Is the patient's return of fever on fluconazole (fluconazole) due to complications of coccidioidomycosis (valley fever) or inadequate hydrocortisone (hydrocortisone) replacement dosage for primary adrenal insufficiency?

Fluconazole-Induced Adrenal Insufficiency is Causing the Return of Fever

The patient's return of fever while on fluconazole is most likely due to inadequate hydrocortisone replacement dosage for primary adrenal insufficiency during active infection, requiring an increased stress dose of hydrocortisone. 1, 2

Pathophysiology and Mechanism

The patient has two concurrent medical issues:

1. Coccidioidomycosis (Valley Fever) being treated with fluconazole
2. Primary adrenal insufficiency requiring hydrocortisone replacement

This situation is complicated by:

• Recent reduction in hydrocortisone dosage from 70mg to 50mg daily
• Active infection requiring increased cortisol needs
• Fluconazole's potential effect on adrenal function

Fluconazole's Impact on Adrenal Function

Fluconazole, like other azole antifungals, can cause adrenal insufficiency by inhibiting steroidogenesis:

• The FDA label for fluconazole specifically states: "Adrenal insufficiency has been reported in patients receiving azoles, including fluconazole" 3
• Multiple case reports document fluconazole-induced adrenal insufficiency, particularly at higher doses or in critically ill patients 4, 5
• This effect is reversible upon discontinuation of fluconazole 4

Stress Dosing Requirements During Infection

According to guidelines from the Association of Anaesthetists, Royal College of Physicians, and Society for Endocrinology:

• During physiological stress like infection, patients with adrenal insufficiency require increased glucocorticoid doses 1
• The standard recommendation is to double or triple the maintenance dose during illness with fever 2
• For a patient with primary adrenal insufficiency with fever, the hydrocortisone dose should be at least doubled 1, 2

Assessment of the Current Situation

The patient's clinical course strongly suggests inadequate cortisol replacement:

1. Initial improvement when starting fluconazole (fever subsided for three nights)
2. Return of fever coinciding with reduction in hydrocortisone from 70mg to 50mg daily
3. Morning fever of 101°F suggests inadequate overnight cortisol levels

The combination of:

• Active infection increasing cortisol requirements
• Reduced hydrocortisone dosage
• Potential adrenal suppression from fluconazole

Creates a "perfect storm" for relative adrenal insufficiency.

Management Recommendations

1. Immediately increase hydrocortisone dosage to at least 100-150mg daily in divided doses during the active infection phase 1, 2

2. Consider hydrocortisone administration schedule:

   • Higher morning dose (e.g., 50mg on waking)
   • Afternoon dose (e.g., 30mg at midday)
   • Evening dose (e.g., 20mg in early evening)
   • Consider additional overnight dose if early morning fevers persist

3. Monitor for signs of adequate replacement:

   • Resolution of fever
   • Improvement in energy levels
   • Normalization of blood pressure
   • Absence of nausea/vomiting

4. Continue fluconazole for coccidioidomycosis treatment, but with increased hydrocortisone dosing to compensate

5. Once the infection resolves, gradually taper hydrocortisone back to maintenance dosing

Common Pitfalls to Avoid

1. Misattribution of symptoms: Fever may be incorrectly attributed to worsening infection rather than inadequate adrenal replacement

2. Inadequate stress dosing: Guidelines clearly state that during illness, especially with fever, hydrocortisone doses should be doubled or tripled 1, 2

3. Failure to recognize drug interactions: Fluconazole can exacerbate adrenal insufficiency, requiring even higher replacement doses 3, 4

4. Insufficient overnight coverage: Early morning fevers may indicate inadequate overnight cortisol levels

5. Abrupt dose reductions: Reducing from 70mg to 50mg during active infection likely precipitated symptoms

Monitoring and Follow-up

• Daily temperature monitoring, especially early morning
• Electrolyte monitoring (particularly sodium and potassium)
• Blood pressure and heart rate assessment
• Clinical assessment of symptoms (fatigue, nausea, dizziness)
• Consider morning cortisol levels once stabilized to guide maintenance dosing

In conclusion, the patient's return of fever while on fluconazole is most likely due to inadequate hydrocortisone replacement during active infection, compounded by fluconazole's potential to cause adrenal suppression. Increasing the hydrocortisone dose according to stress dosing protocols should resolve the fever while continuing appropriate antifungal therapy.