High hepatotoxicity of pyrazinamide and ethambutol for treatment of latent tuberculosis

Pyrazinamide (PZA) combined with either ethambutol (EMB) or a fluoroquinolone for 6-12 months is one of the treatments recommended for latent tuberculosis infection (ILTBI) in contacts exposed to multidrug-resistant tuberculosis (MDR-TB). The aim of the present study was to describe the side effects related to combined PZA and EMB treatment given for ILTBI, in contacts previously exposed to MDR-TB. In total, 12 consecutive contacts, all of African origin and aged 38 +/- 5 yrs, were treated with daily PZA (23 +/- 4 mg center dot kg(-1)) and EMB (17 +/- 4 mg center dot kg(-1)) at Geneva University Hospital outpatient clinic (Switzerland), as a result of contact-tracing procedures for two patients with contagious MDR-TB. Clinical status and liver function tests (aspartate aminotransferase (ALAT) and alanine aminotransferase (ASAT)) were monitored monthly. In seven cases (58%) treatment was discontinued after a median of 119 days, due to hepatic toxicity in six cases (ALAT or ASAT elevation more than four times the upper normal limit), and gastrointestinal symptoms in one case. In conclusion, combined pyrazinamide and ethambutol for latent tuberculosis infection may be associated with a high risk of hepatic toxicity, and warrants close monitoring. There is clearly a need for alternative preventive treatments for contacts exposed to multidrug-resistant tuberculosis.