The clinical activity of TMC207 validates ATP synthase as a viable target for the treatment of tuberculosis. (ClinicalTrials.gov number, NCT00449644.)

The 2-year follow-up results for a randomized placebo-controlled study of 47 patients with multidrug-resistant pulmonary tuberculosis treated with either the new diarylquinoline TMC207, recently renamed bedaquiline, or placebo, added to the first 8 weeks of a background regimen, are presented. Bedaquiline significantly reduced the time to culture conversion over 24 weeks (hazard ratio, 2.253; 95% confidence interval, 1.08 to 4.71; P ‫؍‬ 0.031). With the exception of nausea reported in 26% of patients receiving bedaquiline and none receiving placebo, adverse events occurred at similar frequencies in both groups of patients: bilateral hearing impairment, extremity pain, acne, and noncardiac chest pain occurred in 13 and 21%, 17 and 13%, 9 and 17%, and 4 and 17% of patients, respectively, receiving bedaquiline or placebo. Excluding resistance to ethambutol and ethionamide, only one patient receiving bedaquiline acquired resistance to companion drugs, but five patients receiving placebo (4.8% versus 21.7%; P ‫؍‬ 0.18) acquired resistance to companion drugs, and resistance to ofloxacin was acquired in four patients receiving placebo and none receiving bedaquiline (0% versus 22%; 0 ‫؍‬ 0.066). In all, 23 patients (49%), including 13 receiving placebo (54%) and 10 receiving bedaquiline (44%), discontinued the study prior to its completion, 12 during the first 24 weeks of treatment. Eight subjects were withdrawn for noncompliance or default, and seven withdrew consent, citing the rigorous program of investigations for safety and pharmacokinetic monitoring. Bedaquiline may contribute to the management of multidrug-resistant tuberculosis by effecting more rapid sputum culture negativity and by preventing acquired resistance to companion drugs. M ultidrug-resistant (MDR) tuberculosis (TB) is a serious form of TB and the term MDR implies resistance to at least the essential first-line agents isoniazid (INH) and rifampin (RMP); because INH and RMP are no longer effective, patients with MDR pulmonary TB must be treated for at least 20 months with potentially toxic, less efficacious drugs (20). MDR Mycobacterium tuberculosis isolates will frequently also be resistant to the other first-line drugs pyrazinamide (PZA), ethambutol (EMB), or streptomycin (or SM) and, at times, other drugs such as ethionamide (Eth), a fluoroquinolone, or injectable drugs such as kanamycin (KAN), amikacin, or capreomycin (CAP). MDR TB with additional resistance to the last two mentioned classes is termed extensively drug-resistant (XDR). The spread of MDR TB, particularly among communities with a high prevalence of human immunodeficiency virus (HIV) infection, is threatening the foundations of TB control programs worldwide (19). TMC207, recently renamed bedaquiline, is a diarylquinoline with a novel mode of action specifically inhibiting mycobacterial ATP synthase (1).The present randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and efficacy of bedaquiline when it is added to a background regimen (BR) in newly d...

