What is the recommended treatment for coccidioidomycosis?

Treatment of Coccidioidomycosis

For most patients with coccidioidomycosis, oral fluconazole 400 mg daily is the first-line treatment, with observation alone appropriate for mild, self-limited primary pulmonary disease, while severe or rapidly progressive cases require intravenous amphotericin B until stabilization. 1, 2

Primary Pulmonary Disease

Mild Disease

• Close observation without antifungal therapy is appropriate for patients with mild, nondebilitating symptoms or substantially improved illness at diagnosis, as 92% of primary pulmonary cases historically resolved without treatment 2
• Serial clinical assessments for 1-2 years are necessary to document resolution or identify complications early 2

Moderate Disease Requiring Treatment

• Fluconazole 400 mg daily orally is the first-line treatment for acute pulmonary coccidioidomycosis in adults with normal renal function 1, 2
• There is no role for fluconazole doses <400 mg daily in adults without substantial renal impairment 1, 2
• Itraconazole 200 mg twice daily is an alternative, though it requires closer monitoring for adequate absorption and has more drug-drug interactions than fluconazole 1

Severe or Rapidly Progressive Disease

• Intravenous amphotericin B is recommended for very severe and/or rapidly progressing acute pulmonary coccidioidomycosis until the patient stabilizes 3, 2
• Initiate amphotericin B when significant hypoxia is present, deterioration is rapid, or diffuse pulmonary involvement exists 3
• Several weeks of amphotericin B therapy are typically required before clear evidence of improvement appears 3
• After clinical stabilization, switch to oral fluconazole 400 mg daily (or higher doses up to 800 mg if needed) for long-term management 3
• The combined duration of amphotericin B plus oral azole therapy should total at least one year 3

Cavitary Pulmonary Disease

Chronic Progressive Fibrocavitary Pneumonia

• Oral azole antifungals (fluconazole or itraconazole) are recommended as initial treatment 3
• Surgical options should be explored when cavities are persistently symptomatic despite antifungal treatment, have been present for more than 2 years, or when symptoms recur whenever antifungal treatment is stopped 1, 3
• Video-assisted thoracoscopic surgery (VATS) is recommended if the surgeon has significant expertise in VATS 1

Ruptured Cavities

• Prompt decortication and resection of the cavity is recommended if possible 1
• If the pleural space is massively contaminated, decortication combined with prolonged chest tube drainage may be more appropriate 1
• Oral azole therapy is recommended for ruptured cavities; intravenous amphotericin B is recommended for patients who do not tolerate oral azoles or whose disease requires 2 or more surgical procedures for control 1

Extrapulmonary Soft Tissue Disease

• Antifungal therapy is recommended in all cases of extrapulmonary soft tissue coccidioidomycosis 1
• Oral azoles, particularly fluconazole or itraconazole, are recommended for first-line therapy 1
• As many as 90% of persons with disseminated infection to the skin have other extrapulmonary sites of infection, prompting investigation for other foci 4

Bone and Joint Disease

Non-Severe Skeletal Disease

• Azole therapy is recommended for bone and joint coccidioidomycosis, unless the patient has extensive or limb-threatening skeletal or vertebral disease causing imminent cord compromise 1
• A randomized trial showed neither fluconazole 400 mg daily nor itraconazole 200 mg twice daily was superior overall, though subgroup analysis suggested slightly greater efficacy of itraconazole for skeletal infection 1
• The recommended minimum dose of fluconazole is 800 mg daily for skeletal disease (based on its apparent inferiority to itraconazole at 400 mg daily) 1
• Most patients are treated with an azole for a protracted period of 3 years to lifetime depending on disease severity and host immunocompetence 1

Severe Osseous Disease

• For severe osseous disease, amphotericin B is recommended as initial therapy, with eventual change to azole therapy for the long term 1
• In practice, amphotericin B is usually used for a relatively brief time (≤3 months) in severe disease that threatens patient function 1

Vertebral Disease

• Surgical consultation is recommended for all patients with vertebral coccidioidal infection to assist in assessing the need for surgical intervention 1
• Surgical procedures are recommended in addition to antifungal drugs for patients with bony lesions that produce spinal instability, spinal cord or nerve root compression, or significant sequestered paraspinal abscess 1
• Surgical consultation should be obtained periodically during the course of medical treatment 1
• Spinal cord or nerve root compression is considered a surgical emergency 1

Coccidioidal Meningitis

Initial Therapy

• Fluconazole 400-1200 mg orally daily is recommended as initial therapy for most patients with normal renal function 1
• There is no role for a dose <400 mg daily in the adult patient without substantial renal impairment 1
• Some experts prefer itraconazole 200 mg 2-4 times daily, but this requires closer monitoring to assure adequate absorption and has more drug-drug interactions than fluconazole 1

Duration of Therapy

• Azole treatment for life is recommended for coccidioidal meningitis 1

Diagnostic Considerations

• Lumbar puncture with cerebrospinal fluid analysis is recommended only in patients with unusual, worsening, or persistent headache, altered mental status, unexplained nausea or vomiting, or new focal neurologic deficit after adequate imaging of the CNS 1, 2

Emerging Evidence

• Recent pediatric data suggest that intravenous liposomal amphotericin B as an adjunct to fluconazole may help reduce disease progression and improve symptom resolution in CNS coccidioidomycosis, though this is based on a small case series 5

Special Populations

Transplant Recipients

• For autologous or allogeneic hematopoietic stem cell transplant or solid organ transplant recipients with acute or chronic pulmonary coccidioidomycosis who are clinically stable and have normal renal function, fluconazole 400 mg daily is recommended 1
• For severe or rapidly progressing disease in transplant recipients, reduce immunosuppression when possible until infection begins to improve 3
• Patients with severe immunodeficiency should continue oral azole therapy as lifelong secondary prophylaxis after completing initial treatment 3

Pregnant Patients

• Intravenous amphotericin B is the treatment of choice in the first trimester 2
• Azole antifungals can be considered after the first trimester 2

Common Pitfalls to Avoid

• Do not treat all seropositive patients reflexively, as 95% of uncomplicated primary infections resolve without therapy 2
• Do not rely solely on complement fixation antibody titers to diagnose disseminated disease, as tissue diagnosis is usually required 2
• Do not use fluconazole <400 mg daily in adults without substantial renal impairment 1, 2
• Be aware that the relapse rate following therapy is high (37% in one study), particularly after discontinuation of treatment 6
• Obtain tissue diagnosis whenever possible through culture or histopathology, as this provides definitive identification and eliminates reliance on potentially cross-reactive serology 7