Ceftriaxone-induced Encephalopathy: A Pharmacokinetic Approach

We report a case of ceftriaxone-induced encephalopathy correlated with high cerebrospinal fluid concentration. Neurotoxicity of cephalosporin is increasingly reported, especially regarding fourth-generation cephalosporins. The factors influencing the corticospinal fluid (CSF) concentration are plasma concentration, liposolubility, ionization, molecular weight, protein binding and efflux. In our patient, high levels of ceftriaxone (27.9 mg/l) were found in the CSF. β-lactam associated neurotoxicity is mainly related to similarities between GABA and β-lactam ring. Because of disparate CSF/plasma ratio and blood-brain barrier efflux among patients, plasmatic drug monitoring probably cannot be used as a surrogate of CSF concentration. This is, as we know, the first case of described ceftriaxone-induced encephalopathy associated with an objective excessive cerebrospinal concentration.

Cerebrospinal fluid exposure to bictegravir/emtricitabine/tenofovir in HIV-1-infected patients with CNS impairment

Objectives The penetration of antiretroviral drugs into deep compartments, such as the CNS, is a crucial component of strategies towards an HIV cure. This study aimed to determine CSF concentrations of bictegravir, emtricitabine and tenofovir in patients with HIV-related CNS impairment (HCI) enrolled in a real-life observational study. Methods Patients with HCI treated by optimized ART, including bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) for at least 1 month were enrolled. Plasma and CSF concentrations were measured by quality control-validated assays (LC-MS/MS). The inhibitory quotient (IQARV) was calculated as the ratio of unbound (bictegravir) or total (emtricitabine and tenofovir) concentration to half (or 90%) maximal inhibitory concentration for bictegravir (or emtricitabine and tenofovir). All numerical variables are expressed as median (range). Results Twenty-four patients (nine women) were enrolled. The age was 45 (26–68) years. Unbound bictegravir and total emtricitabine and tenofovir CSF concentrations were 4.4 (1.6–9.6), 84.4 (28.6–337.4) and 1.6 (0.7–4.3) ng/mL, respectively. The unbound bictegravir CSF fraction was 34% (15%–82%) versus 0.33% (0.11%–0.92%) in plasma. Three patients had an IQARV above unity for the three antiretrovirals. Factors positively associated with the CSF concentration (unbound for bictegravir) were age and total plasma concentration for the three antiretrovirals. Patients aged over 51 years had higher CSF concentrations (unbound for bictegravir). Conclusions We observed low CSF exposure to bictegravir, emtricitabine and tenofovir. These results suggest that BIC/FTC/TAF should be used with caution as first-line treatment for people living with HIV with HCI under 51 years of age.

Cerebrospinal Fluid IL-17A Could Predict Acute Disease Severity in Non-NMDA-Receptor Autoimmune Encephalitis

IntroductionMost of our knowledge into autoimmune encephalitis (AE) comes from N-Methyl-D-Aspartate Receptor (NMDAR) encephalitis. The concentrations of cytokines in cerebrospinal fluid (CSF) including IL-17A have been found to be increased and associated with poor outcome. However, data on the cytokine concentration in CSF and its correlation with outcome is lacking for other types of AE.ObjectiveTo report the concentrations of CSF sIL-2R, IL-6, IL-8, IL-10 and IL-17A and to correlate it with acute disease severity and the 1-year outcome in non-NMDAR AE.MethodsWe measured the CSF concentration of each cytokine in 20 AE patients, and compared IL-6 and IL-17A concentrations with 13 patients with CNS demyelinating diseases and 20 non-inflammatory controls. Patients were > 18yr and had at least 1-year clinical follow-up. Intracellular and NMDAR antibody (Ab) -mediated encephalitis were excluded. A mRS ≤ 2 was retained as a 1-year good outcome.ResultsThe IL-17A concentration in CSF was higher in AE patients than in both control groups (p<0.01). No difference was observed in CSF concentration of IL-6 between groups. At disease onset, a high CSF IL-17A concentration correlated with a high modified Rankin Scale (p<0.05), a high Clinical Assessment Scale for Autoimmune Encephalitis score (p<0.001) and ICU admission (p<0.01). There was no correlation between the concentration of all CSF cytokines and the 1-year clinical outcome.ConclusionOur results show that CSF IL-17A could be interesting to assess initial severity in non-NMDAR AE. Thus, CSF IL-17A could be an interesting therapeutic target and be useful to assess early selective immunosuppressive therapy.

