Linezolid-Associated Neurologic Adverse Events in Patients with Multidrug-Resistant Tuberculosis, France - Volume 26, Number 8—August 2020 - Emerging Infectious Diseases journal - CDC

Linezolid-Associated Neurologic Adverse Events in Patients with Multidrug-Resistant Tuberculosis, France - Volume 26, Number 8—August 2020 - Emerging Infectious Diseases journal - CDC

Volume 26, Number 8—August 2020

Research

Linezolid-Associated Neurologic Adverse Events in Patients with Multidrug-Resistant Tuberculosis, France

Marie Jaspard , Nathalie Butel, Najoua El Helali, Dhiba Marigot-Outtandy, Helene Guillot, Gilles Peytavin, Nicolas Veziris, Bahram Bodaghi, Philippe Flandre, Gregoire Petitjean, Eric Caumes, and Valerie Pourcher

Author affiliations: Sorbonne Université, Paris, France (M. Jaspard, H. Guillot, N. Veziris, B. Bodaghi, E. Caumes, V. Pourcher); Assistance Publique–Hôpitaux de Paris, Hôpitaux Universitaires Pitié-Salpêtrière Charles Foix, Paris (M. Jaspard, H. Guillot, E. Caumes, V. Pourcher); Assistance Publique – Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Paris (N. Butel, B. Bodaghi); Groupe Hospitalier Paris Saint Joseph, Paris (N. El Helali, G. Petitjean); Bligny Medical Center, Briis sous Forges, France (D. Marigot-Outtandy); Assistance Publique–Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, Paris (G. Peytavin); Université Paris Diderot, Sorbonne Paris Cité, Paris (G. Peytavin); Assistance Publique–Hôpitaux de Paris, Hôpitaux Universitaires de l’Est Parisien, Paris (N. Veziris); Institut Pierre Louis Institute d’Épidémiologie et de Santé Publique, Paris (P. Flandre, E. Caumes, V. Pourcher)

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Abstract

Linezolid is one of the most effective drugs for treating multidrug-resistant tuberculosis (MDR TB), but adverse effects remain problematic. We evaluated 57 MDR TB patients who had received >1 dose of linezolid during 2011–2016. Overall, patients received 600 mg/day of linezolid for a median of 13 months. In 33 (58%) patients, neurologic or ophthalmologic signs developed, and 18 (32%) had confirmed peripheral neuropathy, which for 78% was irreversible at 12 months after the end of TB treatment despite linezolid withdrawal. Among the 19 patients who underwent ophthalmologic evaluation, 14 patients had optic neuropathy that fully reversed for 2. A total of 16 (33%) of 49 patients had a linezolid trough concentration >2 mg/L, and among these, 14 (88%) experienced adverse effects. No significant association was found between trough concentration and neurologic toxicity. These findings suggest the need to closely monitor patients for neurologic signs and discuss optimal duration of linezolid treatment.

Worldwide, tuberculosis (TB) affects 10 million persons every year. Among them, multidrug-resistant TB (MDR TB) is diagnosed for 484,000 (1); and among MDR TB cases, 10% are caused by extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. Outcomes for patients in TB-endemic countries are very poor, particularly for those with XDR TB; cure rates are <20% (2). However, even in TB-endemic countries, individualized treatment adapted to drug susceptibility achieves cure rates of only 60% in patients with XDR TB (3,4). Similarly, a meta-analysis of 50 studies performed in 25 countries and including 12,030 patients receiving individualized treatment for MDR TB found a pooled success rate of 61% for combination therapy regimens containing linezolid (5). At Pitié-Salpêtrière Hospital in Paris, France, the survival rate for XDR TB patients for whom highly effective drugs (e.g., linezolid, bedaquiline, or both) were prescribed was 80% (6–8). Overall, an 80% cure rate can be achieved for patients with MDR TB treated with a drug regimen that includes linezolid (9–12).

The 2014 World Health Organization (WHO) guidelines promote using highly active drugs for MDR TB, especially that caused by XDR TB strains (13). In 2016 and 2018, these recommendations were updated, and linezolid, along with bedaquiline and levofloxacin/moxifloxacin, were upgraded to group A drugs that should be offered to all patients (14,15).

Although linezolid is highly effective, its long-term use in patients with MDR TB is impaired by its adverse effects. Myelosuppression occurs in ≈30% of patients, particularly those receiving high doses (>600 mg/d) (9,12), and neurotoxicity with peripheral neuropathy is experienced by 30% of patients after 2 to 4 months of receiving low doses (<600 mg/d) (12). Furthermore, linezolid-associated optic neuropathy appears after 5 to 10 months of treatment for 30% of patients (11,16). It is still debated whether linezolid trough concentrations >2 mg/L (17) or long-term exposure could predict the occurrence of adverse effects (18,19). We therefore evaluated the occurrence and management of neurologic and ophthalmologic adverse effects among MDR TB patients receiving a linezolid-based treatment regimen.