High dose fluconazole in salvage therapy for HIV-uninfected cryptococcal meningitis

Abstract

Background: The 2010 Infectious Diseases Society of America (IDSA) guidelines for management of cryptococcal diseases recommend high dose fluconazole (≥ 800 mg/day), either alone or with other antifungal drugs, as alternative anticryptococcal choices. But evidence for its use in the treatment of HIV-uninfected cryptococcal meningitis (CM) remains sparse.

Methods: A retrospective analysis of HIV-uninfected CM patients who received fluconazole 800 mg/day for salvage therapy from January 2011 to December 2016 at Huashan Hospital, Shanghai, China was performed. Efficacy and safety were assessed, and mortality and prognostic factors evaluated.

Results: A total of 44 patients were studied including 19 refractory to amphotericin B induction therapy, 8 refractory to fluconazole consolidation therapy (400 mg/d), and 17 intolerant of antifungal drugs. For salvage, 11 patients received triple therapy of high dose fluconazole, amphotericin B and flucytosine, 20 received dual therapy of high dose fluconazole and flucytosine, 13 received monotherapy of high dose fluconazole. Median duration of high dose fluconazole in salvage regimens was 136.5 days (range, 1-667 days). Clinical response rates were 72.1% (31/43) and 83.7% (36/43) when assessed at 2 weeks and the end of salvage therapy, respectively. Adverse events possibly related to high dose fluconazole occurred in 54.5% (24/44) of the patients, and all were mild or moderate. From the initiation of salvage therapy, 1-year all-cause mortality was 13.6% (6 of 44 patients) among the study population with no significant difference in refractory or intolerant patients.

Conclusions: Adherence to guideline recommendations of high dose fluconazole, alone or in combination with other antifungals, was safe and often effective for salvage therapy of HIV-uninfected CM patients.

Keywords: Cryptococcal meningitis; Efficacy; HIV-uninfected; High dose fluconazole; Safety.

Conflict of interest statement

Ethics approval and consent to participate

This study was reviewed and approved by the local medical Ethics Committee of Huashan Hospital, Fudan University, Shanghai, China. As this is a retrospective study, data was obtained through medical records and analyzed anonymously, and therefore informed consent of the participants was not required.

Consent for publication

Not applicable.

Competing interests

TSH reports an investigator award and honoraria from Gilead Sciences, advisory board fees from Viamet, gift of tests for research from Immuno-Mycologics, and honoraria from Pfizer. All authors declare no competing interests.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Profiles of initial therapy and salvage therapy in 44 difficult-to-treat cryptococcal meningitis patients. AmB amphotericin B; 5FC flucytosine; Vor voriconazole; L-Flu low dose fluconazole (≤ 400 mg/day); H-Flu high dose fluconazole (800 mg/day); CR complete response; PR partial response; DILI drug induced liver injury. Addition or removal of 5FC during initial and salvage therapy were not listed. An example for reading the figure: * means that the patient received AmB and flucytosine for a duration of 23 days as induction therapy, followed by consolidation therapy with low dose fluconazole for 142 days, and then switched to salvage therapy with high dose fluconazole for 246 days, and finally achieved partial response at the end of salvage therapy

Fig. 2

All-cause mortality in three groups of cryptococcal meningitis patients treated with high dose fluconazole for salvage therapy. Unk status unknown