Author(s): Jacques H Grosset [*] 2 , Nicole C Ammerman 1
antimicrobial activity; bedaquiline; dose ranging; early bactericidal activity; loading doses; tuberculosis treatment
On 28 December 2012, the US FDA approved the new antibiotic molecule bedaquiline (BDQ), formerly called TMC207, for use "as part of combination therapy to treat adults ([greater than or equal]18 years) with pulmonary multidrug resistant tuberculosis (MDR-TB)" only under the circumstances "when an effective treatment regimen cannot otherwise be provided"  . BDQ is a diarylquinoline which targets the proton pump of ATP synthase leading to inadequate synthesis of ATP [2-4] . This drug has a MIC for Mycobacterium tuberculosis as low as 0.03-0.06 µg/ml and does not exhibit cross-resistance with any of the first-line anti-TB drugs.
In the mouse model of TB, the culture conversion rate achieved by BDQ alone and in combination with other drugs, was so impressive that it promoted the conduct of a 7-day human trial to study the pharmacokinetics, safety, tolerability and early bactericidal activities of three daily oral doses of BDQ (25, 100 and 400 mg) in patients with smear-positive, drug-susceptible pulmonary TB  . The early bactericidal activity (EBA) is the drug- or regimen-induced decrease in M. tuberculosis colony forming units (CFUs) in overnight-collected sputum samples of TB patients. It is arbitrarily defined as the fall in log10 CFU of M. tuberculosis per milliliter of sputum per day. The sputum samples are homogenized but not decontaminated, after which they are inoculated on 7H11 selective agar. Initially EBA studies were conducted during the first 2 days of treatment  , then the first 7 days  , and finally extended to the first 14 days  .
The results of the first trial on BDQ, published in 2008  , indicated that after 7 days of drug treatment, the peak plasma concentrations of BDQ were obtained 4 h after drug administration, reaching 0.3, 1.2 and 5.5 µg/ml after 25, 100 and 400 mg doses, respectively. Twenty four hours after dosing, the residual plasma concentrations were approximately 0.1, 0.4 and 1.5 µg/ml after 25, 100 and 400 mg doses, respectively, indicating that BDQ has a very long half-life and consequently accumulates during treatment at plasma concentrations above the MIC. However, a steady state of drug concentrations in plasma was not yet attained after the 7 days of drug administration. Importantly, the decline of CFU counts in sputum samples of the patients during the 7 days of treatment was practically nil in those receiving either 25 or 100 mg daily therapy (despite plasma concentrations well above MIC) and began only after 5 days of treatment in those receiving 400 mg per day. These results suggest that BDQ needs to accumulate in M. tuberculosis in order to exert its potent antimicrobial activity and that such accumulation is dose related.
Summary of methods & results
The latest manuscript by Diacon et al . is the logical complement of the previous manuscript  . It reports the results of a 14-day EBA study in which loading doses of BDQ were administered to try...