Objective and methodsOur objective was to investigate the role of patient pharmacogenetic variability in determining site of action target attainment during tuberculous meningitis (TBM) treatment. ...Show moreObjective and methodsOur objective was to investigate the role of patient pharmacogenetic variability in determining site of action target attainment during tuberculous meningitis (TBM) treatment. Rifampin and isoniazid PBPK model that included SLCO1B1 and NAT2 effects on exposures respectively were obtained from literature, modified, and validated using available cerebrospinal-fluid (CSF) concentrations. Population simulations of isoniazid and rifampin concentrations in brain interstitial fluid and probability of target attainment according to genotypes and M. tuberculosis MIC levels, under standard and intensified dosing, were conducted.ResultsThe rifampin and isoniazid model predicted steady-state drug concentration within brain interstitial fluid matched with the observed CSF concentrations. At MIC level of 0.25 mg/L, 57% and 23% of the patients with wild type and heterozygous SLCO1B1 genotype respectively attained the target in CNS with rifampin standard dosing, improving to 98% and 91% respectively with 35 mg/kg dosing. At MIC level of 0.25 mg/L, 33% of fast acetylators attained the target in CNS with isoniazid standard dosing, improving to 90% with 7.5 mg/kg dosing.ConclusionIn this study, the combined effects of pharmacogenetic and M. tuberculosis MIC variability were potent determinants of target attainment in CNS. The potential for genotype-guided dosing during TBM treatment should be further explored in prospective clinical studies. Show less
In patients with acute headache who present to the emergency room the yield of a CTA is highest in patients with an abnormality on head NCCT. The yield in patients with normal NCCT is low. A... Show moreIn patients with acute headache who present to the emergency room the yield of a CTA is highest in patients with an abnormality on head NCCT. The yield in patients with normal NCCT is low. A multivariable prediction model showed that clinical symptoms have no added value over the variable ‘normal NCCT’ alone. In patients with acute headache and a normal NCCT the yield of CTA is higher than in the general population, but findings consist mainly of unruptured intracranial aneurysms that do not always have treatment implications and may generate anxiety. The sporadically found cervical dissection, CVT or RCVS may justify performing CTA. At the moment there are no clinical factors, which can predict which patients will have an abnormality on CTA after a normal NCCT. In patients who are suspected of CVT but who have no additional risk factors besides headache, CT venography is unnecessary if the D-dimer level in serum is normal. The negative predictive value of D-dimer in this group is very high for excluding CVT. If CSF testing for the presence of bilirubin is required, the Leiden method, an iterative calculation model, is 100% sensitive. Specificity can be increased if the UK NEQAS method is applied on the CSF’s that test positive with the Leiden method. This workflow assures both highest specificity and highest laboratory workforce efficiency. In patients suspected of bacterial meningitis procalcitonin determination in CSF may become a valuable marker particularly in patients with confounding factors such as recent neurosurgical intervention. The differentiation from aseptic or septic meningitis in this group is difficult and an additional marker would be valuable to avoid unnecessary antibiotic treatment. Show less
