FUNGAL OSTEOMYELITIS - RARE BUT RISING THREAT
Candida | Aspergillus | Endemic Mycoses | Cryptococcus | Immunocompromised Hosts
FUNGAL OSTEOMYELITIS BY ORGANISM
Critical Must-Knows
- Candida is most common fungal cause of osteomyelitis - think IV drug users and vertebral involvement
- Tissue biopsy is ESSENTIAL for diagnosis - fungal cultures and special stains (GMS, PAS)
- 1,3-beta-D-glucan serum marker helpful but NOT specific for site of infection
- Prolonged antifungal therapy 6-12 months - much longer than bacterial osteomyelitis
- Surgical debridement often required - antifungals alone frequently insufficient
Examiner's Pearls
- "Fungal osteomyelitis has INDOLENT course - delayed diagnosis is common
- "Aspergillus in immunocompromised is aggressive and often fatal without early treatment
- "Coccidioides is endemic to southwestern USA - soil exposure history critical
- "Australia has Cryptococcus gattii which can affect IMMUNOCOMPETENT patients
Critical Fungal Osteomyelitis Exam Points
Think Fungal When...
Consider fungal osteomyelitis if: immunocompromised patient (HIV, transplant, chemotherapy), culture-negative osteomyelitis not responding to antibiotics, IV drug user with vertebral infection, or endemic area travel history. Index of suspicion is key.
Diagnosis Requires Tissue
Tissue biopsy is ESSENTIAL - blood cultures rarely positive, 1,3-beta-D-glucan is nonspecific. Send for fungal stains (GMS, PAS), fungal culture (takes 4-6 weeks), and histopathology showing granulomatous inflammation with fungal elements.
Treatment Duration
6-12 months antifungal therapy - much longer than bacterial osteomyelitis. Choice depends on organism: fluconazole for Candida, voriconazole for Aspergillus, itraconazole for endemic mycoses. Surgical debridement often needed.
Australian Context
Cryptococcus gattii is endemic to Australia and can cause osteomyelitis in immunocompetent hosts - unlike C. neoformans which affects immunocompromised. Think of this in Australian patients with lytic bone lesions.
Comparison of Fungal Organisms Causing Osteomyelitis
| Organism | Risk Factors | Sites | Treatment | Prognosis |
|---|---|---|---|---|
| Candida species | IV drug use, TPN, central lines, neutropenia, diabetes | Vertebrae (most common), sternum, ribs | Fluconazole 6-12 months; AmB if severe | Good if early diagnosis |
| Aspergillus species | Neutropenia, transplant, steroids, CGD | Vertebrae, ribs, skull base | Voriconazole first-line; surgery essential | Poor - high mortality |
| Coccidioides immitis | Endemic SW USA, soil exposure, Filipino/African heritage | Vertebrae, pelvis, long bones, skull | Fluconazole or itraconazole 12+ months | Chronic relapsing course |
| Blastomyces dermatitidis | Endemic Mississippi/Ohio River, soil/wood | Vertebrae, ribs, long bones | Itraconazole; AmB for severe | Good with treatment |
| Histoplasma capsulatum | Endemic Ohio/Mississippi Valley, bird/bat droppings | Vertebrae, ribs, long bones | Itraconazole 12 months | Good with treatment |
| Cryptococcus neoformans/gattii | HIV/AIDS (neoformans), immunocompetent - Australia (gattii) | Vertebrae, skull, long bones | Fluconazole long-term; AmB induction | Variable - depends on immune status |
CANDID HOSTRisk Factors for Fungal Osteomyelitis
Memory Hook:A CANDID HOST lets fungi in - immunocompromised patients are susceptible to fungal bone infection!
BIOPSYFungal Osteomyelitis Diagnosis
Memory Hook:BIOPSY is the key - tissue diagnosis is ESSENTIAL for fungal osteomyelitis!
FAVIAntifungal Drug Selection
Memory Hook:FAVI your treatment - choose the right antifungal based on the organism!
Overview and Epidemiology
Why This Topic Matters
Fungal osteomyelitis is rare but increasing with rising immunocompromised populations (HIV, transplant recipients, chemotherapy). The indolent course leads to delayed diagnosis. Examiners expect you to recognize risk factors, order appropriate investigations (tissue biopsy), and know prolonged treatment duration.
