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. 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 highperformance 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 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.

Pharmacokinetics of Rifampin and Isoniazid in Tuberculosis-HIV-Coinfected Patients Receiving Nevirapine- or Efavirenz-Based Antiretroviral Treatment

“…Of note, we found undetectable or low concentrations of rifampin and isoniazid in one of the included patients, who died from wasting syndrome shortly after sampling for drug assay. Such a discrepancy between rifampin and isoniazid exposure levels could be related to poor rifampin absorption in critically ill patients (39). Several factors could be associated with relatively good rifampin and isoniazid exposure.…”

Early antituberculosis drug exposure in hospitalized patients with human immunodeficiency virus‐associated tuberculosis

“…Other factors in advanced HIV infection such as intestinal TB, HIV‐related enteropathy, and gastrointestinal opportunistic infections and macro‐ or micronutrient deficiencies could contribute to reduced drug exposure. Limited existing data suggest that anti‐TB drug exposure in critically ill patients is inadequate . Elevated blood lactate is used as a marker of sepsis severity and is associated with mortality in hospitalized patients with HIV‐TB …”

Validation of a severity-of-illness score in patients with tuberculosis requiring intensive care unit admission

“…[7] Management, course and complications All patients were managed according to local guidelines and received maximal supportive therapy. [2,8] The standard combination anti-TB treatment regimen was used unless significant renal or hepatic impairment or confirmed drug resistance was present. [8] Standard diagnostic criteria for the diagnosis of shock, renal failure, multiorgan dysfunction syndrome (MODS) and acute respiratory distress syndrome (ARDS) were used, as defined by accepted international criteria.…”

“…[2,8] The standard combination anti-TB treatment regimen was used unless significant renal or hepatic impairment or confirmed drug resistance was present. [8] Standard diagnostic criteria for the diagnosis of shock, renal failure, multiorgan dysfunction syndrome (MODS) and acute respiratory distress syndrome (ARDS) were used, as defined by accepted international criteria. [9][10][11] Patients were categorised as either ICU/hospital survivors or non-survivors.…”