The Comparison of Plasma and Cerebrospinal Fluid R(−)- and S(+)-Flurbiprofen Concentration After Intravenous Injection of Flurbiprofen Axetil in Human Subjects

Background: Flurbiprofen axetil is a prodrug that releases the active substance through enzymatic removal of the ester moiety. It is formulated through encapsulation in a lipid microsphere carrier, and widely used to treat perioperative pain. Here, we studied the distribution of R (−)- and S (+)-flurbiprofen in human plasma and cerebrospinal fluid (CSF) after intravenous injection of flurbiprofen axetil.Methods: A total of 70 adult patients undergoing elective lower limb surgery under spinal anesthesia were given a single intravenous injection of 100-mg flurbiprofen axetil. The patients were randomly assigned to 10 groups for plasma and CSF sampling at 10 time points (5–50 min) after subarachnoid puncture and before actual spinal anesthesia. R (−)- and S (+)-flurbiprofen and CSF/plasma ratio were determined by liquid chromatography–tandem mass spectrometry.Results: R (−)-flurbiprofen concentration ranged from 2.01 to 10.9 μg/mL in plasma and 1.46–34.4 ng/mL in CSF. S (+)-flurbiprofen concentration ranged from 1.18 to 10.8 μg/mL in plasma and from 2.53 to 47 ng/mL in CSF. In comparison to S (+)-flurbiprofen, R (−)-flurbiprofen concentration was significantly higher in plasma at all time points (p < 0.05) except at 30 or 40 min, and lower in CSF at all time points (p < 0.05) except at 10, 15 and 40 min. Analysis after correcting drug concentration for body mass index also revealed higher plasma and lower CSF R (−)-flurbiprofen concentration. In comparison to S (+)-flurbiprofen, AUC0–50 for R (−)-flurbiprofen was larger in plasma and smaller in CSF (p < 0.05 for both), and accordingly smaller CSF/plasma AUC0–50 ratio (p < 0.05). There was a positive correlation between R (−)-flurbiprofen concentration and S (+)-flurbiprofen concentration in plasma (r = 0.725, p < 0.001) as well as in CSF (r = 0.718, p < 0.001), and a negative correlation between plasma and CSF concentration of S (+)-flurbiprofen (r = −0.250, p = 0.037), but not R (−)-flurbiprofen.Conclusion: Distribution of R (−)- and S (+)-flurbiprofen in plasma and CSF differed significantly. Penetration of R (−)-flurbiprofen into the CNS was lower than S (+)-flurbiprofen.

Pharmacokinetics of remdesivir and GS-441524 in two critically ill patients who recovered from COVID-19

Background Remdesivir is a prodrug of the nucleoside analogue GS-441524 and is under evaluation for treatment of SARS-CoV-2-infected patients. Objectives To evaluate the pharmacokinetics of remdesivir and GS-441524 in plasma, bronchoalveolar aspirate (BAS) and CSF in two critically ill COVID-19 patients. Methods Remdesivir was administered at 200 mg loading dose on the first day followed by 12 days of 100 mg in two critically ill patients. Blood samples were collected immediately after (C0) and at 1 (C1) and 24 h (C24) after intravenous administration on day 3 until day 9. BAS samples were collected on Days 4, 7 and 9 from both patients while one CSF on Day 7 was obtained in one patient. Remdesivir and GS-441524 concentrations were measured in these samples using a validated UHPLC-MS/MS method. Results We observed higher concentrations of remdesivir at C0 (6- to 7-fold higher than EC50 from in vitro studies) and a notable decay at C1. GS-441524 plasma concentrations reached a peak at C1 and persisted until the next administration. Higher concentrations of GS-441524 were observed in the patient with mild renal dysfunction. Mean BAS/plasma concentration ratios of GS-441524 were 2.3% and 6.4% in Patient 1 and Patient 2, respectively. The CSF concentration found in Patient 2 was 25.7% with respect to plasma. GS-441524 levels in lung and CNS suggest compartmental differences in drug exposure. Conclusions We report the first pharmacokinetic evaluation of remdesivir and GS-441524 in recovered COVID-19 patients. Further study of the pharmacokinetic profile of remdesivir, GS-441524 and the intracellular triphosphate form are required.

