Measurement of Anti-TB Drugs in Lung Tissue From Patients Having Surgery to Treat Tuberculosis

Rifampicin or rifampin (RIF) is a semi-synthetic compound derived from Amycolatopsis rifamycinica. It is mostly used in combination to treat TB, while other disease indications include brucellosis, leprosy, legionnaire's disease and problematic drug-resistant staphylococcal infections. RIF inhibits DNA-dependent RNA polymerase in bacterial cells by binding its beta-subunit, thus preventing transcription to RNA. Its MIC against replicating TB bacilli is 0.1 g/ml and its minimum bactericidal activity (MBC) is 0.5 g/mL. It is one of the rare anti-TB drugs with some activity against nonreplicating cells.

Isoniazid (INH) is a first-line antituberculous medication discovered in 1952 and used in the prevention (alone) and treatment (in combination) of tuberculosis. Isoniazid is a prodrug and must be activated by a bacterial catalase to inhibit the synthesis of mycolic acids in the mycobacterial cell wall. Consequently, INH is bactericidal to rapidly-dividing mycobacteria, with an MIC of 0.05 g/ml and an MBC of 1 g/ml, but is inactive if the mycobacterium is nonreplicating or slow-growing.

Pyrazinamide (PZA) is a synthetic derivative of nicotinamide requiring ctivation by the mycobacterial enzyme pyrazinamidase, only active under acidic conditions which are thought to be found within the phagolysosomal compartment of macrophages. The conversion product, pyrazinoic acid, inhibits fatty acid synthetase I, required by the bacterium to synthesize fatty acids, though this has been disputed. It has an MIC of 6 g/ml and is not cidal under in vitro conditions. Overall, its mechanism of action and reasons for good sterilizing activity in vivo are poorly understood. It is part of the 4-drug combination recommended by the WHO to treat drugsensitive tuberculosis and is also included in most econd-line regimens.

Kanamycin (KM) is an aminoglycoside antibiotic belonging to the same class of drugs as Streptomycin, one of the first drugs used to treat TB in the 50 s. It kills sensitive bacteria by binding to the 30S ribosomal subunit and interfering with protein synthesis. Its MIC and MBC against MTB are 2 and 6 g/mL, respectively, with a remarkably low MBC/MIC ratio. However, KM is only used to treat serious bacterial infections due to severe renal toxicity and ototoxicity. No interaction with the metabolism of other drugs has been reported. The drug is approved by the Korean Ministry of Food and Drug Safety (MFDS) but not the US FDA for use against pulmonary TB.

Moxifloxacin (MXF) is a synthetic fluoroquinolone antibiotic. It inhibits bacterial topoisomerase II (DNA gyrase) and topoisomerase IV, which are essential enzymes playing a crucial role in the replication and repair of bacterial DNA. Its MIC, MBC and intracellular activity against MTB are 0.5, 2 and 1 g/mL, respectively, with again a low MBC/MIC ratio.