Pyrazinamide (PZA) is a relative of nicotinamide. It is stable and slightly soluble in water. It is inactive at neutral pH, but at pH 5.5 it inhibits tubercle bacilli at concentrations of approximately 20 mcg/mL. The drug is taken up by macrophages and exerts its activity against mycobacteria residing within the acidic environ-ment of lysosomes.
Pyrazinamide is converted to pyrazinoic acid—the active form of the drug—by mycobacterial pyrazinamidase, which is encoded bypncA. The specific drug target is unknown, but pyrazinoic aciddisrupts mycobacterial cell membrane metabolism and transport functions. Resistance may be due to impaired uptake of pyrazin-amide or mutations in pncA that impair conversion of pyrazin-amide to its active form.
Serum concentrations of 30–50 mcg/mL at 1–2 hours after oral administration are achieved with dosages of 25 mg/kg/d. Pyrazinamide is well absorbed from the gastrointestinal tract and widely distributed in body tissues, including inflamed meninges. The half-life is 8–11 hours. The parent compound is metabolized by the liver, but metabolites are renally cleared; therefore, pyra-zinamide should be administered at 25–35 mg/kg three times weekly (not daily) in hemodialysis patients and those in whom the creatinine clearance is less than 30 mL/min. In patients with nor-mal renal function, a dose of 40–50 mg/kg is used for thrice-weekly or twice-weekly treatment regimens.
Pyrazinamide is an important front-line drug used in conjunc-tion with isoniazid and rifampin in short-course (ie, 6-month) regimens as a “sterilizing” agent active against residual intracellular organisms that may cause relapse. Tubercle bacilli develop resis-tance to pyrazinamide fairly readily, but there is no cross-resistance with isoniazid or other antimycobacterial drugs.
Major adverse effects of pyrazinamide include hepatotoxicity (in 1–5% of patients), nausea, vomiting, drug fever, and hyperurice-mia. The latter occurs uniformly and is not a reason to halt ther-apy. Hyperuricemia may provoke acute gouty arthritis.