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 > = 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 < 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA < 0.20 to those with EFA > = 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 < .01) and lower proportion of patients with CSF pleocytosis (P < .001). Conclusions EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of > = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA < 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

scholarly journals Bacterial Meningitis in the Absence of Cerebrospinal Fluid Pleocytosis: A Case Report and Review of the Literature

2014 ◽  
Vol 25 (5) ◽  
pp. 249-251 ◽  
Author(s):  
Ryota Hase ◽  
Naoto Hosokawa ◽  
Makito Yaegashi ◽  
Kiyoharu Muranaka
Keyword(s):  
Cerebrospinal Fluid ◽  
Bacterial Meningitis ◽  
Lumbar Puncture ◽  
Early Stage ◽  
Review Of The Literature ◽  
Csf Analysis ◽  
Cell Counts ◽  
Csf Pleocytosis ◽  
Cerebrospinal Fluid Pleocytosis ◽  
Rule Out

Elevation of cerebrospinal fluid (CSF) cell count is a key sign in the diagnosis of bacterial meningitis. However, there have been reports of bacterial meningitis with no abnormalities in initial CSF testing. This type of presentation is extremely rare in adult patients. Here, a case involving an 83-year-old woman who was later diagnosed with bacterial meningitis caused byNeisseria meningitidisis described, in whom CSF at initial and second lumbar puncture did not show elevation of cell counts. Twenty-six non-neutropenic adult cases of bacterial meningitis in the absence of CSF pleocytosis were reviewed. The frequent causative organisms wereStreptococcus pneumoniaeandN meningitidis. Nineteen cases had bacteremia and seven died. The authors conclude that normal CSF at lumbar puncture at an early stage cannot rule out bacterial meningitis. Therefore, repeat CSF analysis should be considered, and antimicrobial therapy must be started immediately if there are any signs of sepsis or meningitis.

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.

Implementation of an Algorithmic Approach to Molecular Infectious Disease Laboratory Testing on Cerebrospinal Fluid Samples

2019 ◽  
Vol 152 (Supplement_1) ◽  
pp. S143-S143
Author(s):  
Alexander Maris ◽  
Caitlin Hughes ◽  
Thessicar Antoine-Reid ◽  
Jonathan Schmitz
Keyword(s):  
Infectious Disease ◽  
Cerebrospinal Fluid ◽  
Laboratory Testing ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Turnaround Time ◽  
Cns Infection ◽  
Algorithmic Approach ◽  
Cell Counts ◽  
Csf Pleocytosis

Abstract Rapid turnaround time for infectious disease laboratory testing is critical for the encephalitic/meningitic patient. Clinicians and emergency medicine providers often will bundle cerebrospinal fluid (CSF) studies (cell counts, glucose, protein) with molecular infectious disease laboratory (MIDL) assays, up front, to expedite clinical decision making about antimicrobial therapy and hospital admission. Many patients, however, ultimately do not have CSF pleocytosis and, predictably, have negative MIDL results. We quantified patients who had MIDL testing ordered, without concurrent CSF pleocytosis, to justify a mandated algorithm for CSF MIDL testing. Four months of MIDL CSF results were reviewed (viral monoplex PCRs); 274 patients were identified. Forty-seven percent of patients (128/274) were neonates (<2 months old) and thus may not have had the immunologic capacity to mount a pleocytosis to CNS infection. Of the remaining 53% of patients (>2 months old), who would have been expected to generate a CSF pleocytosis, 55% (81/146) had one or more MIDL studies ordered without CSF pleocytosis; 3.4% of these patients (5/146) did not have CSF cell counts ordered. Among all patients, 7.7% (21/274) had positive MIDL results (1 HSV1; 2 HSV2; 18 enterovirus). Seventeen patients had CSF pleocytosis; the 4 patients without CSF pleocytosis were neonates (3) or had no cell counts ordered (1). A ratio of 700 RBC to 1 WBC was used to approximate the expected number of CSF WBC in bloody taps (10%; 28/274). We show that over half of patients >2 months old had MIDL studies ordered without CSF pleocytosis; all patients with positive MIDL results had CSF pleocytosis or were neonates or had no cell counts ordered. An algorithm will be implemented in which all neonates with concern for CNS infection will have CSF MIDL tests ordered; among nonneonates, only those with documented CSF pleocytosis may have MIDL assays ordered (with rare exceptions; eg, leukopenia).

