Pyrazinamide: An overview

INTRODUCTION — 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 [1].

Issues related to the clinical use of PZA will be reviewed here. Issues related to treatment of latent and active TB are discussed separately. (See related topics.)

MECHANISM OF ACTION — The mechanism of action for PZA is unknown [2,3]. The parent compound enters the bacterium passively and is metabolized via pyrazinamidase (PZase) within the cytoplasm to pyrazinoic acid; pyrazinoic acid is the active form of the drug [4]. PZA and its analog, 5-chloro-PZA, may inhibit the fatty acid synthetase I enzyme of M. tuberculosis [5,6]. PZA is generally considered to be a bacteriostatic agent.

PZA is thought to be more active at an acidic pH (eg, within macrophages). It demonstrates activity against both replicating and slow-growing populations [3]. The role of PZA against intracellular organisms remains uncertain [7]. 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 [8]. 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 [4].

When used as part of combination therapy, PZA appears to accelerate the sterilizing effect of isoniazid, rifampin, and bedaquiline [1,9]. In selected populations, this has enabled reduction in the duration of treatment infection due to susceptible M. tuberculosis isolates.

RESISTANCE — PZA is not used as monotherapy in the treatment of M. tuberculosis because of the rapid development of resistance to the drug. The major mechanism of resistance to PZA arises from mutations in the gene encoding PZase, pncA [10]. A number of different mutations in this gene have been demonstrated [11-13]. Rates of tuberculosis resistance to PZA have been reported to be approximately 16 percent [14] but can range from 10 to 85 percent depending on geography and patient population [14].

Phenotypic susceptibility testing for PZA is challenging and (as a result) its role in routine care is not routinely recommended [15,16]. The role of genotypic testing was evaluated in a study including 157 patients with MDR-TB, genotypic PZA resistance was associated with a longer time to sputum culture conversion [17].

PHARMACOKINETICS — Absorption of PZA is thought to be rapid after oral administration, with peak serum concentrations achieved within one to two hours [1,18]. Only minor changes in bioavailability and peak serum concentrations are demonstrated when PZA is taken with meals [18,19]. Serum concentrations have been reported to range from 30 to 50 mcg/mL after a 25 mg/kg dose [1]. Limited data are available to determine PZA outside the blood; modeling with standard exposures report that extrapulmonary concentrations may be below critical concentrations at most sites of infection [20].

Protein binding of PZA is very low (median of 1 percent in one report) [21]. PZA is thought to be widely distributed in many body tissues and fluids, with a volume of distribution estimated to be 0.6 to 0.7 L/kg. Intrapulmonary concentrations of PZA are high (4 to 40 times the reported minimum inhibitory concentration for PZA-susceptible strains in one study) [22]. PZA distributes well into the cerebrospinal fluid, with concentrations reported to be up to 90 percent to those observed in simultaneous serum samples [23]. Intracellular PZA concentrations are similar to those of extracellular fluids. Children appear to have a larger volume of distribution and a slower absorption and clearance of PZA than adults [24].

PZA undergoes extensive hepatic metabolism. Approximately 70 percent of the dose is excreted in the urine in the form of metabolites. The half-life is approximately 9 to 10 hours in patients with normal renal and hepatic function [1]. The drug and its metabolites are removed by hemodialysis [25].

Significant variability of PZA exposure has been reported when dosing is based on body weight. Factors thought to contribute to such variability may include HIV coinfection, age, gender, weight, and organ dysfunction (hepatic or renal).

PHARMACODYNAMICS — Data reporting relationships between PZA concentrations and clinical outcomes are sparse. Studies suggest a relationship between higher maximum concentration and both reduced time to culture conversion and a higher probability of two-month culture conversion [26]. In another report, relationships between PZA area under the time-concentration curve ≤363 mg·hour/L was associated with poor treatment outcome [27].

DOSING AND ADMINISTRATION — Intermittent dosing is performed as part of directly observed therapy (DOT) (table 1).

One study including 72 adults receiving PZA suggested that, based on pharmacodynamic targets (which define the optimal relationship between drug exposure and pathogen susceptibility), the weight-based dosing recommendations described above may be inadequate [28]. This study suggested that optimal dosing may be between 35 and 50mg/kg/day for most patients. However, thus far, such dosing has not been adopted in published guidelines. Higher doses of PZA (25 to 40 mg/kg daily) have also been proposed in patients with multidrug-resistant strains [29].

SPECIAL POPULATIONS

Renal insufficiency — PZA dosing requires adjustment in patients with severe renal insufficiency. In patients with a creatinine clearance <30 mL/min or in patients with end-stage kidney disease requiring hemodialysis, 25 to 35 mg/kg per dose should be administered three times a week (after hemodialysis if applicable). Since PZA and pyrazinoic acid are removed by hemodialysis, doses should be administered after dialysis [30]. PZA increases the risk of hyperuricemia in patients with renal insufficiency.

Liver dysfunction — Dose adjustment may be required in patients with hepatic dysfunction, though there are no published guidelines available for administration of PZA to patients with significant liver disease.

Children — Issues related to PZA dosing in children are discussed separately. (See "Tuberculosis disease in children: Treatment and prevention".)

