Is it safe to use pyrazinamide in older patients with TB?

Adding pyrazinamide (PZA) to the initial tuberculosis (TB) treatment in older patients may lead to an increase in the incidence of adverse events (AEs), particularly allergic reactions, but not in-hospital mortality, length of hospital stay, or hepatotoxicity, reports a study, which used data from the Japanese Diagnosis Procedure Combination inpatient database.

“Advanced age alone may therefore not be a reason for avoiding PZA in patients with TB,” the researchers said.

This retrospective study included 19,930 patients who had been admitted for TB between July 2010 and March 2022. The researchers categorized patients into HRE (ie, isoniazid, rifampicin, and ethambutol) and HREZ (ie, isoniazid, rifampicin, ethambutol, and PZA) groups. They analysed data via propensity score matching and performed a subgroup analysis for those aged ≥75 years.

In-hospital mortality and overall AEs, defined by a composite of hepatotoxicity, gout attack, allergic reactions, and gastrointestinal intolerance, were the primary outcomes. Other outcomes assessed were length of hospital stay, 90-day readmission, and use of drugs related to the primary outcome AEs.

Of the eligible patients, 8,924 received HRE and 11,006 received HREZ. In propensity score matching, a total of 3,578 matched pairs (mean age 80 years) were made. [Respirology 2024;29:905-913]

Patients treated with HREZ, compared with HRE, had a higher proportion of overall AEs (4.7 percent vs 3.1 percent; p<0.001), allergic reactions (2.5 percent vs 1.4 percent; p<0.001), and antihistamine use (27.6 percent vs 21.9 percent; p<0.001). Other outcomes, including in-hospital mortality, length of hospital stay, and hepatoxicity, did not significantly differ between treatment groups.

These findings persisted in the subgroup analysis.

“Medical practitioners may consider adding PZA to an initial treatment regimen even in [older] patients with TB,” the researchers said.

Allergic reactions

Previous studies have reported the association of PZA use with allergic reactions, such as skin rashes. [Am J Respir Crit Care Med 2003;167:1472-1477; BMC Infect Dis 2013;13:121; Cent Afr J Med 1998;44:34-37; Allergy 2002;57:964-965]

“Although it may be difficult to identify a suspected drug when allergic reactions occur during TB treatment initiated with multiple drugs, the increase in allergic reactions to PZA may be greater than anticipated,” the researchers said.

Furthermore, given that hepatotoxicity due to PZA is considered a great concern, earlier studies on PZA administration and hepatotoxicity in older TB patients have been performed following the latest guidelines. [PLoS One 2020;15:e0236109; Drugs & Aging 2021;38:43-52; J Infect Chemother 2019;25:1026-1030; Clin Infect Dis 2016;63:e147-e195; Eur Respir J 2017;50(suppl 61):PA3045]

"By integrating the results of our study with those of previous studies, we found that advanced age alone may be a less likely risk factor for hepatotoxicity,” the researchers said.

Notably, previous studies have also found that comorbidities such as HIV, hepatitis, and liver disease appear to heighten the severe side effects of PZA. [Am J Respir Crit Care Med 2003;167:1472-1477; Am J Respir Crit Care Med 2008;177:1391-1396; Am J Respir Crit Care Med 2006;174:935-952]

"[T]he low rates of these comorbidities in [the current] study may therefore explain why the incidences of side effects (including hepatotoxicity) and mortality did not increase,” the researchers said.