What is the best course of treatment for a patient in their 20s with chronic coccidiomycosis (fungal infection) on fluconazole (Diflucan) (fluconazole), recently diagnosed with influenza A, presenting with headache, hydrocephalus on MRI (Magnetic Resonance Imaging), and elevated white blood cells in the cerebrospinal fluid (leukocytosis)?

Management of Coccidioidal Meningitis with Hydrocephalus

This patient requires immediate escalation of fluconazole to 800-1200 mg daily, urgent neurosurgical consultation for CSF shunting to manage hydrocephalus, and consideration of adjunctive intravenous liposomal amphotericin B given the severity of presentation. 1, 2

Immediate Diagnostic Confirmation

• Complete CSF analysis is essential to confirm coccidioidal meningitis (CM), including cell count with differential, glucose, protein, coccidioidal antibody testing (immunodiffusion or complement fixation), and fungal culture. 1
• The presence of 40 WBCs in CSF with hydrocephalus and headache in a patient with known coccidioidomycosis strongly suggests CM, which is nearly always fatal if untreated. 1, 2
• Expect CSF protein commonly >150 mg/dL and glucose depressed to less than one-half to two-thirds of fasting blood sugar. 1
• CSF cultures are positive in only approximately 25% of adults, so negative culture does not exclude diagnosis. 1
• Serum coccidioidal IgG antibody should be obtained as it supports the diagnosis when CSF findings are consistent. 1

Antifungal Therapy Escalation

The current fluconazole dose must be increased immediately to at least 800 mg daily, with consideration for doses up to 1200 mg daily. 1

• There is no role for fluconazole doses <400 mg daily in adult patients with CM without substantial renal impairment. 1
• The 2016 IDSA guidelines recommend fluconazole 400-1200 mg orally daily as initial therapy for CM with normal renal function (strong recommendation, moderate evidence). 1
• Given the severity of presentation with hydrocephalus, starting at the higher end of the dosing range (800-1200 mg daily) is warranted. 1, 2

Consideration of Adjunctive Amphotericin B

For severe presentations with hydrocephalus, adding intravenous liposomal amphotericin B to fluconazole should be strongly considered. 3

• Recent pediatric data suggests that combination therapy with IV liposomal amphotericin B plus fluconazole may reduce disease progression and improve outcomes compared to fluconazole alone. 3
• While the 2016 IDSA guidelines focus on fluconazole monotherapy, they acknowledge that intrathecal amphotericin B is reserved for fluconazole failures. 1
• The presence of hydrocephalus at presentation indicates severe disease that may benefit from more aggressive initial therapy. 2, 3
• If amphotericin B is used, continue until clinical stabilization, then maintain high-dose fluconazole. 1

Urgent Neurosurgical Management of Hydrocephalus

Hydrocephalus in CM is nearly always communicating and requires mechanical CSF shunting in addition to antifungal therapy. 4, 2, 5

• Hydrocephalus is a common complication of CM and can develop even during appropriate antifungal treatment. 4, 5
• Patients with hydrocephalus and evidence of increased intracranial pressure require urgent shunt placement. 4, 5
• Ventriculoperitoneal shunting is the standard approach for communicating hydrocephalus in CM. 4, 5
• Do not delay neurosurgical consultation—acute decompensation can occur rapidly. 6
• In children with CM and hydrocephalus, initial ventricular cultures are commonly positive (unlike lumbar CSF), so consider obtaining ventricular fluid at time of shunt placement. 1

Monitoring Intracranial Pressure

• Opening pressure should be measured during lumbar puncture if safe to perform. 1
• Pressures of 180-250 mm H₂O are concerning but may not require specific intervention beyond shunting. 1
• Pressures ≥250 mm H₂O define the need for urgent or emergent intervention. 1
• There may be few or no radiographic changes associated with acute increased ICP, so clinical assessment is critical. 1

Addressing the Influenza A Co-infection

• The recent influenza A infection is likely coincidental and should be managed supportively if still symptomatic.
• Ensure the patient is not on medications that could interact with high-dose fluconazole.
• Monitor for hepatotoxicity given the combination of recent viral infection and high-dose azole therapy.

Lifelong Antifungal Therapy

Azole therapy must be continued for life in patients with CM. 1

• Azole therapy alone appears to suppress rather than cure coccidioidal meningeal disease. 1
• The evidence for lifelong therapy is the extremely high relapse rate (80%) when azoles are reduced in dose or discontinued, even in patients who are clinically well with normalized CSF parameters. 1
• Relapses occur even in patients without HIV infection in 25-33% of cases with disseminated disease. 1

Monitoring Treatment Response

Serial CSF analysis and complement fixation titers should be obtained approximately every 12 weeks to assess treatment response. 1

• A combination of clinical, CSF, and radiographic parameters should be used to define treatment success or failure. 1
• CSF parameters are the most important variable for monitoring. 1
• Treatment success is defined as a decrease in baseline score by 40% without relapse while treatment is continued, achieving near-normal clinical and CSF results. 1
• Rising CF titers suggest recurrence of clinical disease. 1

Management of Treatment Failure

If the patient fails to improve on high-dose fluconazole (800-1200 mg daily), alternative options include: 1

• Switching to itraconazole 200 mg 2-4 times daily (requires closer monitoring for absorption and has more drug-drug interactions). 1
• Considering voriconazole or posaconazole, though data are limited. 1
• Initiating intrathecal amphotericin B therapy if oral azoles fail. 1

Critical Pitfalls to Avoid

• Do not continue the current fluconazole dose—it is inadequate for CM. 1
• Do not delay neurosurgical evaluation for hydrocephalus management. 6, 4
• Do not plan to discontinue antifungal therapy after clinical improvement—CM requires lifelong treatment. 1
• Do not rely solely on CSF culture for diagnosis—it is positive in only 25% of adults. 1
• Ventricular fluid is not useful for evaluating disease activity during treatment—lumbar or cisternal CSF must be obtained. 1

Monitoring for Shunt Complications

• Shunt malfunction is a common complication in patients with CM who initially improve. 1
• If new neurologic problems develop, obtain repeat MRI of brain and possibly spinal cord with and without contrast, plus reanalysis of spinal fluid from lumbar or cisternal aspiration. 1
• Shunt infection with Coccidioides can occur and may require shunt removal with external ventricular drain placement followed by reimplantation after sterilization. 1