Pyrazinamide: An overview
- Richard H Drew, PharmD, MS, FCCP, FIDP
Richard H Drew, PharmD, MS, FCCP, FIDP
- 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.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Heifets L. Antimycobacterial agents: Pyrazinamide. In: Antimicrobial Therapy and Vaccines, Yu VL, Merigan TC, Barriere SL (Eds), Williams and Wilkins, 1999.
- Raynaud C, Lanéelle MA, Senaratne RH, et al. Mechanisms of pyrazinamide resistance in mycobacteria: importance of lack of uptake in addition to lack of pyrazinamidase activity. Microbiology 1999; 145 ( Pt 6):1359.
- Zimhony O, Cox JS, Welch JT, et al. Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis. Nat Med 2000; 6:1043.
- Ngo SC, Zimhony O, Chung WJ, et al. Inhibition of isolated Mycobacterium tuberculosis fatty acid synthase I by pyrazinamide analogs. Antimicrob Agents Chemother 2007; 51:2430.
- Heifets L, Higgins M, Simon B. Pyrazinamide is not active against Mycobacterium tuberculosis residing in cultured human monocyte-derived macrophages. Int J Tuberc Lung Dis 2000; 4:491.
- Zhang Y, Scorpio A, Nikaido H, Sun Z. Role of acid pH and deficient efflux of pyrazinoic acid in unique susceptibility of Mycobacterium tuberculosis to pyrazinamide. J Bacteriol 1999; 181:2044.
- Ramaswamy S, Musser JM. Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuber Lung Dis 1998; 79:3.
- Sachais BS, Nachamkindagger I I, Mills JK, Leonard DG. Novel pncA Mutations in Pyrazinamide-Resistant Isolates of Mycobacterium tuberculosis. Mol Diagn 1998; 3:229.
- Lemaitre N, Sougakoff W, Truffot-Pernot C, Jarlier V. Characterization of new mutations in pyrazinamide-resistant strains of Mycobacterium tuberculosis and identification of conserved regions important for the catalytic activity of the pyrazinamidase PncA. Antimicrob Agents Chemother 1999; 43:1761.
- Marttila HJ, Marjamäki M, Vyshnevskaya E, et al. pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis isolates from northwestern Russia. Antimicrob Agents Chemother 1999; 43:1764.
- Whitfield MG, Soeters HM, Warren RM, et al. A Global Perspective on Pyrazinamide Resistance: Systematic Review and Meta-Analysis. PLoS One 2015; 10:e0133869.
- Peloquin CA, Bulpitt AE, Jaresko GS, et al. Pharmacokinetics of pyrazinamide under fasting conditions, with food, and with antacids. Pharmacotherapy 1998; 18:1205.
- Saktiawati AM, Sturkenboom MG, Stienstra Y, et al. Impact of food on the pharmacokinetics of first-line anti-TB drugs in treatment-naive TB patients: a randomized cross-over trial. J Antimicrob Chemother 2016; 71:703.
- Conte JE Jr, Golden JA, Duncan S, et al. Intrapulmonary concentrations of pyrazinamide. Antimicrob Agents Chemother 1999; 43:1329.
- Roy V, Tekur U, Chopra K. Pharmacokinetics of pyrazinamide in children suffering from pulmonary tuberculosis. Int J Tuberc Lung Dis 1999; 3:133.
- Malone RS, Fish DN, Spiegel DM, et al. The effect of hemodialysis on isoniazid, rifampin, pyrazinamide, and ethambutol. Am J Respir Crit Care Med 1999; 159:1580.
- Alsultan A, Savic R, Dooley KE, et al. Population Pharmacokinetics of Pyrazinamide in Patients with Tuberculosis. Antimicrob Agents Chemother 2017; 61.
- Centers for Disease Control and Prevention (CDC), American Thoracic Society. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection--United States, 2003. MMWR Morb Mortal Wkly Rep 2003; 52:735.
- Schaberg T, Rebhan K, Lode H. Risk factors for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis. Eur Respir J 1996; 9:2026.
- Chang KC, Leung CC, Yew WW, et al. Hepatotoxicity of pyrazinamide: cohort and case-control analyses. Am J Respir Crit Care Med 2008; 177:1391.
- Koumbaniou C, Nicopoulos C, Vassiliou M, et al. Is pyrazinamide really the third drug of choice in the treatment of tuberculosis? Int J Tuberc Lung Dis 1998; 2:675.
- Campbell R, James C. National Tuberculosis Curriculum Consortium TB Drug Reference Sheet. National Heart, Lung & Blood Institute, San Diego. http://ntcc.ucsd.edu/TB.drug.reference.sheet_final2007.pdf (Accessed on October 31, 2012).
- Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis. Drugs 2002; 62:2169.