Cerebrospinal fluid microscopy as an index for predicting the prognosis of cryptococcal meningitis patients with and without HIV

2020 ◽  
Vol 15 (17) ◽  
pp. 1645-1652
Author(s):  
Keming Zhang ◽  
Hang Li ◽  
Lei Zhang ◽  
Wanqing Liao ◽  
Liyan Ling ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Clinical Data ◽  
Cryptococcal Meningitis ◽  
Fungal Burden ◽  
Hospital Patients ◽  
Patient Prognosis ◽  
Worse Prognosis ◽  
Fluid Test

Aim: To evaluate the clinical data and quantitative cerebrospinal fluid for associations with the outcome of cryptococcal meningitis (CM) patients in the hospital. Patients & methods: We retrospectively analyzed a total of 139 CM patients comprising 108 without HIV and 31 with HIV admitted in a Jiang Xi hospital. Resμlts: We found that CM patients with the high fungal burden (≥10 yeasts/μl) (26.3%) had a worse prognosis than those with the low fungal burden (<10 yeasts/μl). (4.9%) (p = 0.0007 <0.05). Conclusion: In CM patients, a fungal burden of 10 yeasts/μl in the first cerebrospinal fluid test may be used as an indicator of patient prognosis, and we can personalize patients’ treatment based on the fungal burden to improve prognosis.

scholarly journals On the design of early-phase Alzheimer’s disease clinical trials with cerebrospinal fluid tau outcomes

2021 ◽  
pp. 174077452110344
Author(s):  
Michelle M Nuño ◽  
Joshua D Grill ◽  
Daniel L Gillen ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cerebrospinal Fluid ◽  
Phosphorylated Tau ◽  
Inclusion Criteria ◽  
Eligibility Criteria ◽  
Total Tau ◽  
Prodromal Alzheimer’S Disease ◽  
Study Power

Background/Aims: The focus of Alzheimer’s disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with “prodromal Alzheimer’s disease” to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer’s disease dementia. The use of these eligibility criteria may affect study power. Methods: We investigated outcome variability and study power in the setting of proof-of-concept prodromal Alzheimer’s disease trials that incorporate cerebrospinal fluid levels of total tau (t-tau) and phosphorylated (p-tau) as primary outcomes and how differing biomarker inclusion criteria affect power. We used data from the Alzheimer’s Disease Neuroimaging Initiative to model trial scenarios and to estimate the variance and within-subject correlation of total and phosphorylated tau. These estimates were then used to investigate the differences in study power for trials considering these two surrogate outcomes. Results: Patient characteristics were similar for all eligibility criteria. The lowest outcome variance and highest within-subject correlation were obtained when phosphorylated tau was used as an eligibility criterion, compared to amyloid beta or total tau, regardless of whether total tau or phosphorylated tau were used as primary outcomes. Power increased when eligibility criteria were broadened to allow for enrollment of subjects with either low amyloid beta or high phosphorylated tau. Conclusion: Specific biomarker inclusion criteria may impact statistical power in trials using total tau or phosphorylated tau as the primary outcome. In concert with other important considerations such as treatment target and population of clinical interest, these results may have implications to the integrity and efficiency of prodromal Alzheimer’s disease trial designs.

scholarly journals Preclinical evaluation of eltrombopag in a PDX model of myelodysplastic syndromes

Leukemia ◽  
2021 ◽  
Author(s):  
Nanni Schmitt ◽  
Johann-Christoph Jann ◽  
Eva Altrock ◽  
Johanna Flach ◽  
Justine Danner ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Myelodysplastic Syndromes ◽  
Preclinical Study ◽  
Preclinical Research ◽  
Individual Level ◽  
Specific Effects ◽  
Pdx Model ◽  
Whole Exome ◽  
Thrombopoietin Receptor ◽  
Therapeutic Concepts

AbstractPreclinical research of myelodysplastic syndromes (MDSs) is hampered by a lack of feasible disease models. Previously, we have established a robust patient-derived xenograft (PDX) model for MDS. Here we demonstrate for the first time that this model is applicable as a preclinical platform to address pending clinical questions by interrogating the efficacy and safety of the thrombopoietin receptor agonist eltrombopag. Our preclinical study included n = 49 xenografts generated from n = 9 MDS patient samples. Substance efficacy was evidenced by FACS-based human platelet quantification and clonal bone marrow evolution was reconstructed by serial whole-exome sequencing of the PDX samples. In contrast to clinical trials in humans, this experimental setup allowed vehicle- and replicate-controlled analyses on a patient–individual level deciphering substance-specific effects from natural disease progression. We found that eltrombopag effectively stimulated thrombopoiesis in MDS PDX without adversely affecting the patients’ clonal composition. In conclusion, our MDS PDX model is a useful tool for testing new therapeutic concepts in MDS preceding clinical trials.

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