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BackgroundBedaquiline (BDQ), by targeting the electron transport chain and having a long half-life, is a good candidate to simplify leprosy treatment. Our objectives were to (i) determine the minimal effective dose (MED) of oral BDQ, (ii) evaluate the benefit of adding another inhibitor of the respiratory chain to oral BDQ (i.e.clofazimine (CFZ)) and (iii) evaluate the benefit of an intramuscular injectable long-acting formulation of BDQ (intramuscular BDQ; BDQ-LA IM), in a murine model of leprosy.Methodology/ Principal FindingsTo determine the MED of oral BDQ and the benefit of adding CFZ, 100 four-week-old female nude mice were inoculated in the footpads with 5.103bacilli ofM. lepraestrain THAI53. Mice were randomly allocated into: 1 untreated group, 5 groups treated with oral BDQ (0.10 to 25 mg/kg), 3 groups treated with CFZ 20 mg/kg alone or combined with oral BDQ 0.10 or 0.33 mg/kg, and 1 group treated with rifampicin (RIF) 10 mg/kg. Mice were treated 5 days a week during 24 weeks.To evaluate the benefit of the BDQ-LA IM, 340 four-week-old female Swiss mice were inoculated in the footpads with 5.103to 5.101bacilli (or 5.100for the untreated control group) ofM. lepraestrain THAI53. Mice were randomly allocated into the following 11 groups treated with a single dose (SD) or 3 doses (3D) 24h after the inoculation: 1 untreated group, 2 treated with RIF 10 mg/kg SD or 3D, 8 treated with oral BDQ or BDQ-LA IM 2 or 20 mg/kg, SD or 3D.Twelve months later, mice were sacrificed andM. lepraebacilli enumerated in the footpad. All the footpads became negative with BDQ at 3.3 mg/kg. The MED of oral BDQ againstM. lepraein this model is therefore 3.3 mg/kg. The addition of CFZ to a dose of BDQ 10-fold lower than this MED increased the bactericidal activity of BDQ suggesting synergies between both drugs. The BDQ-LA IM displayed similar or lower bactericidal activity than the oral BDQ.ConclusionWe demonstrated that the MED of oral BDQ againstM. lepraewas 3.3 mg/kg in mice and the addition of CFZ to oral BDQ may improve the efficacy of BDQ. BDQ-LA IM was similar or less active than oral BDQ at equivalent dosing and frequency but should be tested at higher dosing in order to reach equivalent exposure in further experiments. |