Neonatal CSF vasopressin concentration predicts later medical record diagnoses of autism spectrum disorder

Autism spectrum disorder (ASD) is a brain disorder characterized by social impairments. ASD is currently diagnosed on the basis of behavioral criteria because no robust biomarkers have been identified. However, we recently found that cerebrospinal fluid (CSF) concentration of the “social” neuropeptide arginine vasopressin (AVP) is significantly lower in pediatric ASD cases vs. controls. As an initial step in establishing the direction of causation for this association, we capitalized upon a rare biomaterials collection of newborn CSF samples to conduct a quasi-prospective test of whether this association held before the developmental period when ASD first manifests. CSF samples had been collected in the course of medical care of 0- to 3-mo-old febrile infants (n = 913) and subsequently archived at −70 °C. We identified a subset of CSF samples from individuals later diagnosed with ASD, matched them 1:2 with appropriate controls (n = 33 total), and quantified their AVP and oxytocin (OXT) concentrations. Neonatal CSF AVP concentrations were significantly lower among ASD cases than controls and individually predicted case status, with highest precision when cases with comorbid attention-deficit/hyperactivity disorder were removed from the analysis. The associations were specific to AVP, as ASD cases and controls did not differ in neonatal CSF concentrations of the structurally related neuropeptide, OXT. These preliminary findings suggest that a neurochemical marker of ASD may be present very early in life, and if replicated in a larger, prospective study, this approach could transform how ASD is detected, both in behaviorally symptomatic children, and in infants at risk for developing it.

0002 Decreased Concentration of Klotho and Increased Concentration of FGF-23 in the Cerebrospinal Fluid of Patients with Narcolepsy

Introduction Narcolepsy is a disorder characterized by hypersomnolence, cataplexy, sleep paralysis, hallucinations and sleep fragmentation. Patients with type 1 narcolepsy have cataplexy and/or hypocretin-1 deficiency. Klotho is a protein expressed by kidneys and choroid plexus, with anti-aging properties. Fibroblast growth factor 23 (FGF-23) is a hormone secreted by osteocytes with actions on mineral metabolism. The purpose of study was to explore the status of concentration of klotho and FGF23 in the cerebrospinal fluids (CSF) of patients with narcolepsy. Methods 59 patients with narcolepsy and 17 individuals were enrolled. We used a radioimmunoassay technique, human klotho enzyme-linked immunosorbent assay (ELISA), human intact FGF23 ELISA and spectrophotometry to measure hypocretin-1, klotho, FGF-23 and phosphorus, respectively. T-Student Test was used to compare klotho and phosphate concentrations and Mann-Whitney U Test was used to compare FGF-23 levels between groups. ANOVA Test was used to compare klotho and phosphate CSF concentrations among narcolepsy patients with CSF hypocretin-1 <110pg/ml (HCRT-) and narcolepsy patients with CSF hypocretin-1 >110pg/ml (HCRT+) versus control subjects. Results Klotho and phosphorus CSF levels were lower in narcoleptic patients than in control (908.18 ± 405.51 versus 1265.78 ± 523.26 pg/ml; p=0.004 and 1.34 ± 0.25 versus 1.58 ± 0.23 mg/dl; p= 0.001, respectively). We found higher median FGF-23 levels in narcoleptic patients (5.51 versus 4.00 RU/ml; p= 0.001). Klotho and phosphorus CSF levels were lower in both HCRT-/HCRT+ than controls (892.63 ± 388.34/ 925.95 ± 430.76 versus 1265.78 ± 523.26 pg/ml; p=0.014 and 1.35 ± 0.28/ 1.33 ± 0.22 versus 1.58 ± 0.23 mg/dl; p= 0.004). Moreover, we found higher median FGF-23 levels in both HCRT-/HCRT+ groups versus controls (5.51/ 6.02 versus 4.00 RU/ml in controls), p= 0.009. Conclusion Patients with narcolepsy have decreased CSF concentration of klotho and increased CSF levels of FGF-23. These findings may play a role in understanding the pathogenesis of narcolepsy. Support

CSF sTREM2 correlates with CSF tau in advancing Parkinson’s disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD) and affects 1% of the population above 60 years old. Although PD commonly manifests with motor symptoms, a majority of patients with PD subsequently develop cognitive impairment which often progresses to dementia, a major cause of morbidity and disability. PD is characterized by α-synuclein accumulation that frequently associates with amyloid beta (Aβ) and tau fibrils, the hallmarks of AD neuropathologic changes; this co-occurrence suggests that onset of cognitive decline in PD may be associated with appearance of pathologic Aβ and/or tau. Recent studies have highlighted the appearance of the soluble form of the Triggering Receptor Expressed on Myeloid cells 2 (sTREM2) receptor in CSF during development of AD. Given the known association of microglial activation with advancing PD, we investigated whether CSF and/or plasma sTREM2 increased with progression to PD dementia. We examined 165 participants consisting of 17 cognitively normal elderly, 45 PD patients with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF Aβ and tau levels revealed that CSF sTREM2 concentrations were elevated in PD subgroups with abnormal tau, but not Aβ, CSF concentration. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in PD that is associated with cognitive decline.One sentence summaryCSF sTREM2 correlates with CSF tau in PD