Assessment of linezolid efficacy and safety in MDR- and XDR-TB: an Indian perspective

To the Editors:

We read with interest the analysis of the efficacy, tolerability and safety profile of linezolid in multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) in the retrospective TBNET (Tuberculosis Network European Trials group) study by Migliori et al. 1. Before this publication, scattered case reports and small case series have been the only source of data on the efficacy and safety of this drug in the treatment of MDR- and XDR-TB cases.

Linezolid is the first oxazolidinone to be developed and introduced in clinical use. In vitro studies have shown good activity against different species of mycobacteria, including resistant strains. The linezolid minimum inhibitory concentration to inhibit the growth of 90% of organisms for Mycobacterium tuberculosis is in the range of 1–2 mg·L⁻¹ 2. However, clinical experience with the use of linezolid in the management of mycobacterial infection is still sparse.

The use of linezolid is especially relevant in a country like India, which bears the burden of a third of the world's MDR-TB patients. The most recent, i.e. fourth, World Health Organization global resistance report, released in February 2008, estimated there were 110,132 cases of MDR-TB from India in 2006. This accounted for 20% of the world's MDR-TB burden. Between them, India and China accounted for 50% of the global MDR-TB burden 3.

Acquired drug resistance, not just to isoniazid and rifampicin, but also to other second-line drugs is also common in India and XDR-TB strains have been increasingly reported since the first report from India was published in 2007 4. Physicians increasingly need to fall back on newer (Group V) and experimental drugs in order to make up the minimum recommended number of active drugs (ideally four or five) to ensure a successful regime. Linezolid has been increasingly used in this role. It is relatively cheap, available off-patent and there are currently 10 generic preparations available in the Indian market. Little is known about its efficacy or toxicity in the Indian context.

We report our clinical experience with the use of linezolid in a cohort of 78 Indian MDR- and XDR-TB patients (36 males and 42 females) being treated at the chest outpatient department of a large private tertiary referral hospital in Mumbai (India). In this prospective, non-randomised study from 2000 to 2007, 18 out of the 78 patients received linezolid. Of these 18 patients, seven harboured XDR-TB and 11 were MDR-TB patients. The mean duration of therapy with the drug was as long as 20.6 months. All 18 patients received the drug only in a dose of 600 mg, once a day. Of these 18 cases, 11 patients were cured, four failed treatment and three were lost to follow-up. In our cohort, the use of linezolid was not associated with any difference in treatment outcome.

In comparison with the TBNET cohort (table 1⇓), we noticed a higher incidence of major adverse reactions (61%) in our patients. Chief among these was a severe peripheral neuropathy. 16 patients were affected by sensory-motor neuropathy. Nerve conduction study was performed in nine of the 16 patients, revealing axonopathy in all cases studied. The adverse event was always affecting the lower limbs. Neuropathy was often disabling and crippling and persisted for several years after stopping the drug. The higher incidence of neuropathy in our series could have been due to the fact that our Indian MDR-TB patients are likely to have been more malnourished than their European counterparts. 16 out of the 18 patients in the linezolid group were malnourished with BMI <18 kg·m⁻².

One of our patients developed bilateral blindness secondary to a linezolid-induced bilateral optic neuropathy. This developed 3 months after the drug was initiated and reversed completely within 1 month of stopping linezolid. Only one other case report is available in literature documenting optic neuropathy after the use of linezolid 6. Only one patient developed anaemia severe enough to need transfusion.

In conclusion, linezolid proved to be an effective but highly toxic drug in Indian patients with MDR-TB. We have learned to use it with caution, in a dose never exceeding 600 mg, once a day, in patients with MDR- and XDR-TB, who have few other drug options. All of our patients were given written instruction on the side-effects that they are likely to encounter and, at each follow-up, these were diligently checked for. In all patients treated with linezolid, clinical, haematological and neurological evaluations are mandatory on a monthly basis, as well as frequent opthalmological tests.

To conclude, the high frequency of adverse effects to linezolid warrants extreme caution when this drug is used for prolonged periods of time in MDR-TB patients. Thus, prospective, randomised and multicentre evaluations are needed in order to test the efficacy of linezolid as well as the short- and long-term tolerability of the drug in TB patients.

Statement of interest

None declared.