. Both of these factors contribute to long delays in diagnosis, especially in patients with vertebral osteomyelitis. The most common symptom of Candida osteomyelitis is local pain. When a joint is infected, the major symptoms are pain and decreased range of motion. (See 'Clinical manifestations' above.)

●Diagnosis – A high index of suspicion is required to establish the diagnosis of Candida osteoarticular infections because the clinical, laboratory, and radiologic findings are not specific. The diagnosis is established by culture of the infected site. Even a single colony of Candida on culture of joint fluid or bone biopsy or aspirate should be viewed as pathogenic, and the patient should be treated with antifungal agents. (See 'Diagnosis' above.)

●Septic arthritis – Adequate drainage is essential for the treatment of all cases of Candida septic arthritis. (See 'Septic arthritis' above.)

Antifungal treatment recommendations for septic arthritis include oral fluconazole daily for at least six weeks or an intravenous (IV) echinocandin daily for at least 2 weeks, followed by oral fluconazole daily for at least 4 weeks (table 1). Antifungal regimens for non-albicans Candida infections are discussed above. (See 'Septic arthritis' above and 'Candida glabrata' above and 'Other Candida species' above.)

●Prosthetic joint infections – In addition to antifungal drugs, the cure of prosthetic joint infections almost always requires removal of all prosthetic material. (See 'Prosthetic joint infections' above.)

●Osteomyelitis – Treatment recommendations for osteomyelitis include oral fluconazole daily for 6 to 12 months or an IV echinocandin daily for at least 2 weeks followed by oral fluconazole for 6 to 12 months (table 1). (See 'Osteomyelitis' above.)

Surgical debridement plays an important role in the treatment of Candida osteomyelitis involving non-vertebral sites, but the role of surgical debridement for vertebral osteomyelitis is less clear. Most authors note efficacy with antifungal therapy alone although some favor debridement. Surgery is clearly indicated if there is an associated epidural abscess, neurological compromise, or instability of the spine. (See 'Osteomyelitis' above.)