Epidemiology
- Rare: Less than 1% of all osteomyelitis cases
- Increasing incidence: Rising immunocompromised population
- Candida most common: 40-60% of fungal osteomyelitis
- Mortality: Aspergillus 50-80%, others 10-20% with treatment
- Delayed diagnosis: Average 6 months symptom-to-diagnosis
At-Risk Populations
- HIV/AIDS: CD4 less than 200 - Cryptococcus, Histoplasma
- Organ transplant: Aspergillus in first 6 months post-transplant
- Haematologic malignancy: Neutropenia - Aspergillus, Candida
- IV drug users: Candida vertebral osteomyelitis
- Diabetes mellitus: Candida, mucormycosis
Definition
Fungal osteomyelitis is bone infection caused by pathogenic fungi, typically occurring in immunocompromised hosts or following exposure to endemic fungi in specific geographic regions. The infection has an indolent course with nonspecific symptoms, leading to delayed diagnosis averaging 6 months.
Key Pathophysiology
Fungal pathogens reach bone through:
- Hematogenous spread - most common (Candida, Cryptococcus)
- Direct inoculation - trauma, surgery
- Contiguous spread - from adjacent soft tissue infection
Unlike bacterial osteomyelitis, fungal infections typically cause granulomatous inflammation with tissue destruction and minimal periosteal reaction on imaging.
Microbiology
Candida Species
Organism Characteristics
- C. albicans most common (50-70% of cases)
- Other species: C. tropicalis, C. glabrata, C. parapsilosis
- Yeast form - oval budding cells
- Pseudohyphae - can form in tissue
- Normal commensal - becomes pathogenic when host defenses impaired
Clinical Features
- Hematogenous spread from candidemia
- Vertebral osteomyelitis most common site
- IV drug users - lumbosacral spine, sternoclavicular joint
- TPN/central line patients - any bone
- Indolent course with back pain, low-grade fever
IV Drug User with Back Pain
An IV drug user presenting with chronic back pain and low-grade fever should prompt consideration of Candida vertebral osteomyelitis. Blood cultures are only positive in 50% - tissue biopsy is essential. Treatment is fluconazole 400-800mg daily for 6-12 months.
Treatment
- Fluconazole 400-800mg daily - first-line for susceptible Candida
- Amphotericin B deoxycholate or liposomal - severe infection, azole resistance
- Echinocandins (caspofungin, micafungin) - alternative for azole-resistant species
- Duration: 6-12 months - longer than bacterial osteomyelitis
- Surgical debridement - recommended if abscess, instability, or poor response
Candida treatment is generally successful with appropriate antifungal therapy and debridement when indicated.
Clinical Presentation
Indolent Course - High Index of Suspicion Required
Fungal osteomyelitis has an indolent, insidious course with nonspecific symptoms. Average time from symptom onset to diagnosis is 6 months. Think fungal when: culture-negative osteomyelitis, not responding to antibiotics, immunocompromised host, or endemic area exposure.
Clinical Features
Local Symptoms
- Pain - most common symptom (90%)
- Usually dull, aching, progressive
- May be present for weeks to months before diagnosis
- Swelling - variable, often minimal early
- Limited range of motion if near joint
Systemic Symptoms
- Low-grade fever - less than 38.5C (often absent)
- Night sweats - especially endemic mycoses
- Weight loss - chronic infection
- Malaise, fatigue
- High fever less common than bacterial osteomyelitis
Key Distinguishing Features
- Longer symptom duration before diagnosis than bacterial (months vs weeks)
- Less acute presentation - indolent course
- Lower inflammatory markers - CRP/ESR often only mildly elevated
- Poor response to antibiotics - key clue to fungal etiology
- Immunocompromised status - should prompt fungal workup
Symptoms vary by causative organism and immune status of the host.
Diagnosis
Tissue Biopsy is Essential
Blood cultures are often negative in fungal osteomyelitis. Serology and beta-D-glucan are nonspecific. Tissue biopsy with fungal stains and culture is ESSENTIAL for diagnosis. Do not delay biopsy - fungal cultures take 4-6 weeks.
