The safety of pyrazinamide in pediatric drug-sensitive tuberculosis treatment: A real-world study.

BACKGROUND: Pyrazinamide (PZA) is a cornerstone of first-line treatment for tuberculosis (TB), yet its safety profile in children is not well-established. This evidence gap creates a significant discrepancy between international guidelines and real-world clinical practice. We aimed to analyze the usage patterns and safety of PZA in a large cohort of pediatric TB patients.

METHODS: We conducted a multicenter retrospective study at 11 referral hospitals from 2017 to 2022. From an initial cohort of all hospitalized children with TB, we identified 552 patients with drug-sensitive TB who constituted the final analytical cohort. Clinical data, including detailed medication regimens, dosages, treatment durations, and adverse events, were collected.

RESULTS: Of all included children, about a quarter were diagnosed with extrapulmonary TB. The dosage and duration of PZA often did not align with WHO guidelines: only 42.6 % of children received the recommended daily dose, while 71.2 % underwent PZA treatment extending beyond the standard two-month. Overall, adverse events occurred in 21.4 % of children, with hepatotoxicity being the most common. Adjusted Cox regression models shown that children treated with the enhanced combination regimen (supplemented with ethambutol or second-line drugs) appeared to have a 1.27-times (95 %CI: 1.05-1.56) higher risk of any adverse event than those receiving the HRZ/HR(Z) regimen. Adverse event rates did not differ significantly across PZA dosage groups. Time-varying Cox models shown that the first adverse events predominantly occurred within the initial two months of concomitant PZA use. However, this adverse effect was no longer observed among children on the HRZ/HR regimen.

CONCLUSIONS: Real-world PZA dosage and duration in pediatric drug-sensitive TB frequently deviated from WHO guidelines. The initial two months of concomitant PZA use may warrant particular safety attention, especially in children on the enhanced combination regimen.