In vitro optimization of crushed drug-sensitive antituberculosis medication when administered via a nasogastric tube

Abstract

ABSTRACT In low-resource settings, access to intravenous formulations of antituberculosis drugs is lacking or absent. Thus, critically ill patients with tuberculosis (TB) are often treated with readily available tablets which are crushed, mixed with water, and administered via a nasogastric tube (NGT). This has been associated with plasma concentrations below the recommended target, particularly of rifampicin (RIF) and isoniazid (INH), leading to clinical failure and development of drug resistance. We aimed to identify physiochemical factors contributing to lower plasma concentrations of antituberculosis drugs when administered in this manner using laboratory-based techniques, including the addition of ascorbic acid (AA) for optimum administration. Aqueous solubility of crushed medication using the inversion mixing method was evaluated against easily implementable mixing methods (sonication/vortexing) with or without AA. Stability of crushed medication in simulated-gastrointestinal fluids was evaluated with or without AA. Drug loss via NGT surface adsorption was quantitatively determined. RIF demonstrated poor aqueous solubility of 5.2%. Incorporation of AA improved the solubility to 29.7%, and with the addition of mixing techniques, solubility improved to 86.3%. Mixing methods with AA further improved the solubilities of both INH (80%) and pyrazinamide (PZA, 64%) to over 90%. AA also showed protective effects against unstable RIF in simulated-gastric fluid. Conventional flushing of NGT after drug administration with 10 mL of water resulted in drug losses of 1.5%, 0.13%, and 1.4% for RIF, INH, and PZA, respectively. An additional flushing step halved this amount. These interventions may improve the poor plasma concentrations of crushed antituberculosis drugs in critically ill patients. IMPORTANCE The incidence of tuberculosis (TB) in intensive care units (ICUs) can be as high as 3% in high-burden settings, translating to more than 7,500 patients admitted to the ICU annually. In resource-limited settings, the lack or absence of intravenous formulations of drug-sensitive antituberculosis medications necessitates healthcare practitioners to crush, dissolve, and administer the drugs to critically ill patients via a nasogastric tube (NGT). This off-label practice has been linked to plasma concentrations below the recommended target concentrations, particularly of rifampicin and isoniazid, leading to clinical failure and the development of drug resistance. Optimizing the delivery of crushed drug-sensitive antituberculosis medication via the NGT to critically ill patients is of utmost importance.