Linezolid treats Chronic Extensively Drug-Resistant TB but has a high incidence of adverse effects

Image: PD/CDC

Key study points:  

1. Many patients with XDR-TB who did not respond to initial treatment regimens became culture negative at 6 months with addition of linezolid (34 out of 39 patients).

2.  A large number of patients (82%) who received linezolid experienced adverse events possibly related to linezolid.  A lower rate of adverse events was observed in patients who received lower does of linezolid.

3.  Acquired resistance to linezolid by the TB isolates occurred in 11% of patients in the study.

Primer: Extensively Drug-Resistant Tuberculosis (XDR-TB) is defined as TB that is resistant to the main first-line anti-mycobacterial agents isoniazid and rifampin, as well as resistant to at least one fluoroquinolone and one injectable agent (such as amikacin).

Initial reports of XDR-TB surfaced in 2006, and it has subsequently been reported in 68 countries in all geographic areas of the world, including the U.S.  Current estimates place the global cases of XDR-TB to be approximately 40,000, with most cases concentrated in Southeast Asia and Eastern Europe.  It is believed that the incidence of XDR-TB is growing worldwide and therefore new drugs are being sought for its treatment.

Linezolid is a bacteriostatic agent that inhibits the bacterial ribosome.  In vitro studies demonstrated that linezolid inhibits XDR-TB strains with a minimum inhibitory concentration (MIC) of less than 1ug/ml.  Case reports and retrospective studies have shown the potential benefit of adding linezolid to drug regimens for patients with XDR-TB; however there have been no randomized studies to support its use.

Background reading:

1. Dietze R, Hadad DJ, McGee B, et al. Early and extended early bactericidal activity of linezolid in pulmonary tuberculosis. Am J Respir Crit Care Med 2008;178:1180-1185

2. Anger HA, Dworkin F, Sharma S, Munsiff SS, Nilsen DM, Ahuja SD. Linezolid use for treatment of multidrug-resistant and extensively drug-resistant tuberculosis, New York City, 2000-06. J Antimicrob Chemother 2010;65:775-783

3. Fortun J, Martin-Davila P, Navas E, et al. Linezolid for the treatment of multidrug-resistant tuberculosis. J Antimicrob Chemother 2005;56:180-185

This [prospective randomized] trial by Lee et al, published in NEJM, added linezolid to the regimens of 41 patients with XDR-TB who had undergone 6 months of standard therapy with no response.  The study randomized 41 patients to receive the addition of 600mg linezolid daily to their anti-TB regimens either immediately or after a 2 month delay.  The delay was performed to ensure any observed changes in outcome were due to specifically to the linezolid.

Patients were excluded if they had prior treatment with linezolid, were HIV positive, or had other laboratory anomalies or medical history relevant to the adverse of effects of linezolid.  Patients received therapy until they had 2 consecutive weeks of negative sputum cultures or received 4 months of therapy; whichever outcome came first.

Patients then underwent a second randomization to receive either 300mg or 600mg daily of linezolid for an additional 18 months to evaluate for efficacy of a lower dose that might reduce adverse effects.

34 of 38 patients (89%) who received linezolid were culture negative by 6 months of treatment.  87% of patients had clinically significant adverse effects, while 82% had events possibly due to the linezolid including neuropathy and myelosuppresion.

During the second randomization, 88% of the 600mg group experienced an adverse event, compared to only 69% of the 300mg group.  4 patients did not respond to therapy.  Sequencing analysis of the TB isolates from the non-responders revealed mutations in either the 23S rRNA or in ribosomal protein L3 – both of which are mutations associated with linezolid resistance.  The serum linezolid peak and trough levels of the 600mg group were consistently above the MIC for XDR-TB.  The troughs of 9 patients in the 300mg group dipped below the MIC – including the 2 patients whose isolates developed resistance to linezolid.

In sum: While previous case reports and retrospective studies have suggested the utility of linezolid in treating XDR-TB, this study is the first randomized study to support its use.  The majority of patients (89%) were culture negative by 6 months.  However, 87% experienced an adverse event.  Additionally, resistance to linezolid was discovered in 4 patients.  Though compelling, this study leaves several areas that will require further elucidation.

Importantly, this study excluded patients with HIV.  Though variable throughout the world, there is a significant incidence of HIV/TB coinfection that can drastically affect treatment outcome.  Additionally, the high incidence of adverse events is concerning.  Last, resistance to linezolid emerged in 11% of cases, 2 of which occurred in the group receiving the 600mg standard dose of linezolid.  Further studies may need to evaluate for the role of serum-drug level monitoring to tailor regimens to optimize balancing adverse events and sustaining the MIC.

Click to read the study in NEJM

By [AS] and [MP]

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