The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care

Background. There is a paucity of data on the pharmacokinetics of fixed-dose combination enteral antituberculosis treatment in critically ill patients. Objectives. To establish the pharmacokinetic profile of a fixed-dose combination of rifampicin, isoniazid, pyrazinamide and ethambutol given according to weight via a nasogastric tube to patients admitted to an intensive care unit (ICU). Methods. We conducted a prospective, observational study on 10 patients (mean age 32 years, 6 male) admitted to an ICU and treated for tuberculosis (TB). Serum concentrations of the drugs were determined at eight predetermined intervals over 24 hours by means of high-performance liquid chromatography. Results. The therapeutic maximum plasma concentration (C-max) for rifampicin at time to peak concentration was achieved in only 4 patients, whereas 2 did not achieve therapeutic C-max for isoniazid. No patient reached sub-therapeutic C-max for pyrazinamide (6 were within and 4 above therapeutic range). Three patients reached sub-therapeutic C-max for ethambutol, and 6 patients were within and 1 above the therapeutic range. Patients with a sub-therapeutic rifampicin level had a higher mean Acute Physiology and Chronic Health Evaluation 11 (APACHE II) score (p=0.03) and a lower estimated glomerular filtration rate (GFR) (p=0.03). Conclusions. A fixed-dose combination tablet, crushed and mixed with water, given according to weight via a nasogastric tube to patients with TB admitted to an ICU resulted in sub-therapeutic rifampicin plasma concentrations in the majority of patients, whereas the other drugs had a more favourable pharmacokinetic profile. Patients with a sub-therapeutic rifampicin concentration had a higher APACHE II score and a lower estimated GFR, which may contribute to suboptimal outcomes in critically ill patients. Studies in other settings have reported similar proportions of patients with 'sub-therapeutic' rifampicin concentrations.