Regimen non-inferior to standard IV treatment

For the treatment of early, limited Buruli ulcer, a fully oral regimen with rifampicin and clarithromycin is non-inferior to a regimen of oral rifampicin plus intramuscular streptomycin and was associated with fewer adverse events, according to results published in The Lancet.

“In rural African regions endemic for Buruli ulcer, access to health care is difficult; hospital-based care and injections impose physical and financial barriers. Fully oral treatment provides the opportunity of decentralized care with optimal chances of healing, and an excellent safety profile,” according to researchers, led by Richard O. Phillips, MD, PhD, of the Komfo Anokye Teaching Hospital, Kumasi, Ghana.

Caused by Mycobacterium ulcerans, Buruli ulcer is a tropical disease most prevalent in western and central Africa and Australia. Standard treatment is comprised of oral rifampicin plus intramuscular streptomycin, but although it is effectively, the streptomycin injections are painful and may cause harmful side effects.

Consequently, researchers sought to study the efficacy and safety of a fully oral formulation of rifampicin combined with extended-release clarithromycin as a potential alternative.

For this phase III, open-label, non-inferiority, randomized, multicenter study, Phillips and fellow researchers compared treatment with fully oral rifampin (10 mg/kg) plus clarithromycin (15 mg/kg; RC8) with oral rifampicin (10 mg/kg) plus intramuscular streptomycin (15 mg/kg; RS8), both given once daily for 8 weeks to patients with early, limited Buruli ulcer lesions. They included subjects aged 5 years or older with typical Buruli ulcer with no more than one category I or II lesion ≤ 10 cm.

Among the 310 participants (median age: 14 years; 52% female), 297 had PCR-confirmed Buruli ulcers. In all, 151 were randomized to treatment with RS8 and 146 to oral RC8. Most lesions (55%) were located on the lower limbs and were primarily ulcers (53%).

In patients treated with RS8, lesions healed in 95% (95% CI: 91-98), compared with 96% (95% CI: 91-99) in the oral RC8 group. Oral RC8 treatment was non-inferior to RS8 for lesion healing at 52 weeks, as demonstrated by the difference in proportion, −0.5% (95% CI: −5.2-4.2), which was not significantly greater than zero (P=0.59). The non-inferiority margin was 12%, and the upper limit of the 95% CI of the difference of 4.2%, showing non-inferiority.

Median time to healing was 24 weeks in the RS8 group, compared with 16 weeks in the oral RC8 group. No recurrences were seen, and treatment failure rates within 12 months were similar between the two groups. Treatment failure occurred in seven patients receiving RS8 and in six receiving oral RC8.

In the RS8 group, healing of category I lesions (less than 5 cm) took a median of 16 weeks (IQR: 6-28), compared with 13 weeks (IQR: 6-24) I the oral RC8 group. In the RS8 group, ulcers healed at a median of 20 weeks (IQR: 8-28) compared with 24 weeks (IQR: 6-25) for non-ulcerated lesions (P=0.31). In the oral RC8 group, these median healing rates were 12 weeks (IQR: 8-24) and 20 weeks (IQR: 8-25; P=0.60), respectively.

The number of participants who experienced hearing loss was similar in the RS8 and oral RC8 groups (2% vs 1%, respectively). Dizziness with or without accompanying imbalance or tinnitus occurred in 3% of participants in the RS8 group, and in none of the patients treated with oral RC8.

Most adverse events were grade 1 and 2, but one patient treated with RS8 developed serious ototoxicity and stopped treatment after 6 weeks. In all, 13% of patients treated with RS8 developed treatment-related adverse events, compared with 7% in the oral RC8 group. In each study group, two patient required skin grafts, but non needed surgical resection.

Limitations of the study include the inability of researchers to enroll the originally planned number of participants due to slow recruitment. Researchers were also unable to assess the efficacy of the oral RC8 regimen on Buruli ulcers that were larger than 10 cm because they were excluded.

“A fully oral treatment comprising rifampicin and clarithromycin is non-inferior to streptomycin–rifampicin in healing of early, limited Buruli ulcer lesions and is associated with a better safety profile. Fully oral rifampicin and clarithromycin can be provided as decentralized care and should be considered the new standard of care for patients with Buruli ulcer disease; patients with limited lesions given the treatment have an excellent chance of healing without additional surgery,” concluded Phillips and colleagues.

“This much anticipated trial provides us with a high degree of confidence that an 8-week course of oral rifampicin and clarithromycin should now be the cornerstone of the treatment of Buruli ulcer everywhere. However, this finding does not mean that Buruli ulcer is cured at 8 weeks,” wrote Paul D.R. Johnson, of Austin Health and the University of Melbourne, Melbourne, Australia, in an accompanying editorial.

The median times to healing were long and highlight the finding that although oral antibiotics are effective for Buruli ulcer, further care of infected patients is necessary.

“In the study by Phillips and colleagues, the median time to healing was 24 weeks (IQR 8–28) for RS8 and 16 weeks (IQR 8–25) for RC8. Practically, this result means that Buruli lesions are typically not healed at the completion of 8 weeks of antibiotics and it is important for clinicians to understand this. Frequent dressings, support, and reassurance, and, in selected cases, limited surgical debridement or grafting might still be needed. However, we now know that we can trust oral antibiotics for Buruli ulcer, even if this might not be clinically apparent at 8 weeks,” Johnson concluded.

  1. An oral regimen of rifampicin/clarithromycin is non-inferior to one of oral rifampicin/intramuscular streptomycin in the treatment of early Buruli ulcers.

  2. An oral regimen of rifampicin/clarithromycin was well tolerated in patients with Buruli ulcers and associated with fewer adverse events than a regimen of oral rifampicin/intramuscular streptomycin.

E.C. Meszaros, Contributing Writer, BreakingMED™

Phillips and Johnson declare no conflicts of interest.

This study was funded by the World Health Organization, MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac.

Cat ID: 190

Topic ID: 79,190,730,190,192,925