Pregnancy — Issues related to use of PZA in pregnancy are discussed separately. (See "Tuberculosis disease (active tuberculosis) in pregnancy".)

Breastfeeding — Because of the low concentrations of PZA expected in breastmilk, the United States Centers for Disease Control and Prevention does not discourage breastfeeding in women taking PZA [31].

Obesity — Weight-based dosing of PZA is based on estimation of lean body weight. Dosing recommendations for obese patients are not available [29].

HIV coinfection — Pharmacokinetic studies of PZA in patients coinfected with HIV have reported subtherapeutic PZA, which was impacted by concomitant use of antiretroviral therapy. The authors recommended PZA dosing be based on gender and serum creatinine in this patient population [32].

ADVERSE EFFECTS — The most clinically significant adverse events associated with PZA administration are hepatotoxicity, gastrointestinal intolerance, nongouty polyarthralgias, and asymptomatic hyperuricemia.

Hepatotoxicity — Hepatotoxicity due to PZA can manifest as elevated aspartate aminotransferase concentration, jaundice, and liver tenderness. Hepatotoxicity appears to be dose and duration-related, and is infrequent at daily doses of ≤25 mg/kg per day when administered in multi-drug regimens for active tuberculosis (TB) [26]. Prior liver disease, age over 60 years, and concomitant use of isoniazid and rifampin appear to increase risk for development of hepatotoxicity [33,34].

Unexpectedly high rates of hepatotoxicity have been observed with administration of PZA in combination with rifampin for treatment of latent TB infection (LTBI). The mechanism for this enhanced toxicity is not clear; revised guidelines from the United States Centers for Disease Control recommend against the use of this combination for treating LTBI [30,35]. Some reports have suggested that PZA used with a second drug for treating LTBI may also potentiate hepatotoxicity.

Other reactions — Pyrazinoic acid, the active metabolite of PZA, competes with uric acid for elimination via the kidneys, resulting in asymptomatic hyperuricemia and exacerbations of gout in susceptible individuals [36]. Labile blood glucose concentrations have been observed in diabetic patients. Gastrointestinal intolerance may result in nausea and vomiting. Dermatologic (maculopapular rash, urticaria, photosensitivity) and hematologic (thrombocytopenia, sideroblastic anemia) side effects have been described but are relatively rare. (See "Sideroblastic anemias: Diagnosis and management", section on 'Medications'.)

MONITORING — Patients receiving PZA (in combination with other antituberculous agents) should undergo baseline assessment and periodic monitoring of liver function. Serum uric acid measurements may be obtained in individuals who have a history of gout, who are receiving concomitant medications that alter uric acid excretion (such as loop diuretics), or who are at increased risk for hyperuricemia due to underlying renal dysfunction.

PZA serum concentration monitoring is not routinely performed but may be considered in patients with delayed or poor response to TB treatment or relapse after therapy is complete. Those with gastrointestinal disorders, diabetes mellitus, HIV co-infection, or malnutrition may experience reductions in drug absorption. In addition, those patients with risk factors for PZA-related toxicity may also be considered. While the data to support a target concentration are sparse, a proposed peak therapeutic serum concentration range two hours following administration (Cmax) is 20 to 60 mcg/mL [37].

DRUG INTERACTIONS — Combination therapy with rifampin and PZA has been associated with severe and fatal hepatotoxic reactions.

SUMMARY

●Pyrazinamide (PZA) is an antimicrobial agent 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. PZA is not used as monotherapy in the treatment of Mycobacterium tuberculosis because of rapid development of resistance to the drug. (See 'Introduction' above.)

●The mechanism of action for PZA is not fully understood; it may inhibit the fatty acid synthetase I enzyme of M. tuberculosis. PZA is thought to be more active in acidic environments (eg, within macrophages). When administered as part of combination therapy, PZA appears to accelerate the sterilizing effect of isoniazid and rifampin. (See 'Mechanism of action' above.)

●PZA is thought to be widely distributed in many body tissues and fluids. Intrapulmonary concentrations of PZA are high. PZA also distributes well into the cerebrospinal fluid. PZA undergoes extensive hepatic metabolism; approximately 70 percent of the dose is excreted in the urine in the form of metabolites. The half-life is approximately 9 to 10 hours in patients with normal renal and hepatic function. (See 'Pharmacokinetics' above.)

●Dosing is summarized in the table (table 1). PZA dosing requires adjustment in patients with severe renal insufficiency and may also be required in patients with hepatic dysfunction. For patients on hemodialysis, the PZA should be administered after dialysis. (See 'Dosing and administration' above.)

●Adverse effects associated with PZA administration include hepatotoxicity, gastrointestinal intolerance, polyarthralgia, and asymptomatic hyperuricemia. PZA should not be used with rifampin for treating latent TB infection due to high rates of hepatotoxicity. PZA increases the risk of hyperuricemia most commonly in the setting of renal insufficiency or with the use of concomitant medications, which decrease uric acid excretion. (See 'Adverse effects' above.)

●Patients receiving PZA should undergo baseline assessment and periodic monitoring of liver function. Serum uric acid measurements may be obtained in individuals who have a history of gout, who are receiving concomitant medications that decrease uric acid excretion (such as loop diuretics), or who are at increased risk for hyperuricemia due to underlying renal dysfunction. (See 'Monitoring' above.)