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    • The first finding is that

    2018-11-13

    The first finding is that even in the era of highly effective TB chemotherapy (namely the regimen used in the IMPI trial), the mortality of TB pericarditis is still high, with an overall mortality rate of 1.43 per 100person-months in a median follow-up of 11.97months. The most plausible explanation for this finding derived from a highly adherent population, is the inadequate antibiotic concentrations in the pericardial fluid (especially rifampin and pyrazinamide), due to poor penetration (). Moreover, since severe immunosuppression was an independent predictor of death, deprivation of the inherent egfr inhibitors defensive mechanisms offers an additional explanation.
    Tuberculosis (TB) continues to be a major global health issue, with the World Health Organization (WHO) reporting 9 million new TB cases worldwide in 2013 (). Since its endorsement by the WHO in 1991, a combination of rifampicin, isoniazid, pyrazinamide and ethambutol or streptomycin during the first 2months of treatment has remained part of the standard first-line TB treatment regimen globally (). These guidelines are based on historic trials that assessed outcome during pulmonary TB treatment (). TB drug regimens used for extra-pulmonary TB, including frequently fatal forms such as TB pericarditis and TB meningitis (TBM), follow the same principles but not guided by trials that assessed patient outcome. Inadequate TB drug exposure (as measured by pharmacokinetic/pharmacodynamic [PK/PD] parameters in blood) is associated with a poor clinical response, treatment failure and acquisition of drug resistance in pulmonary TB patients (). It is intuitive to assume that reduced drug exposure in tissues due to inadequate drug penetration into extra-pulmonary disease sites may enhance these detrimental effects. In this issue of , Shenje and colleagues present findings of the first study to egfr inhibitors determine TB drug concentrations in pericardial fluid of adults with pericardial TB (). The study was divided into two phases: 1) a pilot study, during which rifampicin concentrations were determined in paired blood and pericardial fluid samples taken once only at various time points in 16 patients and, 2) an intensive phase, during which intensive pharmacokinetic blood and pericardial fluid sampling were performed over a 24-hour period in 11 additional patients. All participants received a standard fixed-dose-combination daily TB drug regimen, including rifampicin (600mg), isoniazid (300mg), pyrazinamide (1600mg) and ethambutol (1100mg). Penetration of rifampicin into pericardial fluid was poor; the ratio of rifampicin concentration in pericardial fluid to paired blood concentration was 0.19±0.33 (mean±SD) in the pilot study. Non-protein bound rifampicin concentration (indicating active rifampicin) in pericardial fluid was extremely low (<1mg/L) in all patients, and the median peak concentration in pericardial fluid (performed in the intensive phase) was lower than the median minimum inhibitory concentration (MIC) determined for TB strains collected previously from the same setting. Previous studies in TBM similarly showed that rifampicin at doses of 10mg/kg/day seldom reaches cerebrospinal fluid (CSF) concentrations exceeding the MIC (). Shenje and colleagues () further report poor ethambutol penetration into pericardial fluid; both 0–24hour area under the concentration–time curve (AUC) and peak concentrations (C) were significantly lower in pericardial fluid compared to plasma, resulting in ethambutol concentrations also falling below the typical MIC. Pyrazinamide concentrations in pericardial fluid were similar to that in plasma. However, pyrazinamide is only active under acidic conditions and after adjusting the MIC according to the measured pH of pericardial fluid (7.34±0.11), pyrazinamide peak concentrations were ~40-times lower than the pH-adjusted MIC. Of the four drugs tested, isoniazid was the only one to reach effective pericardial fluid concentrations. Likewise in TBM, the contribution of ethambutol during treatment is questionable as ethambutol has poor CSF penetration (). Isoniazid and pyrazinamide are considered invaluable during TBM treatment as both penetrate well into CSF (). However, adequate C concentrations proposed for pyrazinamide in TBM are based on findings of in vitro studies, healthy volunteers and pulmonary TB and have not been informed by the pH of CSF during TBM.