scholarly journals Fungal Burden, Early Fungicidal Activity, and Outcome in Cryptococcal Meningitis in Antiretroviral-Naive or Antiretroviral-Experienced Patients Treated with Amphotericin B or Fluconazole

2007 ◽  
Vol 45 (1) ◽  
pp. 76-80 ◽  
Author(s):  
T. Bicanic ◽  
G. Meintjes ◽  
R. Wood ◽  
M. Hayes ◽  
K. Rebe ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Cryptococcal Meningitis ◽  
Fungicidal Activity ◽  
Fungal Burden ◽  
Early Fungicidal Activity

scholarly journals A randomized open label trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis.

2019 ◽  
Vol 4 ◽  
pp. 8 ◽  
Author(s):  
Nguyen Thi Thuy Ngan ◽  
Nguyen Thi Hoang Mai ◽  
Nguyen Le Nhu Tung ◽  
Nguyen Phu Huong Lan ◽  
Luong Thi Hue Tai ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Cryptococcal Meningitis ◽  
Treatment Guidelines ◽  
Controlled Trial ◽  
Safety Data ◽  
Open Label ◽  
Receptor Modulator ◽  
Open Label Trial ◽  
Early Fungicidal Activity

Background: Cryptococcal meningitis is a leading cause of death in HIV-infected patients. International treatment guidelines recommend induction therapy with amphotericin B and flucytosine. This antifungal combination is most effective, but unfortunately flucytosine is expensive and unavailable where the burden of disease is greatest. Where unavailable, guidelines recommend treatment with amphotericin and fluconazole, but this is less effective, with mortality rates of 40-50%. Faster rates of clearance of yeast from cerebrospinal fluid (CSF) are associated with better outcomes - improving the potency of antifungal therapy is likely to be an effective strategy to improve survival. Tamoxifen, a selective estrogen receptor modulator used to treat breast cancer, has anti-cryptococcal activity, appearing synergistic when combined in vitro with amphotericin, and fungicidal when combined with fluconazole. It is concentrated in the brain and macrophages, off-patent, cheap and widely available. We designed a randomized trial to deliver initial efficacy and safety data for tamoxifen combined with amphotericin and fluconazole. Method: A phase II, open-label, randomized (1:1) controlled trial of tamoxifen (300mg/day) combined with amphotericin (1mg/kg/day) and fluconazole (800mg/day) for the first 2 weeks therapy for HIV infected or uninfected adults with cryptococcal meningitis. The study recruits at Cho Ray Hospital and the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. The primary end point is Early Fungicidal Activity (EFA-the rate of yeast clearance from CSF), over the first two weeks of treatment. 50 patients will be recruited providing ≈80% and 90% power to detect a difference in the EFA of -0.11 or -0.13 log10CFU/ml/day, respectively. Discussion: The results of the study will inform the decision to proceed to a larger trial powered to mortality. The size of effect detectable has previously been associated with reduced mortality from this devastating disease. Particular side effects of interest include QT prolongation. Trial registration: Clinicaltrials.gov NCT03112031 (11/04/2017)

Unique clinical features of cryptococcal meningitis among Chinese patients without predisposing diseases against patients with predisposing diseases

2019 ◽  
Vol 57 (8) ◽  
pp. 944-953 ◽  
Author(s):  
Lijun Xu ◽  
Xinyue Zhang ◽  
Yongzheng Guo ◽  
Ran Tao ◽  
Xiahong Dai ◽  
...  
Keyword(s):  
Risk Factors ◽  
Serum Albumin ◽  
Amphotericin B ◽  
Clinical Features ◽  
Cryptococcal Meningitis ◽  
White Blood Cells ◽  
Chinese Patients ◽  
Fungal Burden ◽  
Risk Of Death ◽  
Culture Positivity

Abstract The clinical features of cryptococcal meningitis (CM) in patients without predisposing diseases (PD) remain unclear. In sum, 162 of the 167 patients without PD and 162 of the 309 patients with PD were enrolled after propensity score matching. Demographic characteristics, symptoms, blood, and cerebrospinal fluid (CSF) characteristics were compared between the two groups. Kaplan-Meier curves and a Cox proportional hazards model were used to assess the factors associated with 10-week mortality. In total, approximately 35.1% of CM patients were without PD. CM patients without PD had blood profiles of higher white blood cells (WBC) [8.9(6.7–11.0) × 109/l], hemoglobin (128.4 ± 20.9 g/l), platelets [(226.2 ± 64.1) × 109/l], and serum albumin (41.2 ± 5.8 g/l) (all P ≤ .001) and CSF profiles of lower glucose (2.0 ± 1.2 mmol/l), pleocytosis [65.0 (18.0–160.0) × 106/l] and higher total protein [0.9 (0.7–1.4)g/l] (all P < .05). CM patients without PD had lower Cryptococcus culture positivity in CSF (62.5% vs. 74.1%, P = .039) but higher 2-week of CSF culture sterilization rates (69.4% vs. 51.3%, P = .031). The overall 10-week survival rate was 84.7% in patients without PD and 81.1% in patients with PD (Log-rank P = .439). CSF glucose <1.5 mmol/l, CSF fungal burden >20 cells/high power field and treatment lacking amphotericin B had a 3–4 times higher risk of death in patients without PD, whereas serum albumin <35 g/l, CSF glucose < 1.5 mmol/l, and CSF WBC <55 × 106 cell/l were risk factors for patients with PD. CM patients without PD had unique blood and CSF profiles, especially, had lower Cryptococcus culture positivity in CSF, and higher 2-week CSF culture sterilization. Low CSF glucose levels, higher fungal burden, and treatment without amphotericin B were risk factors for 10-week mortality.

