Rifampin was introduced in 1967,^[1] as a major addition to the cocktail-drug treatment of tuberculosis and inactive meningitis, along with pyrazinamide, isoniazid, ethambutol and streptomycin (“PIERS”). It requires a prescription in North America. It must be administered regularly daily for several months without break; otherwise, the risk of drug-resistant tuberculosis is greatly increased.^[1] In fact, this is the primary reason it is used in tandem with the three aforementioned drugs, particularly isoniazid.^[2] This is also the primary motivation behind directly observed therapy for tuberculosis.

Isoniazid also known as isonicotinylhydrazine (INH), is an organic compound that is the first-line medication in prevention and treatment of tuberculosis. The compound was first synthesized in the early 20th century,^[3] but its activity against tuberculosis was first reported in the early 1950s, and three pharmaceutical companies attempted unsuccessfully to simultaneously patent the drug^[4] (the most prominent one being Roche, which launched its version, Rimifon, in 1952). The drug was first tested at Many Farms, a Navajo community, due to the Navajo reservation’s dire tuberculosis problem and the fact that the population was naïve with respect to streptomycin, the main tuberculosis treatment at the time.^[5] With the introduction of isoniazid, a cure for tuberculosis was first considered reasonable.

Antimycobacterial

RIFAMATE^®

Description | Clinical Pharmacology | Microbiology | Indications and Usage | Contraindications | Warnings and Precautions | Adverse Reactions | Overdosage | Clinical Studies | Dosage and Administration | Compatibility, Reconstitution, and Stability | How Supplied | Labels and Packages

Rifampin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase.^[6]

Crystal structure data and biochemical data indicate that rifampicin binds to RNA polymerase at a site adjacent to the RNA polymerase active center and blocks RNA synthesis by physically preventing extension of RNA products beyond a length of 2-3 nucleotides (“steric-occlusion” mechanism).^[7][8]

Resistance to rifampin arises from mutations that alter residues of the rifampin binding site on RNA polymerase, resulting in decreased affinity for rifampin.^[8] Resistant mutations map to the rpoB gene, encoding RNA polymerase beta subunit.

Isoniazid is a prodrug and must be activated by a bacterial catalase-peroxidase enzyme that in M. tuberculosis is called KatG.^[9] KatG couples the isonicotinic acyl with NADH to form isonicotinic acyl-NADH complex. This complex binds tightly to the enoyl-acyl carrier protein reductase known as InhA, thereby blocking the natural enoyl-AcpM substrate and the action of fatty acid synthase. This process inhibits the synthesis of mycolic acid, required for the mycobacterial cell wall. A range of radicals are produced by KatG activation of isoniazid, including nitric oxide,^[10] which has also been shown to be important in the action of another antimycobacterial prodrug PA-824.^[11]

Isoniazid is bactericidal to rapidly dividing mycobacteria, but is bacteriostatic if the mycobacteria are slow-growing.^[12]

Isoniazid inhibits the CYP450 system.^[13]