Edgar Allan Poe (b. 1809; d. 1849), master of the macabre, had good reason to be terrified by “the redness and the horror of blood” – particularly when it arrived in a fit of coughing. Consumption (almost certainly due to pulmonary tuberculosis) orphaned Poe before the age of three, and later caused the death of his young wife and that of his brother. After almost two centuries, the menacing specter of drug-resistant Mycobacterium tuberculosis serves as an eerie reminder that the consumptive disease that continues to plague humankind could once again become an unstoppable epidemic.
Fortunately, there is reason for hope. In this week’s NEJM, Dr Maria Tarcel Gler (Makati Medical Center, Philippines) and colleagues report on the safety and efficacy of delamanid for the treatment of active pulmonary infection with multidrug-resistant Mycobacterium tuberculosis (MDR-TB). The investigators randomly assigned 481 sputum-culture-positive adults to eight weeks of treatment with either delamanid or placebo, superimposing the assigned treatment on the 12-weeks of background antibiotic therapy received by all patients. The primary efficacy endpoint was the proportion of patients with sputum-culture conversion, defined as five or more consecutive weekly sputum cultures negative for M. tuberculosis. Regular safety assessments were also performed.
After twelve weeks, sputum-culture conversion was more common in the delamanid-plus-background groups than in the placebo-plus-background group (45% and 42% versus 30%; p<0.05 for both comparisons). In the safety analysis, the delamanid-plus-background groups had a higher incidence of electrocardiographic QT-interval prolongation (10% and 13% versus 4%; p<0.05 for both comparisons), suggesting that future trials will need to perform careful surveillance for dangerous cardiac arrhythmias.
While delamanid may become another weapon in the antibiotic armamentarium, an accompanying editorial by Drs Richard E Chaisson and Eric L Nuermberger (both from Johns Hopkins University, Baltimore) outlines why we’re still far from winning the war against MDR-TB. First, drug resistance is frighteningly common. For example, as reported in this week’s NEJM, Dr Yanlin Zhao (Chinese Center for Disease Control and Prevention, Beijing, China) and colleagues estimate that there are 110,000 incident cases of MDR-TB annually in China alone. Second, current global screening and resistance testing approaches do not adequately identify drug-resistance when it is present. Third, contemporary research and regulatory environments effectively discourage studies that might identify which drug combinations are optimal for the treatment of MDR-TB.
In the centuries since Edgar Allan Poe’s birth, humankind has witnessed phenomenal improvements in the prevention and treatment of tuberculosis. Recent resurgences in tuberculosis and the evolution of drug-resistant strains have been disappointing developments for researchers, public health professionals, clinicians, and patients alike. Will drug-resistant tuberculosis ultimately hold “illimitable dominion over all”1? Let’s hope not. Living in such a world would be terrifying – even for the master of the macabre.
 Poe, Edgar Allan. “The Masque of the Red Death.” [Internet]. Salt Lake City, Utah: Project Gutenberg; 2010. [First published under current title 19 July 1842; ebook release 6 June 2010; cited 30 May 2012]. Available from: www.gutenberg.org/ebooks/1064.