Laboratory Investigations
Laboratory Tests for Fungal Osteomyelitis
| Test | Findings | Utility |
|---|---|---|
| CRP/ESR | Mildly to moderately elevated | Nonspecific - lower than bacterial osteomyelitis |
| WCC | Often normal or mildly elevated | May be low in neutropenic patients |
| 1,3-beta-D-glucan | Elevated in Candida, Aspergillus, Histoplasma | Nonspecific - does not identify site or organism |
| Galactomannan | Elevated in Aspergillus | More specific for aspergillosis; serum and BAL |
| Blood cultures | Positive in less than 50% of Candida cases | Often negative - not sufficient to rule out fungal infection |
| Tissue culture | Gold standard - takes 4-6 weeks | Send for fungal culture specifically |
| Histopathology | Granulomatous inflammation, fungal elements | GMS and PAS stains essential |
1,3-Beta-D-Glucan
1,3-beta-D-glucan is a cell wall component of most pathogenic fungi (except Cryptococcus and Mucorales). It indicates fungal infection but does NOT identify the organism or site. Tissue diagnosis is still required. False positives occur with hemodialysis, certain antibiotics, and IVIG.
Tissue Biopsy - The Gold Standard
- CT-guided or open biopsy of affected bone
- Multiple samples (3 or more) increase yield
- Send for: fungal culture, bacterial culture, histopathology
- Special stains: GMS (Grocott methenamine silver), PAS (Periodic acid-Schiff)
- PCR - increasingly available for rapid identification
- Fungal cultures take 4-6 weeks - do not delay treatment if high suspicion
Management
Antifungal Drug Selection by Organism
First-Line Antifungal Therapy
| Organism | First-Line Agent | Alternative | Duration |
|---|---|---|---|
| Candida (susceptible) | Fluconazole 400-800mg daily | Amphotericin B or echinocandin | 6-12 months |
| Candida (resistant) | Echinocandin then oral azole | Amphotericin B | 6-12 months |
| Aspergillus | Voriconazole 6mg/kg then 4mg/kg BD | Isavuconazole, liposomal AmB | 6-12 months minimum |
| Coccidioides | Fluconazole 400-800mg daily | Itraconazole, amphotericin B | 12+ months, may be lifelong |
| Blastomyces | Itraconazole 200mg BD | Amphotericin B for severe | 6-12 months |
| Histoplasma | Itraconazole 200mg BD | Amphotericin B for severe | 12 months |
| Cryptococcus | Fluconazole 400-800mg daily | AmB + flucytosine induction | 6-12 months, secondary prophylaxis in HIV |
Voriconazole for Aspergillus
Voriconazole is first-line for invasive aspergillosis including osteomyelitis. It has excellent bone penetration. Monitor liver function and visual symptoms. Drug-drug interactions are common - check all medications. Continue until immune reconstitution.
Key Principles
- Prolonged treatment - 6-12 months minimum (longer than bacterial)
- Source control - surgical debridement often required
- Treat underlying immunocompromise - improve host defenses
- Monitor drug levels - especially voriconazole, posaconazole
- Watch for toxicity - hepatic, renal, visual (voriconazole)
Duration should be individualized based on clinical and radiological response.
Evidence Base
Candida Osteomyelitis Treatment Outcomes
- Systematic review of 207 cases of Candida osteomyelitis
- Vertebral involvement in 53% of cases
- Surgical debridement performed in 53% of patients
- Overall mortality 8.5% with treatment
- Fluconazole equivalent to amphotericin B for susceptible strains
Aspergillus Osteomyelitis - Poor Prognosis
- Review of 310 cases of Aspergillus osteomyelitis
- Vertebral involvement in 42%, skull base 18%
- Most patients had underlying hematological malignancy or transplant
- Overall mortality 25-30% even with treatment
- Surgical debridement improved outcomes significantly
Coccidioidal Osteomyelitis Treatment Duration
- IDSA guidelines for coccidioidomycosis management
- Bone and joint involvement requires prolonged therapy 12+ months
- Fluconazole 400-800mg daily is first-line
- Surgical debridement for abscesses or instability
- Lifelong suppression may be needed in immunocompromised
1,3-Beta-D-Glucan for Diagnosis
- Meta-analysis of beta-D-glucan for invasive fungal infection
- Sensitivity 77%, specificity 85% for invasive fungal disease
- Does not identify specific organism or site of infection
- False positives with hemodialysis, antibiotics, IVIG
- Useful adjunct but does not replace tissue diagnosis
Surgical Debridement Impact on Fungal Osteomyelitis Outcomes
- Retrospective review of 89 patients with fungal osteomyelitis
- Surgical debridement performed in 67% of patients
- Patients receiving surgery plus antifungals had 85% cure rate vs 62% antifungals alone
- Aspergillus cases had mandatory surgical intervention due to angioinvasive nature
- Average antifungal duration was 9.2 months in cured patients
Exam Viva Scenarios
Practice these scenarios to excel in your viva examination
Scenario 1: IV Drug User with Vertebral Osteomyelitis
"A 35-year-old IV drug user presents with 3 months of progressive lower back pain. MRI shows L2-L3 vertebral osteomyelitis with disc involvement. Blood cultures are negative. He has been on empirical flucloxacillin for 4 weeks with no improvement. What is your differential diagnosis and management plan?"
