What is the recommended treatment for valley fever (coccidioidomycosis) in immunocompetent adults with mild to moderate pulmonary disease, severe pulmonary disease, disseminated infection, and coccidioidal meningitis, including appropriate drug choices, dosing, and duration?

Treatment for Valley Fever (Coccidioidomycosis)

For mild, non-debilitating pulmonary coccidioidomycosis in immunocompetent adults, observation with patient education and supportive care is recommended, as 92-95% of cases resolve spontaneously without antifungal therapy. 1

Risk Stratification and Treatment Decision Algorithm

Mild or Non-Debilitating Disease

• Observation alone is appropriate for patients with mild symptoms or those who have substantially improved by the time of diagnosis 1
• Provide patient education and reconditioning physical therapy 1
• Serial clinical assessments every 3-6 months for up to 2 years to document resolution or identify complications early 1, 2
• No randomized trials demonstrate that antifungal treatment shortens illness duration or prevents complications in uncomplicated cases 1

Indications for Antifungal Treatment

Initiate treatment for:

• Significantly debilitating illness at diagnosis 1
• Extensive pulmonary involvement 1
• Concurrent diabetes mellitus 1
• Frail patients due to age or comorbidities 1
• African or Filipino ancestry (some experts recommend) 1
• Severe pneumonia with respiratory failure 1, 3
• Immunocompromised patients (HIV with CD4+ <250 cells/μL, transplant recipients, patients on biologic response modifiers) 1, 2

First-Line Treatment Regimens

Oral Azole Therapy (Preferred for Stable Disease)

Fluconazole is the first-line agent:

• Dose: 400 mg orally daily (minimum dose for adults without substantial renal impairment) 1
• Can increase to 800-1200 mg daily for severe disease or treatment failure 3, 4
• Duration: At least 1 year for chronic pulmonary disease 3, 2
• Duration: 6-12 months minimum for extrapulmonary disease, often requiring years 3

Itraconazole (alternative):

• Dose: 200 mg twice daily or 3 times daily orally 1, 3
• Requires serum level monitoring after 2 weeks to ensure adequate absorption 1, 3
• More drug-drug interactions than fluconazole 2
• Clinical response rate approximately 55% after 8 months for chronic pulmonary infections 4, 2

Amphotericin B (For Severe or Rapidly Progressive Disease)

Indications:

• Severe pneumonia with respiratory failure 1, 3
• Rapidly progressive pulmonary disease 3, 2
• Widespread disseminated disease 3
• Immunocompromised patients with active disease 3
• First trimester of pregnancy (azoles are teratogenic) 1, 3

Dosing:

• Amphotericin B deoxycholate: 0.7-1.0 mg/kg/day IV 3
• Lipid formulations: 3-5 mg/kg/day IV 3
• Continue for several weeks until clinical stabilization 3
• Then transition to fluconazole 400 mg daily for at least 1 year total therapy 3

Disease-Specific Management

Chronic Pulmonary Disease

• Fluconazole 400 mg daily or itraconazole 200 mg twice daily 3, 2
• Minimum duration: 1 year 3, 2
• Surgical resection considered if cavities remain symptomatic despite antifungals, have been present >2 years, or symptoms recur when treatment stops 2

Disseminated Extrapulmonary Disease

• Soft tissue/skin: Fluconazole 400-800 mg daily for minimum 6-12 months 3
• Bone/joint: Fluconazole 400 mg daily or itraconazole 200 mg twice daily for many months to years 3
• Severe osseous disease: Amphotericin B initially, then transition to azole for long-term therapy 3
• Relapse rates range from 11-60% depending on treatment duration 3

Coccidioidal Meningitis

• Fluconazole 400-800 mg daily (after first trimester in pregnancy) 1
• Intrathecal amphotericin B during first trimester of pregnancy 1
• Lifelong therapy required 5
• Nearly always fatal if untreated 4

Special Populations

Pregnancy

• First trimester: Amphotericin B only (azoles are teratogenic) 1, 3
• After first trimester: Fluconazole or itraconazole can be considered 1
• For meningitis in first trimester: Intrathecal amphotericin B 1
• Women with prior coccidioidomycosis not on therapy have low reactivation risk; obtain serologies at initial visit and every 6-12 weeks throughout pregnancy 1

Immunocompromised Patients

• HIV with CD4+ <250 cells/μL: Initiate antifungal therapy for all infections; continue as long as CD4+ remains <250 cells/μL 2
• Transplant recipients: Fluconazole 400 mg daily for stable disease; amphotericin B for severe/rapidly progressive disease until stabilization 2
• Patients on biologic response modifiers (BRMs): Most can safely resume BRM therapy after coccidioidomycosis treatment; 75% of patients in one cohort continued or resumed immunosuppressive therapy without subsequent dissemination 1, 6
• Consider reducing immunosuppression until infection improves 3
• Lifelong suppressive therapy often required 1, 3

Monitoring Strategy

Serial Assessments

• Clinical evaluations every 2-4 weeks initially for treated patients 4
• Repeat coccidioidal serologic testing (complement fixation titers) every 2 weeks to several months, comparing to baseline 4
• Rising titers suggest treatment failure or disease progression 4
• Chest radiographs every several weeks to several months depending on clinical course 4
• ESR should not be measured more frequently than weekly 4
• For patients on itraconazole: measure serum concentrations after 2 weeks 3

Duration of Monitoring

• Continue follow-up for at least 2 years after treatment completion 5
• For patients treated with antifungals, follow complement fixation titers for at least 2 years 5

Critical Pitfalls to Avoid

Do not treat all positive serologies: Positive antibody tests indicate recent or active infection but do not automatically mandate therapy in asymptomatic or mildly symptomatic patients 2

Avoid inadequate fluconazole dosing: Do not use <400 mg daily for adults without substantial renal impairment, as this leads to treatment failure 4, 2

Screen for meningitis: Perform lumbar puncture if patient develops unusual/persistent headache, altered mental status, unexplained nausea/vomiting, or new focal neurologic deficits 4, 2

Do not dismiss persistent symptoms: Rising complement fixation titers or worsening radiographic findings indicate treatment failure requiring intervention, not "normal" post-treatment course 4

Recognize treatment failure early: Symptoms recur in approximately 30% of patients upon discontinuation of therapy 4

Do not overlook dissemination risk: Monitor high-risk patients (African or Filipino ancestry, diabetes, immunocompromised) closely for extrapulmonary spread 1

Serologic tests may be negative early: If clinical suspicion is high with negative serology, consider culture or molecular testing 2