Provisional CDC Guidelines for the Use and Safety Monitoring of Bedaquiline Fumarate (Sirturo) for the Treatment of Multidrug-Resistant Tuberculosis

摘要

Introduction Tuberculosis (TB) is caused by the bacteria of the Mycobacterium tuberculosis complex, most commonly M. tuberculosis. TB usually is transmitted from one person to another by airborne droplet nuclei containing the bacteria. For most persons who have drug-susceptible TB, cure is achieved with a combination of first-line drugs (e.g., isoniazid [INH], rifampin [RIF], ethambutol [EMB], and pyrazinamide [PZA]) administered as a 6-month standard regimen. In contrast, multidrug-resistant tuberculosis (MDR TB), defined as TB that is caused by M. tuberculosis resistant to at least INH and RIF, generally requires 18–24 months of treatment after sputum culture conversion (SCC) with five or six drugs (e.g., susceptible first-line drugs plus an injectable agent, a fluoroquinolone, and other second-line drugs as needed) that are less effective, more toxic, and more costly than a standard first-line regimen ( 1 ,2). MDR TB impacts communities worldwide and poses an urgent public health threat that transcends borders. In 2011, an estimated 630,000 cases of MDR TB (range: 460,000–790,000) occurred among the world's 12 million persons with prevalent cases of TB. An estimated 3.7% of persons with newly diagnosed TB and 20% of persons with previously treated TB have MDR TB. Extensively drug-resistant tuberculosis (XDR TB), defined as MDR TB with additional resistance to any fluoroquinolone and to at least one of three injectable anti-TB drugs (i.e., kanamycin, amikacin, or capreomycin), has been reported in 84 countries; on average, 9% of persons with MDR TB have additional resistance qualifying as XDR TB. India and China contribute the greatest numbers of MDR TB cases to the global burden, but the Russian Federation has the highest MDR TB rates per 100,000 population (3,4). Compared with drug-susceptible TB, MDR TB causes greater morbidity and mortality, and overall patient outcomes are worse (i.e., death, relapse [reverting to sputum culture-positive after becoming culture-negative while on treatment], treatment failure [remaining sputum culture-positive while on treatment], or disability). Mortality rates for patients being treated for MDR-TB usually exceed 10% (range: 8%–21%) (5). A recently published individual patient data meta-analysis of 9,153 patients with MDR TB yielded a mortality rate of 15% (6). MDR TB develops when TB that is susceptible to first-line drugs is not treated adequately because of the selection of substandard treatment regimens or nonadherence with (or interruption in) treatment. Other factors (e.g., malabsorption of drugs or drug-drug interactions) also can lead to the selection of drug-resistant strains (2). Once drug-resistant TB has developed, person-to-person transmission is possible, potentially leading to outbreaks (7). MDR TB must be rapidly diagnosed and treated with an effective drug regimen to prevent further transmission of these difficult-to-cure strains of TB. One of the challenges in the treatment of MDR TB is the lack of effective, well-tolerated medications. There are very few medications and fewer classes of medications for treatment of MDR TB, and adverse drug reactions commonly necessitate discontinuing medications (2). On December 28, 2012, the Food and Drug Administration (FDA) approved the use of bedaquiline fumarate (Sirturo or bedaquiline) as part of combination therapy (minimum four-drug therapy) administered by direct observation to adults aged ≥18 years with a diagnosis of pulmonary MDR TB when an effective treatment regimen cannot otherwise be provided (e.g., because of extensive resistance, drug intolerance, or drug-drug interactions) (8). The recommended dose of bedaquiline for the treatment of pulmonary MDR TB in adults is 400 mg administered orally once daily for 2 weeks, followed by 200 mg administered orally three times weekly, for an entire treatment duration of 24 weeks. Bedaquiline is taken with food and in combination with other anti-TB drugs. The drug is available in 100 mg tablets (9,10). FDA approves drug products for lawful marketing?for specific intended uses based on data that establish safety and efficacy, and approves labeling specific to those uses. FDA approved bedaquline as part of combination therapy to treat adults with pulmonary MDR TB when other alternatives are not available. The drug was approved under FDA's accelerated approval program, which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients (11). FDA approved bedaquiline with a black box warning alerting health-care professionals to an increase in all-cause mortality and to a prolongation of the QTcF* in patients treated with bedaquiline versus placebo. Bedaquiline, a diarylquinoline, is the first drug with a novel mechanism of action against M. tuberculosis that has been approved by FDA since 1971 (12). FDA considered