Scenario 2: Immunocompromised Patient with Aggressive Bone Destruction
"A 55-year-old woman 6 weeks post-allogeneic stem cell transplant for AML presents with worsening left shoulder pain and fever. She is on immunosuppression and has been neutropenic. CT shows aggressive destruction of the proximal humerus with soft tissue extension. What organism do you suspect and how would you manage this?"
Scenario 3: Travel History with Lytic Bone Lesion
"A 40-year-old Australian man presents with 4 months of left knee pain. He returned from a 6-month work assignment in Arizona, USA 3 months ago. Imaging shows a lytic lesion in the distal femur. Biopsy shows granulomatous inflammation. What is your diagnosis and management?"
Australian Context
Cryptococcus in Australia
Australia has a unique epidemiological pattern for cryptococcosis that is important for the fellowship exam:
Cryptococcus gattii
- Endemic to Australia (especially NSW, Victoria, Queensland)
- Associated with Eucalyptus trees
- Affects immunocompetent patients (unlike C. neoformans)
- Can cause osteomyelitis in otherwise healthy Australians
- May present as lytic bone lesion mimicking tumour
Cryptococcus neoformans
- Affects immunocompromised (HIV, transplant)
- CD4 count less than 100 - high risk
- Meningoencephalitis more common than bone involvement
- Associated with pigeon droppings
- Worldwide distribution
Australian Cryptococcus Pearl
In the Australian exam context, remember that Cryptococcus gattii can cause osteomyelitis in immunocompetent patients - this is unusual for fungal infections which typically affect immunocompromised hosts. If an otherwise healthy Australian patient presents with a lytic bone lesion, consider Cryptococcus in your differential.
Australian Treatment Guidelines
The Therapeutic Guidelines (eTG) and Australian Antifungal Guidelines provide local recommendations:
- Candida: Fluconazole first-line, echinocandins for severe or resistant
- Aspergillus: Voriconazole first-line with therapeutic drug monitoring
- Cryptococcus: Amphotericin B + flucytosine induction, then fluconazole consolidation
- Endemic mycoses: Rare in Australia - treat based on IDSA guidelines
Access to Antifungals
- Most antifungals available on PBS for approved indications
- Voriconazole: PBS authority required for invasive aspergillosis
- Liposomal amphotericin B: Available but expensive - hospital approval usually required
- Isavuconazole: TGA approved, PBS listed for invasive aspergillosis
Involve infectious diseases for complex cases and to navigate PBS approval requirements.
FUNGAL OSTEOMYELITIS
High-Yield Exam Summary
Key Organisms
- •Candida = MOST COMMON fungal osteomyelitis overall
- •Aspergillus = immunocompromised, aggressive, high mortality
- •Coccidioides = SW USA endemic, soil exposure
- •Cryptococcus gattii = Australia, can affect IMMUNOCOMPETENT
Risk Factors (CANDID HOST)
- •Chemotherapy, AIDS/HIV, Neutropenia
- •Diabetes, IV drug use, Dialysis/central lines
- •Transplant, Oral steroids, Soil exposure, TPN
Diagnosis
- •TISSUE BIOPSY is ESSENTIAL - blood cultures often negative
- •GMS and PAS stains for fungi
- •Fungal culture takes 4-6 weeks
- •1,3-beta-D-glucan = nonspecific, supports diagnosis
- •Galactomannan = more specific for Aspergillus
Treatment
- •Fluconazole = Candida, Cryptococcus, Coccidioides
- •Voriconazole = Aspergillus (first-line)
- •Itraconazole = Blastomycosis, Histoplasmosis
- •Duration 6-12 MONTHS (much longer than bacterial)
- •Surgical debridement often required
Key Exam Points
- •INDOLENT course - delayed diagnosis is common
- •Think fungal if: culture-negative, not responding to antibiotics
- •Aspergillus = ALWAYS needs surgery, high mortality
- •Travel history for endemic mycoses is crucial
Australian Context
- •Cryptococcus gattii endemic to Australia
- •Can affect immunocompetent (unlike C. neoformans)
- •Associated with Eucalyptus trees
- •Consider in healthy Australian with lytic bone lesion