Linezolid in XDR – Useful to an Extent

Posted by Sushrut Jangi • October 18th, 2012

A few hours north of Durban, South Africa, the little town of Tugela Ferry sits in the shadow of the rugged mountains that run alongside the Indian Ocean.  There are few roads here, gaps in the electrical grid, and a paucity of running water.   The main hospital in town – the three-hundred-and-fifty bed Church of Scotland – serves the 150,000 people that live in the surrounding districts.  A rural and dry landscape, Tugela Ferry was mostly unknown by the rest of the world until 2005, when a number of tuberculosis deaths at the hospital alarmed the global community.

South Africa is no stranger to tuberculosis – the country itself accounts for 5% of worldwide cases of the disease.  Even more troubling, rates of HIV/AIDS are as high as 20% among the South African adult population, rendering immunocompromised patients susceptible to co-infection with tuberculosis.  Between January 2005 and March 2006, epidemiologists noticed a surprisingly high number of tuberculosis cases at Tugela Ferry that did not respond to standard therapies.   Ordinarily, patients resistant to the first-line drugs isoniazid and rifampin have MDR, or multi-drug resistant tuberculosis.  However, these patients did not respond to any of the second-line drugs either.   Researchers termed this new resistant strain of Mycobacterium tuberculosis XDR – extensively drug resistant tuberculosis – an outbreak that many deemed a global emergency.

XDR is now found in 6 continents, and has high mortality and fast progression.  There are no obvious clinical patterns that can initially distinguish XDR from MDR or drug-susceptible tuberculosis.  Resistance testing, while improving, is often unavailable in resource-poor settings.  Even if XDR is identified, therapies are few, riddled with side effects, and until now – have not been not well studied.

For this reason, we welcome a report in this week’s NEJM on the efficacy of linezolid – an antibiotic available since 2000 to treat gram-positive infections – as a potential therapeutic in XDR.   The study was carried out in Korea, another region of the world beset with the epidemic.  Between 2008-2011, adults with pulmonary XDR-TB who had failed prior regimens were randomized to receive linezolid either immediately or after a 2-month delay, in addition to continuing their initial regimen.  After 4 months, nearly 80% of patients who started the drug immediately cleared their sputum of the bacterium; only 35% of patients in the delayed-arm had culture converted at this time, reflecting a significant benefit from immediate linezolid administration.  Overall, after both arms were combined, 90% of patients achieved culture conversion by six months.

Unfortunately, almost 90% of patients also suffered significant adverse events, including bone marrow suppression, neuropathies, and rhabdomyolysis.  Although these events are concerning, most resolved upon dose reduction or temporary discontinuation of the drug.  Whether these reductions in dose nullify the potential benefit of linezolid in XDR therapy in the long term remains to be seen.

Today, Tugela Ferry continues to struggle alongside many rural areas in South Africa in combating tuberculosis.  Even with the arrival of new drugs, diagnosis and treatment in such communities remains problematic.  Patients may walk to a clinic miles away from home, only to be sent back with three or four bottles of medications they take inconsistently. While only 4 patients developed resistance to linezolid in this study, longer treatment durations with poor adherence to multi-drug regimens could create new and hardier strains, underlining the importance of public health measures – like directly observed therapy – in targeting this disease.  Linezolid does expand the armamentarium for treatment of XDR-TB.   However, if we aren’t careful, we may only give the bacillus further opportunity to continue this long-burning and dynamic epidemic.

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