#PharmToExamTable: What is the optimal dose of fluconazole for consolidation therapy in cryptococcal meningitis?

A #PharmToExamTable question about fluconazole dosing, answered by Brady Caverzagie, PharmD, a Graduate of UNMC College of Pharmacy.

(Reviewed by Andrew Watkins, PharmD)

Cryptococcus spp. are fungal pathogens found in the soil and pigeon droppings. Usually, Cryptococcus spp. do not cause severe or life-threatening symptoms in immunocompetent patients; however, in immunocompromised patients, cryptococcal infections can cause serious complications.  Patients who are HIV positive with high viral loads and low CD4 cell counts are especially susceptible to infection with cryptococcal species, which can disseminate throughout the body, including the central nervous system (CNS).  Once in the CNS, patients often have a classic meningitis-like presentation including headache, stiff neck, fever, and photophobia. Standard treatment for cryptococcal meningitis in the setting of HIV includes long courses of antifungals, relief of intracranial pressure, and supportive care.¹

Antifungal treatment includes three different phases: induction, consolidation, and maintenance. The 2010 Infectious Disease Society of America (IDSA) guidelines for cryptococcal meningitis for HIV-infected individuals recommends induction therapy with liposomal amphotericin at a dose of 3-4 mg/kg intravenously per day along with flucytosine 100 mg/kg orally per day in four divided doses for at least two weeks. Induction therapy continues for two weeks or until clearance of Cryptococcus from the cerebrospinal fluid, whichever comes last. Consolidation therapy follows the induction period and consists of 400 mg per day of fluconazole by mouth for a minimum of eight weeks. The last phase is maintenance therapy which is generally 200 mg per day of fluconazole by mouth for 6-12 months.²

There is not an established fluconazole breakpoint for Cryptococcus spp., from the Clinical and Laboratory Standards Institute (CLSI), making it difficult to determine if the recommended treatment is optimal in the setting of elevated minimum inhibitory concentrations (MIC).^3,4 Although the most common fluconazole MIC for Cryptococcus spp. Is 4 mg/L, a systematic review showed the median increase from 4 µg/mL in 2000-2012 to 8 µg/mL in 2014-2018.⁵ Additionally, worse patient outcomes and treatment failures have been observed in patients with cryptococcal isolates that have higher fluconazole MICs.⁶ The recent decrease in susceptibility to fluconazole in cryptococcal species is forcing a reevaluation of the appropriateness of 400mg per day of fluconazole in consolidation therapy for cryptococcal meningitis.^4,5  

Fluconazole works by inhibiting the fungal CYP P450 dependent enzyme lanosterol 14-α-demethylase, which converts lanosterol to ergosterol. Without ergosterol, the fungal cell membrane cannot function properly. Oral bioavailability of fluconazole is excellent at over 90%, making it a good option for long term outpatient therapy. While fluconazole distributes well to the urine and skin, with levels ~10x those seen in plasma, it distributes less well to the cerebrospinal fluid with levels 50-90% of those seen in plasma. The inhibition of human CYP enzymes (primarily CYP 3A4) leads to numerous drug interactions and careful monitoring of these interactions is important during therapy, especially in long courses of fluconazole used in cryptococcal meningitis.⁷

In the face of increasing MICs and an infection in an area of the body with lower drug penetration, the question becomes what dose will work for consolidation therapy in a patient with cryptococcal meningitis once they have completed induction therapy? Based on a model created to investigate fluconazole use for all phases of cryptococcal therapy, 400 mg daily would reach therapeutic levels of >100 AUC:MIC for 53% of isolates, 800 mg daily would reach therapeutic levels for 74% of isolates and 1200 mg would be effective for 83% of isolates.⁵ The data from the model can be reconfigured to demonstrate what dose can reasonably be expected to treat a particular isolate based on MIC (Table 1). The guideline driven 400 mg per day dose of fluconazole for consolidation may only be consistently effective for highly susceptible pathogens, leaving the rising incidence of resistant organisms to grow unchecked.

Table 1: Probability of achieving >100 AUC:MIC based on MIC and dose

Cryptococcal meningitis is a serious infection that needs to be adequately treated, and the MIC of cryptococcal isolates should be taken into consideration, particularly in immunocompromised patients. The guideline dosing for fluconazole consolidation treatment of 400mg daily is likely sufficient for cryptococcal isolates with an MIC of 2 mg/L, however fluconazole MICs among cryptococcal species have been increasing over the past two decades. To adequately reach therapeutic levels in patients with less susceptible organisms, doses of 800-1200mg per day could be necessary. Patients should be monitored carefully because tolerability of fluconazole may become a clinical issue at higher doses. Although limited evidence exists in these situations, an alternative agent may be necessary if MICs exceed 16 mg/L or patients become intolerant to fluconazole therapy.

References:

1. Dipiro JT, et al. Pharmacotherapy A Pathophysiological Approach. 11^th ed. McGraw-Hill 2019.
2. Perfect JR, et al. Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America, Clinical Infectious Diseases, Volume 50, Issue 3, 1 February 2010, Pages 291–322.
3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antifungal Susceptibility Testing of Yeasts. 1^st ed.  CLSI supplement M60. Wayne, PA: CLSI; 2017.
4. Bongomin F, et al. A systematic review of fluconazole resistance in clinical isolates of Cryptococcus species. Mycoses. 2018;61(5):290-297.
5. Chesdachai S, et al., Minimum Inhibitory Concentration Distribution of Fluconazole Against CryptococcusSpecies and the Fluconazole Exposure Prediction Model, Open Forum Infectious Diseases, Volume 6, Issue 10, October 2019.
6. Sai Cheon JW, McCormack J. Fluconazole resistance in cryptococcal disease: emerging or intrinsic?, Medical Mycology, Volume 51, Issue 3, April 2013, Pages 261–269.
7. Diflucan (fluconazole) [package insert] New York, NY: Pfizer Inc; September 2020.