title: The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care.
abstract: BACKGROUND
  There is a paucity of data on the pharmacokinetics of fixed-dose combination enteral antituberculosis treatment in critically ill patients.
  
  
  OBJECTIVE
  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 (Cmax) for rifampicin at time to peak concentration was achieved in only 4 patients, whereas 2 did not achieve therapeutic Cmax for isoniazid. No patient reached sub-therapeutic Cmax for pyrazinamide (6 were within and 4 above therapeutic range). Three patients reached sub-therapeutic Cmax 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 II (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.
authors.affiliation: Department of Medicine, Stellenbosch University, Tygerberg, Western Cape, South Africa. coeniefn@sun.ac.z.
authors.forename: C F N
authors.initials: CF
authors.lastname: Koegelenberg
authors.forename: A
authors.initials: A
authors.lastname: Nortje
authors.forename: U
authors.initials: U
authors.lastname: Lalla
authors.forename: A
authors.initials: A
authors.lastname: Enslin
authors.forename: E M
authors.initials: EM
authors.lastname: Irusen
authors.forename: B
authors.initials: B
authors.lastname: Rosenkranz
authors.forename: H I
authors.initials: HI
authors.lastname: Seifart
authors.forename: C T
authors.initials: CT
authors.lastname: Bolliger
mesh_terms: D018806:APACHE; D000328:Adult; D000995:Antitubercular Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004359:Drug Therapy, Combination; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D011446:Prospective Studies; D013019:South Africa / Q000453:epidemiology; D013607:Tablets; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D013607:Tablets