What is the best course of action for an elderly patient with a history of coccidioidomycosis (valley fever) who is currently being treated with fluconazole (an antifungal medication) and presents with chills, myalgia (muscle aches), nausea, and fatigue without fever for the past 5-6 days?

Evaluation and Management of New Symptoms in an Elderly Patient on Fluconazole for Valley Fever

This elderly patient's new symptoms of chills, myalgia, nausea, and fatigue without fever over 5-6 days during fluconazole treatment most likely represent either disease progression/treatment failure or protracted fatigue from the underlying infection rather than drug toxicity, and requires immediate clinical reassessment with repeat serologic testing and consideration of treatment intensification.

Immediate Clinical Assessment Required

Distinguish Between Three Key Possibilities

1. Disease Progression or Treatment Failure

• Obtain repeat coccidioidal serologic testing (CF or quantitative IDCF antibody) and compare to baseline titers—rising titers suggest treatment failure or disease progression 1
• Perform chest radiography to assess for new pulmonary abnormalities, cavitation, or worsening infiltrates 1
• Consider lumbar puncture if the patient has unusual or persistent headache, altered mental status, unexplained nausea/vomiting, or new focal neurologic deficits to rule out coccidioidal meningitis 2
• In elderly patients, fluconazole failure occurs in approximately 31% of CM cases, though this patient's presentation suggests pulmonary disease 3

2. Protracted Fatigue from Coccidioidomycosis

• Recognize that protracted fatigue, myalgia, and systemic symptoms are common manifestations of primary coccidioidal infection that persist for weeks to months even during appropriate treatment 1
• These symptoms are often the last to resolve and patients may fail to recognize day-to-day improvement 1
• The absence of fever does not exclude active infection, as systemic symptoms without fever are characteristic of chronic coccidioidal illness 1

3. Fluconazole-Related Adverse Effects (Less Likely)

• Fluconazole is generally well-tolerated, particularly at standard doses of 400 mg daily 4
• In elderly patients (≥65 years), spontaneous reports of anemia occurred more frequently in post-marketing surveillance, though causality is difficult to establish 5
• Nausea and gastrointestinal symptoms can occur with fluconazole but are uncommon at standard doses 5

Recommended Diagnostic Workup

Obtain the following tests within 24-48 hours:

• Repeat coccidioidal serology (CF or IDCF titers) with concurrent testing of previous specimen if available—a fourfold increase indicates worsening disease 1
• Erythrocyte sedimentation rate (ESR) as an inexpensive marker of systemic inflammation to monitor improvement 1
• Complete blood count to assess for anemia, which is more common in elderly patients on fluconazole 5
• Comprehensive metabolic panel to evaluate renal function, as elderly patients are more likely to have decreased renal function requiring dose adjustment 5
• Chest radiograph (2 views) to document stability or progression of pulmonary disease 1

Treatment Decision Algorithm

If Serologic Titers Are Rising or Radiographic Findings Worsen:

Consider treatment intensification:

• Increase fluconazole dose from 400 mg to 800-1200 mg daily if currently on lower dose, as there is no role for fluconazole <400 mg daily in adults without substantial renal impairment 2
• Recent evidence shows that 72% of hospitalized patients with coccidioidomycosis improved with fluconazole at median dose of 800 mg daily despite prior outpatient fluconazole exposure 6
• Alternative: Switch to itraconazole 200 mg twice daily, which showed comparable efficacy (55% response rate) in chronic pulmonary coccidioidomycosis 1
• For severe or rapidly progressive disease, initiate intravenous amphotericin B until clinical stabilization, then transition to azole therapy 2

If Serologic Titers Are Stable or Declining and Imaging Is Unchanged:

Manage as protracted fatigue syndrome:

• Continue current fluconazole dose (typically 400 mg daily for pulmonary disease) for at least 1 year total duration 1
• Provide patient education that fatigue, myalgia, and systemic symptoms commonly persist for months and improve gradually 1
• Recommend a symptom journal to help the patient recognize incremental progress over weeks rather than days 1
• Consider referral to physical therapy for "generalized weakness secondary to primary coccidioidal pneumonia" once active infection is controlled—reconditioning programs are highly effective when continued for several weeks to months 1
• Provide medical release from work or obligations if debilitating fatigue prevents normal activities 1

Critical Monitoring Strategy

Serial assessments every 2-4 weeks initially:

• Repeat serologic testing should occur no more frequently than every 2 weeks, typically ranging from 1 month to several months between tests 1
• ESR should not be measured more frequently than weekly 1
• Chest radiographs should be repeated every several weeks to several months depending on clinical course 1
• Monitor for complications including dissemination (especially in elderly patients with risk factors), cavitation, or superinfection 1

Special Considerations in Elderly Patients

Age-related factors requiring attention:

• Elderly patients are more likely to have decreased renal function—adjust fluconazole dose based on creatinine clearance and consider monitoring renal function regularly 5
• Post-marketing surveillance shows higher rates of anemia and acute renal failure in patients ≥65 years, though causality with fluconazole is uncertain 5
• Elderly patients may have atypical presentations and slower recovery from coccidioidomycosis 5
• Ensure adequate hydration and nutrition, as nausea may contribute to deconditioning 1

Key Pitfalls to Avoid

• Do not dismiss these symptoms as "normal" without objective reassessment—rising CF titers or worsening radiographic findings indicate treatment failure requiring intervention 1
• Do not discontinue fluconazole prematurely—treatment courses should continue for at least 1 year, and symptoms recur in approximately 30% of patients upon discontinuation 1
• Do not delay lumbar puncture if any concerning neurologic symptoms develop—coccidioidal meningitis is nearly always fatal if untreated 7
• Do not use fluconazole doses <400 mg daily in adults without substantial renal impairment, as this is inadequate for coccidioidomycosis 2
• Do not attribute all symptoms to drug toxicity—fluconazole is well-tolerated and protracted systemic symptoms are characteristic of the underlying infection 1, 4