Pyrazinamide: An overview
- Richard H Drew, PharmD, MS, FCCP
Richard H Drew, PharmD, MS, FCCP
- Professor, Campbell University College of Pharmacy and Health Sciences
- Associate Professor and Clinical Pharmacist, Infectious Diseases
- Duke University Medical Center
Pyrazinamide (PZA) is an antimicrobial agent that is most commonly used for treatment of active tuberculosis (TB) during the initial phase of therapy (generally the first two months of treatment), in combination with other agents. The spectrum of PZA is relatively narrow; it demonstrates clinically significant antibacterial activity only against Mycobacterium tuberculosis and Mycobacterium africanum .
Issues related to the clinical use of pyrazinamide will be reviewed here. Issues related to treatment of latent and active TB are discussed separately. (See related topics.)
MECHANISM OF ACTION
The parent compound is metabolized via pyrazinamidase (PZase) to pyrazinoic acid; pyrazinoic acid is the active form of the drug . The mechanism of action for pyrazinamide (PZA) is unknown. PZA and its analog, 5-chloro-PZA, may inhibit the fatty acid synthetase I (FASI) enzyme of M. tuberculosis [3,4]. PZA is generally considered to be a bacteriostatic agent.
PZA is thought to be more active at an acidic pH (eg, within macrophages) and against dormant or semidormant microorganisms, although the role of PZA against intracellular organisms remains uncertain . In one study, pyrazinoic acid remained outside of M. tuberculosis cells at a neutral or alkaline pH but accumulated within cells at an acidic pH . In the same study, Mycobacterium smegmatis (which is not susceptible to PZA) was found to convert PZA to pyrazinoic acid but, due to an active efflux mechanism, did not accumulate the metabolite, even at an acidic pH. Other mycobacterial strains appear to have natural resistance to PZA due to lack of PZase activity or absence of transport mechanisms to take up the drug .
When used as part of combination therapy, PZA appears to accelerate the sterilizing effect of isoniazid and rifampin . In selected populations, this has enabled reduction in the duration of treatment infection due to susceptible M. tuberculosis isolates from nine to six months.
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