Tibotec Medicinal Compound 207 (TMC207) is a novel diarylquinoline with a unique mode of action that targets mycobacterial ATP synthase. TMC207 exhibits high in vitro activity against mycobacterial strains either susceptible or resistant to all first-line and many second-line drugs, including fluoroquinolones, and has shown exceptional in vivo activity against several mycobacterial species in different animal models. In this early bactericidal activity study, 75 treatment-naïve patients with smear-positive pulmonary tuberculosis were randomized to once-daily oral TMC207 (25 mg, 100 mg, or 400 mg), 600 mg rifampin (RIF), or 300 mg isoniazid (INH) for 7 days. Sixteen-hour overnight sputum collected at baseline and on each treatment day was plated in serial dilutions on selective agar plates. The bactericidal activity was expressed as the log 10 decrease in CFU/ml sputum/day. Pharmacokinetic sampling was performed on day 7 of TMC207 administration up to 24 h postdose. The decreases in log 10 CFU counts (؎ standard deviation) from baseline to day 7 were 0.04 ؎ 0.46 for 25 mg TMC207 (n ‫؍‬ 14), 0.26 ؎ 0.64 for 100 mg TMC207 (n ‫؍‬ 14), 0.77 ؎ 0.58 for 400 mg TMC207 (n ‫؍‬ 14), 1.88 ؎ 0.74 for INH (n ‫؍‬ 11), and 1.70 ؎ 0.71 for RIF (n ‫؍‬ 14). Significant bactericidal activity of 400 mg TMC207 was observed from day 4 onward and was similar in magnitude to those of INH and RIF over the same period. The pharmacokinetics of TMC207 were linear across the dose range. In summary, TMC207 demonstrated bactericidal activity with a delayed onset and was well tolerated, and no study drug-related serious adverse events occurred.Tuberculosis (TB) has reemerged as one of the most deadly infectious diseases worldwide, killing approximately 1.7 million people in 2004 (25). In Africa, more than 30% of new adult TB cases are coinfected with human immunodeficiency virus (HIV) (5). Widespread efforts to control the resurgence of TB, such as the implementation of outcome-driven treatment programs (16) and the introduction of "directly observed therapy short-course" (26), have had limited success, in part due to constrained public health resources and the length of treatment needed to sterilize infectious TB lesions. The global situation is deteriorating further with the spread of multidrugresistant (MDR) TB (7, 8) and, more recently, extensively drug-resistant TB (9). There is an urgent need for new anti-TB agents that can shorten treatment duration and are effective in treating drug-sensitive, drug-resistant, and latent TB infection (22).Tibotec Medicinal Compound 207 (TMC207) (also known as R207910) belongs to a newly identified chemical class with antimycobacterial properties. TMC207 demonstrates unique and specific antimycobacterial activity by inhibiting the oligomeric and proteolipic subunit c of mycobacterial ATP synthase, a critical enzyme in the synthesis of ATP (17). Binding of TMC207 to subunit c leads to inhibition of ATP synthesis, which subsequently results in bacterial death. In vitro mycobacterial susceptibility experimen...

We studied the early bactericidal activity of twice the standard dose of rifampin in subjects with pulmonary tuberculosis evidenced by positive smears. The observed mean 2-day activity was almost double that reported at the standard dose. Further studies are warranted to establish whether higher rifampin doses might assist in shortening tuberculosis treatment.Rifampin (RMP) is a key drug in standard antituberculosis regimens. The sterilizing properties of RMP in conjunction with pyrazinamide lay the foundation for the current "shortcourse" 6-month regimens (11). The standard RMP dose of 8 to 12 mg/kg of body weight (21) is probably at the lower limit of optimal efficacy (11,13,18,20), but it is not clear whether higher doses of RMP could increase its activity (12). We studied the pharmacokinetics and the 2-day and 5-day early bactericidal activities (EBA) of RMP at a dose of 20 mg/kg of body weight.We included treatment-naïve patients with pulmonary tuberculosis, evidenced by positive smears, who had no past history of liver disease and normal serum transaminase and bilirubin levels. RMP was given daily over five days in a single dose before breakfast. Patients were monitored for unexpected signs and symptoms for 7 days in the hospital and again 2 weeks after the last dose of study medication. Sixteen-hour sputum specimens were collected overnight before and over 5 days after initiation of treatment. Patients commenced standard antituberculosis treatment on discharge. The Committee for Pharmaceutical Trials of the University of Stellenbosch and the South African Medicines Control Council approved the study. All patients gave written informed consent.After sputum digestion (Sputasol; Oxoid Ltd., Poole, England) and homogenization, two series of 10-fold dilutions were incubated on selective 7H10 agar plates for the enumeration of CFU as described previously (17). Serum samples were taken at 1, 1.5, 2, 2.5, 3,4,8,12, and 24 h after the first dose. RMP concentrations were measured by high-pressure liquid chromatography with UV detection as previously described (17). The EBA was defined as (Z 0 Ϫ Z D )/D, where Z 0 and Z D are logarithms of the CFU counts per ml sputum prior to the start of treatment and after D days of treatment, respectively (17). All data are displayed as mean Ϯ standard deviations unless stated otherwise.One of 14 enrolled patients was excluded following an episode of hemoptysis. Thirteen patients whose sputum was at least 2ϩ smear positive for acid-fast bacilli completed the study (age, 27 Ϯ 9 years; 61% male; body weight, 55 Ϯ 16 kg). On chest radiography, all patients had at least one cavity, and 7 (54%) had bilateral disease. Three patients (23%) were human immunodeficiency virus positive. Clinically observed adverse events were mild and transient. One patient suffered a secondary pneumothorax 2 weeks after discharge and received pleural drainage. No other serious adverse events occurred during the study or were evident at the 2-week follow-up.All strains isolated were susceptible to RMP (Bac...

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