scholarly journals Oral versus Intravenous Flucytosine in Patients with Human Immunodeficiency Virus-Associated Cryptococcal Meningitis

2006 ◽  
Vol 51 (3) ◽  
pp. 1038-1042 ◽  
Author(s):  
Annemarie E. Brouwer ◽  
Hendrikus J. M. van Kan ◽  
Elizabeth Johnson ◽  
Adul Rajanuwong ◽  
Prapit Teparrukkul ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Human Immunodeficiency Virus ◽  
Cryptococcal Meningitis ◽  
Fungicidal Activity ◽  
Controlled Trial ◽  
Oral Formulation ◽  
Bone Marrow Toxicity ◽  
Time Curve ◽  
Immunodeficiency Virus ◽  
Early Fungicidal Activity

ABSTRACT In a randomized controlled trial of amphotericin B-based therapy for human immunodeficiency virus (HIV)-associated cryptococcal meningitis in Thailand, we also compared the mycological efficacy, toxicity, and pharmacokinetics of oral versus intravenous flucytosine at 100 mg/kg of body weight/day for the initial 2 weeks. Half of 32 patients assigned to the two arms containing flucytosine were randomized to oral and half to intravenous flucytosine. Early fungicidal activity was determined from serial quantitative cultures of cerebrospinal fluid (CSF), and toxicity was assessed by clinical and laboratory monitoring. Flucytosine and fluorouracil concentrations in plasma and CSF were measured by high-performance liquid chromatography. No significant bone marrow or hepatotoxicity was seen, there was no detectable difference in bone marrow toxicity between patients on intravenous and those on oral formulation, and no patients discontinued treatment. In patients receiving intravenous flucytosine, the median 24-h area under the concentration-time curve was significantly higher than in the oral group. Despite this difference, there was no difference in early fungicidal activity between patients on intravenous compared with patients on oral flucytosine. The results suggest that either formulation can be used safely at this dosage in a developing country setting, without drug concentration monitoring. The bioavailability of the oral formulation may be reduced in late-stage HIV-infected patients in Thailand. Concentrations of flucytosine with intravenous formulation at 100 mg/kg/day may be in excess of those required for maximal fungicidal activity.

scholarly journals Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials

2020 ◽  
Vol 71 (7) ◽  
pp. e45-e49 ◽  
Author(s):  
Matthew F Pullen ◽  
Katherine Huppler Hullsiek ◽  
Joshua Rhein ◽  
Abdu K Musubire ◽  
Lillian Tugume ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cerebrospinal Fluid ◽  
Cryptococcal Meningitis ◽  
Fungicidal Activity ◽  
Surrogate Endpoint ◽  
Individual Level ◽  
Cell Counts ◽  
All Cause Mortality ◽  
Csf Pleocytosis ◽  
Early Fungicidal Activity

Abstract Background In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks. Methods We pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010–2017. All 738 subjects received amphotericin + fluconazole induction therapy and had serial quantitative CSF cultures. The log10-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days. Results Mortality through 18 weeks was 37% for EFA &gt; = 0.60 (n = 170), 36% for 0.40–0.59 (n = 182), 39% for 0.30–0.39 (n = 112), 35% for 0.20–0.29 (n = 87), and 50% for those with EFA &lt; 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA &lt; 0.20 to those with EFA &gt; = 0.20, was 1.60 (95% confidence interval, 1.25, 2.04; P = .002). The lowest EFA group had lower median CD4 T-cell counts (P &lt; .01) and lower proportion of patients with CSF pleocytosis (P &lt; .001). Conclusions EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of &gt; = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA &lt; 0.20. This EFA threshold may be considered a target for a surrogate endpoint. This builds upon existing studies to validate EFA as a surrogate endpoint.

scholarly journals Early Fungicidal Activity as a Candidate Surrogate Endpoint for All-Cause Mortality in Cryptococcal Meningitis: A Systematic Review of the Evidence

PLoS ONE ◽  
2016 ◽  
Vol 11 (8) ◽  
pp. e0159727 ◽  
Author(s):  
Jairo M. Montezuma-Rusca ◽  
John H. Powers ◽  
Dean Follmann ◽  
Jing Wang ◽  
Brigit Sullivan ◽  
...  
Keyword(s):  
Systematic Review ◽  
Cryptococcal Meningitis ◽  
Fungicidal Activity ◽  
Surrogate Endpoint ◽  
All Cause Mortality ◽  
Early Fungicidal Activity
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