What is the maximum recommended dosage of Pyrazinamide (PZA) for treating tuberculosis?

From the Guidelines

The maximum recommended dosage of Pyrazinamide (PZA) for treating tuberculosis is 40 mg/kg daily, with a maximum daily dose not explicitly stated in the most recent guidelines, but typically not exceeding 2000 mg per day for adults, as per the general dosing guidelines. PZA is typically dosed at 25-40 mg/kg daily for adults and children, as indicated in the guidelines from the American Journal of Respiratory and Critical Care Medicine 1. This medication is not used alone but forms part of a multi-drug regimen for tuberculosis treatment, usually combined with isoniazid, rifampin, and ethambutol during the intensive phase of treatment (first 2 months). For patients with renal impairment, dosage adjustments are necessary, with recommendations to extend the dosing interval to three times weekly if creatinine clearance is below 30 mL/min, as suggested by various clinical practice guidelines 1. PZA works by converting to pyrazinoic acid in tuberculosis bacteria, which disrupts membrane transport and energy production in Mycobacterium tuberculosis, particularly in acidic environments like those found in macrophages and areas of acute inflammation. Regular monitoring of liver function is essential during treatment as PZA can cause hepatotoxicity. Patients should be advised to report symptoms such as persistent nausea, vomiting, abdominal pain, or yellowing of the skin or eyes immediately.

Some key points to consider in the treatment regimen include:

• The importance of directly observed therapy (DOT) to ensure compliance and effectiveness of the treatment regimen.
• The need for regular monitoring of liver function and adjustment of the dosage in case of renal impairment.
• The potential for hepatotoxicity and the importance of patient education on recognizing symptoms of this side effect.
• The use of pyridoxine (vitamin B6) to prevent neuropathy in patients at risk, as recommended in the guidelines 1.

Overall, the treatment of tuberculosis with PZA requires careful consideration of the patient's individual needs and close monitoring to minimize the risk of adverse effects and ensure the effectiveness of the treatment regimen.

From the FDA Drug Label

DOSAGE AND ADMINISTRATION: ... Three grams per day should not be exceeded. The CDC recommendations do not exceed 2 g per day when given as a daily regimen Drug Maximal Daily Dose in Children and Adults ... Pyrazinamide 2 g

The maximum recommended dosage of Pyrazinamide (PZA) is 2 g per day when given as a daily regimen, although the drug label also states that 3 g per day should not be exceeded 2.

From the Research

Pyrazinamide Maximum Dosage

The maximum recommended dosage of Pyrazinamide (PZA) for treating tuberculosis is not strictly defined, but various studies provide insights into optimal dosing strategies.

• The World Health Organization (WHO) guidelines suggest weight-adjusted doses of pyrazinamide, with a typical daily dose ranging from 15 to 30 mg/kg of body weight 3, 4.
• A study published in 2017 found that among patients with drug-susceptible TB, adding 400 mg to the dose for those weighing 30 to 54 kg improved exposure, and average pyrazinamide exposure in different weight bands among patients with MDR-TB could be matched by administering 1,500 mg, 1,750 mg, and 2,000 mg to patients in the 33- to 50-kg, 51- to 70-kg, and greater than 70-kg weight bands, respectively 3.
• Another study published in 2024 suggested that flat dosing of pyrazinamide at 1,000 mg/d would be readily implementable and could optimize treatment outcomes in drug-susceptible tuberculosis 5.
• A 2009 study used an in vitro model to examine the pharmacokinetics-pharmacodynamics of pyrazinamide and found that doses of >60 mg/kg per day performed better in achieving the desired sterilizing effect 6.

Dosage Considerations

When considering the maximum dosage of pyrazinamide, it is essential to weigh the potential benefits against the risks of hepatotoxicity, which is a known side effect of the drug 7.

• The risk of hepatotoxicity is dose-dependent, and lower doses may be associated with a reduced risk of this adverse effect 7, 4.
• However, the use of lower doses may also compromise the efficacy of the treatment, and the optimal dosing strategy will depend on various factors, including the patient's weight, renal function, and the presence of any underlying liver disease 3, 5, 6.