Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer

Abstract

ClinicalTrials.gov NCT03474198, NCT01659437.

Fig 1. Response to treatment in M. ulcerans-infected mice treated with rifampin or rifapentine monotherapy at different doses or with standard-of-care regimens or regimens combining high-dose rifamycins with clofazimine.

Mice were infected with M. ulcerans 1059AL. After 5 weeks the swelling grade was nearly 2 on a scale of 0–4 before treatment initiation (D0) with RIF monotherapy at the dose of 10 mg/kg (RIF₁₀, open light red squares, dashed lines). Control mice were left untreated (x). Control combination regimens were RIF₁₀ plus STR (150 mg/kg, green solid squares), CLR (100 mg/kg, blue solid circles), or CFZ (25 mg/kg, orange solid triangles). High-dose rifamycin monotherapy regimens included: RIF at 20 mg/kg (RIF₂₀, open red square, dotted line) or 40 mg/kg (RIF₄₀ open red square, solid line), or rifapentine at 10 mg/kg (RPT₁₀, open light blue diamond, dashed line) or 20 mg/kg (RPT₂₀, open purple diamond, solid line). Test combination regimens included CFZ (12.5 mg/kg) combined with RIF₁₀ (solid light red square, dashed line), RIF₂₀ (solid red square, dotted line), RIF₄₀ (solid red square, solid line), RPT₁₀ (solid light blue diamond, dashed line), or RPT₂₀ (solid purple diamond, solid line). Mice were assessed over the next 4–6 weeks for footpad swelling (A, E, H), mycolactone concentration in footpads (B, I), bacterial burden in terms of colony forming units, CFU (C, F, J), or relative light units, RLU, in footpad homogenates (D, G, K).

Fig 2. Relapse assessment in mice three months after completion of treatment with a combination regimen for four weeks (A) or six weeks (B).

After treatment with one of the control or test combination regimens depicted in Fig 1, both footpads of up to 10 mice per group were assessed for bacterial burden. (RIF+STR, green solid squares), (RIF+CLR, solid blue circles), (RIF+CFZ₂₅, solid orange triangles), (RIF₁₀+CFZ₁₂, open orange triangles), (RIF₂₀+CFZ₁₂, open red squares), (RIF₄₀+CFZ₁₂, solid red squares), (RPT₁₀+CFZ₁₂, light blue diamonds), (RPT₂₀+CFZ₁₂, purple diamonds). Relapse proportions are indicated above each treatment group. Because gavage accidents resulted in loss of 1 mouse in the RIF₁₀+CFZ₂₅, and 2 mice each in the RIF₂₀+CFZ_12.5 and RIF₄₀+CFZ_12.5 groups, these mice were lost to relapse evaluation.