High-Dose Fluconazole Therapy for Cryptococcal Meningitis in Patients with AIDS

Menichetti, Francesco; Fiorio, Maurizio; Tosti, Andrea; Gatti, Giorgio; Pasticci, Maria Bruna; Miletich, Franca; Marroni, Massimo; Bassetti, Dante; Pauluzzi, S

doi:10.1093/clinids/22.5.838

Cited by 86 publications

(54 citation statements)

References 9 publications

(18 reference statements)

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“…Early clinical studies used relatively low dosages for induction therapy (e.g., 200 to 400 mg/day) (4,19,21). While clinical efficacy can be demonstrated with these dosages, the microbiological and clinical outcomes are often inferior to amphotericin B-based regimens, thus prompting studies examining higher dosages of fluconazole (2,3,22). The use of Ն1,200 mg of fluconazole/day as monotherapy is recommended in guidelines from the Infectious Diseases Society of America (15).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Fluconazole for Cryptococcal Meningoencephalitis: Implications for Antifungal Therapy andIn VitroSusceptibility Breakpoints

Sudan

Livermore

Howard

et al. 2013

Antimicrob Agents Chemother

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dFluconazole is frequently the only antifungal agent that is available for induction therapy for cryptococcal meningitis. There is relatively little understanding of the pharmacokinetics and pharmacodynamics (PK-PD) of fluconazole in this setting. PK-PD relationships were estimated with 4 clinical isolates of Cryptococcus neoformans. MICs were determined using Clinical and Laboratory Standards Institute (CLSI) methodology. A nonimmunosuppressed murine model of cryptococcal meningitis was used. Mice received two different doses of fluconazole (125 mg/kg of body weight/day and 250 mg/kg of body weight/day) orally for 9 days; a control group of mice was not given fluconazole. Fluconazole concentrations in plasma and in the cerebrum were determined using high-performance liquid chromatography (HPLC). The cryptococcal density in the brain was estimated using quantitative cultures. A mathematical model was fitted to the PK-PD data. The experimental results were extrapolated to humans (bridging study). The PK were linear. A dose-dependent decline in fungal burden was observed, with near-maximal activity evident with dosages of 250 mg/kg/day. The MIC was important for understanding the exposure-response relationships. The mean AUC/MIC ratio associated with stasis was 389. The results of the bridging study suggested that only 66.7% of patients receiving 1,200 mg/kg would achieve or exceed an AUC/MIC ratio of 389. The potential breakpoints for fluconazole against Cryptococcus neoformans follow: susceptible, <2 mg/liter; resistant, >2 mg/liter. Fluconazole may be an inferior agent for induction therapy because many patients cannot achieve the pharmacodynamic target. Clinical breakpoints are likely to be significantly lower than epidemiological cutoff values. The MIC may guide the appropriate use of fluconazole. If fluconazole is the only option for induction therapy, then the highest possible dose should be used. Cryptococcal meningoencephalitis is a leading cause of global infectious morbidity and mortality (1). There are approximately one million cases per year in the world and 600,000 deaths (1). The majority of the global disease burden occurs in subSaharan Africa, where cryptococcal meningoencephalitis is intricately linked with the extensive and persistent AIDS epidemic. There are relatively few therapeutic options, and little information on the pharmacokinetics and pharmacodynamics (PK-PD) of currently available antifungal agents for the treatment of this neglected fungal disease.In many parts of the world, fluconazole is the only antifungal agent that is available for treatment of cryptococcal meningoencephalitis. While there is extensive information on the use of fluconazole for consolidation and suppressive therapy, there is less information on optimal induction regimens. Recent clinical trials suggest that higher dosages (e.g., 1,200 to 2,000 mg/day) result in improved antifungal activity (2, 3), although further antifungal activity is evident with the addition of flucytosine, suggesting that this dosage may sti...

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Fluconazole for Cryptococcal Meningoencephalitis: Implications for Antifungal Therapy andIn VitroSusceptibility Breakpoints

Sudan

Livermore

Howard

et al. 2013

Antimicrob Agents Chemother

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“…The administration of corticosteroids and discontinuation of ART to reduce meningeal inflammation and neurological symptoms may assist in cases of aseptic paradoxical cryptococcal IRD with documented multiple negative CSF cultures. The duration of antifungal therapy is critical, as the time to sterilization of CSF ranges from 21 to 64 days depending on the fluconazole dose and antifungal regimen (59,74,96).…”

Section: Cryptococcal Ird: Severe Consequences Of a High Antigen Loadmentioning

confidence: 99%

Immune Restoration Diseases Reflect Diverse Immunopathological Mechanisms

et al. 2009

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SUMMARY Up to one in four patients infected with human immunodeficiency virus type 1 and given antiretroviral therapy (ART) experiences inflammatory or cellular proliferative disease associated with a preexisting opportunistic infection, which may be subclinical. These immune restoration diseases (IRD) appear to result from the restoration of immunocompetence. IRD associated with intracellular pathogens are characterized by cellular immune responses and/or granulomatous inflammation. Mycobacterial and cryptococcal IRD are attributed to a pathological overproduction of Th1 cytokines. Clinicopathological characteristics of IRD associated with viral infections suggest different pathogenic mechanisms. For example, IRD associated with varicella-zoster virus or JC polyomavirus infection correlate with a CD8 T-cell response in the central nervous system. Exacerbations or de novo presentations of hepatitis associated with hepatitis C virus (HCV) infection following ART may also reflect restoration of pathogen-specific immune responses as titers of HCV-reactive antibodies rise in parallel with liver enzymes and plasma markers of T-cell activation. Correlations between immunological parameters assessed in longitudinal sample sets and clinical presentations are required to illuminate the diverse immunological scenarios described collectively as IRD. Here we present salient clinical features and review progress toward understanding their pathogeneses.

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“…Fluconazole should be introduced for consolidation regimen whenever the mental status recovered, fever, headache and meningeal symptoms disappear, and/or yeast culture results are negative at the second week. Despite the theoretic antagonism between amphotericin B and fluconazole, most animal model data suggests that both drugs together are a very effective combination against C. neoformans (Menichetti et al, 1996;Larsen et al, 2004;Larsen et al, 2005;Pappas et al, 2009;Perfect et al, 2010).…”

Section: Cryptococcosis and Aidsmentioning

confidence: 99%