Principal Investigator (PI)
Research and Development Agency of Aragon (ARAID) Foundation, Spain
The Foundation is providing £507,601 in support.
Emma Saiz
GSK provides:
1) in-kind scientific.
2) statistical support in the development and delivery of the project; dependent on the needs identified by the investigators and the available GSK expertise.
Buruli ulcer (BU) is a chronic debilitating skin and soft tissue mycobacterial infection that without treatment frequently progresses to massive ulceration. The greatest burden falls on children under the age of 15 years in sub-Saharan Africa. This neglected tropical disease generally affects poor communities in remote rural areas with limited access to health services. Although mortality is low, permanent disfigurement and disability are high, affecting up to 25% of the cases. Before 2004, surgical excision and skin grafting remained the mainstay of BU treatment until clinical evidence showed the effectiveness of rifampicin-streptomycin; however, serious adverse events associated to the injectable streptomycin and the lack of an efficacious oral treatment remained one of the main obstacles to decentralizing care in rural areas.
Today, WHO recommends an 8-week full oral daily combination therapy of rifampicin-clarithromycin; however, access to medicines is difficult, and the need of hospitalization for treatment impacts household's income and compromises patients' adherence to the 8-weeks antibiotic course. A shortened, highly effective, all-oral regimen based on already approved drugs is urgently needed to improve care for this neglected tropical disease by reducing both duration of treatment and time to healing for all type of lesions after therapy completion; this would in addition reduce indirect costs and barriers to access therapy.
Similar to Tuberculosis (TB), rifampicin is the cornerstone drug for BU therapy, showing a direct relation between dose increase and therapy efficacy due to its bactericidal and sterilizing activity. High-dose rifampicin studies suggested that BU treatment could be shortened if rifampicin dose was increased. However, this approach raises concerns due to high-dose rifampicin-related hepatotoxicity and public health implementation. It would be then desirable to maintain current dose and potentiate the activity of rifampicin avoiding its side effects. In addition, TB chemotherapy teaches us that combination therapy is critical for optimal cure outcomes and treatment shortening, suggesting that at least a three-drug regimen might be needed to improve and shorten BU treatment. In fact, synergistic partners could improve rifampicin efficacy without compromising tolerability and toxicity. Beta-lactams are one of the largest groups of antibiotics with an exceptional record of clinical safety.
Recent studies from partners of this Clinical Study Protocol (CSP) provided evidence of their anti-mycobacterial clinical potential, opening a new avenue to optimize current BU therapy. We thus took advantage of knowledge gathered in TB Research and Development (R&D) repurposing programs and showed in in vitro preclinical studies that beta-lactams strongly increased the activity of rifampicin and clarithromycin against Mycobacterium ulcerans (Mul). We further confirmed these observations by time-kill kinetics. Among all beta-lactams, we focused on amoxicillin/clavulanate: oral, suitable for the treatment of children, pregnant women and adults and with a long track record of clinical pedigree. First launched in the UK in 1981, today it is clinically available in various formulations in over 150 countries around the world. The addition of amoxicillin/clavulanate to current WHO recommended therapy could contribute to treatment shortening in several ways:
The median time to healing is directly proportional to the bacterial load in BU lesions at the beginning of therapy. Typically, healing occurs within 25 weeks from the start of treatment but for some BU patients this can take up to one year. One of the reasons for this slow healing could be a high initial bacterial load, since bacteria have been found in slowly healing lesions despite the recommended 8- week antibiotic therapy. Despite antibiotic efficacy, the most common treatment complication of BU patients in Africa is paradoxical reaction, a phenomenon observed following an initial period of clinical improvement characterized by worsening of existing lesion(s) and occurrence of new ones during or after antibiotic therapy due to unspecific immune responses. Importantly, fast bacterial clearance reduces the rate of paradoxical responses. Due to its rapid bactericidal activity, amoxicillin/clavulanate would be extremely effective at targeting extracellular bacteria; thus, reducing initial bacterial burden, paradoxical responses, local levels of the immune-suppressive mycolactone toxin, and allowing recovery of the host immune response to clear remaining bacteria. What is more, in vitro studies have demonstrated the sterilizing activity of synergistic combinations of beta-lactams and rifampicin, these could target the remaining persistent populations having a positive impact in treatment and healing periods.
In this study, we propose the combination of amoxicillin/clavulanate with current oral BU therapy, rifampicin and clarithromycin as a new anti-BU treatment with the potential of treatment shortening and readily implementation in the field.