From Pages to Practice
Published April 29, 2020
In 1952, the Nobel prize in physiology or medicine was awarded to Selman Waksman for his laboratory’s discovery of the antibiotic streptomycin. The drug, first isolated in 1943, gained prominence for its activity against mycobacteria and heralded the chemotherapy era for the treatment of tuberculosis (TB). The study of streptomycin’s efficacy against TB, conducted by the British Medical Research Council in 1948, is often credited as one of the earliest examples of randomized trials in medicine. However, before the clinical trial was reported, evidence of streptomycin-resistant Mycobacterium tuberculosis strains had already been described.
The chemotherapy era of TB treatment has been marked by escalation in therapeutic options in response to increasingly drug-resistant organisms. In the 1990s, multidrug resistant (MDR) strains were first recognized, and in 2006, the World Health Organization identified an outbreak of an extensively drug resistant (XDR) strain in South Africa. Patients battling drug-resistant M. tuberculosis were faced with limited treatment options, often requiring multimodal therapy for upwards of 2 years. In the case of XDR-TB, outcomes were grim with success rates ranging from 2%–22%.
The outlook for XDR tuberculosis remained dire until the last decade when two novel agents — bedaquiline and pretomanid — were shown to have efficacy against drug-resistant TB. In the open-label Nix-TB trial, 109 patients with XDR-TB (n=71) or treatment intolerant/nonresponsive MDR-TB (n=38) were given a 26-week course of bedaquiline, pretomanid, and linezolid. At 6 months, an astounding 90% of patients had achieved clinical resolution and culture negativity. With bedaquiline and pretomanid being two of only three novel antituberculous agents approved for use in the last 40 years, the results of the Nix-TB trial are expected to have an immediate impact on the care of patients with drug-resistant TB.
The following NEJM Journal Watch summary explains the study and results in more detail:
Richard T. Ellison III, MD reviewing Conradie F et al. N Engl J Med 2020 Mar 5
A 26-week oral regimen of bedaquiline, pretomanid, and linezolid was 90% effective in treating patients with XDR-TB.
Current management of extensively drug-resistant tuberculosis (XDR-TB) infections having resistance to agents including isoniazid, rifampin, fluoroquinolones, and aminoglycosides has no standard recommended regimen. Patients generally receive up to 24 months of multiple agents with substantial adverse effects and cure rates of about 14%. Two new agents, bedaquiline and pretomanid, have shown activity against XDR-TB; thus, investigators performed an open-label study in South Africa of a 26-week course of these agents plus linezolid in patients with XDR-TB or complicated multidrug resistant tuberculosis (MDR-TB). Participants received oral bedaquiline (400 mg daily for 2 weeks, then 200 mg thrice weekly for 24 weeks), pretomanid (200 mg daily for 26 weeks), and linezolid (1200 mg daily or 600 mg twice daily for 26 weeks).
Among 109 evaluable patients (median age, 35), 56 were HIV positive, 92 had cavitary lung disease, 71 had XDR-TB, and 100 had received other multidrug TB treatment prior to enrollment. At 6 months after the end of treatment, 98 patients had a favorable outcome (clinical disease resolution, negative culture status). In the remaining 11 patients, 7 deaths, 2 relapses, 1 loss to follow-up, and 1 withdrawal occurred. Nineteen participants experienced serious adverse events and 62 had events of grade ≥3 (predominantly involving peripheral neuropathy or myelosuppression). HIV status did not affect incidence of adverse events.
Comment: The authors acknowledge that this trial had no randomized, controlled group and was performed in one country — still, these findings should fundamentally change the care of patients with MDR- or XDR-TB. The WHO had already issued guidelines recommending bedaquiline and linezolid as first-line agents for MDR-TB, and further revision can be anticipated. The three-drug regimen in this trial was associated with significant toxicity apparently linked to linezolid; hopefully a less toxic but still effective dosing schedule can be developed for that agent.