Buruli ulcer: cured by 8 weeks of oral antibiotics?

In 1998, at a special WHO conference on Buruli ulcer held in Yamoussoukro, Côte d’Ivoire, delegates and heads of state of affected countries recognised Buruli ulcer as a damaging disease about which little was known. Importantly, there seemed to be no reliable chemotherapy, leaving wide excisional surgery and grafting as the only effective treatment.1WHODepartment of Disease ControlPrevention and EradicationBuruli ulcer: management of Mycobacterium ulcerans disease: a manual for health care providers. World Health Organization, Geneva2001https://www.who.int/buruli/resources/who_cds_cpe_gbui_2001.3/en/Date accessed: February 15, 2020Google Scholar Buruli ulcer is caused by Mycobacterium ulcerans—an environmental pathogen with a unique virulence determinant—a potent locally acting toxin. Clinically, Buruli ulcer is a destructive infection of the skin and soft tissue, which can result in severe tissue destruction followed by scarring and contracture. It affects healthy people of all ages, but in Africa mostly children and adolescents because of the young population. Although recorded in 33 countries, Buruli ulcer is of particular concern in certain regions of Africa and Australia.2Omansen TF Erbowor-Becksen A Yotsu R et al.Global epidemiology of Buruli ulcer, 2010–2017, and analysis of 2014 WHO programmatic targets.Emerg Infect Dis. 2019; 25: 2183-2190Crossref PubMed Scopus (10) Google Scholar In The Lancet, Richard Phillips and colleagues3Phillips RO Robert J Abass KM et al.Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trial.Lancet. 2020; (published online March 12.)https://doi.org/10.1016/S0140-6736(20)30047-7Summary Full Text Full Text PDF Scopus (22) Google Scholar report an open-label, non-inferiority, phase 3 randomised trial, which is the culmination of a journey WHO began in 1998. The trial compared the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with the WHO provisionally recommended standard of oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8). 297 people with PCR-confirmed Buruli lesions (≤10 cm in diameter) in Ghana and Benin were randomly assigned; median age was 14 years (IQR 10–29) and 153 (52%) participants were female. The primary endpoint was lesion healing without recurrence at 52 weeks. In the RS8 group, the primary endpoint was met in 144 (95%, 95% CI 91–98) of 151 participants compared with 140 (96%, 91–99) of 146 in the RC8 group, establishing non-inferiority of the newer fully oral regimen. Surgery was not required for cure and only four patients (two in each study group) required skin grafts to repair defects. Both regimens were generally well tolerated, but RS8 was associated with eight cases of otovestibular toxicity compared with only one case in the RC8 group. No residual functional limitation was seen in either group at 52 weeks. The headline finding of the trial is clear and promising: Buruli ulcer was curable with an 8-week course of oral antibiotics and surgery was not required in these patients. So how did this radical change in treatment approach come about? M ulcerans is related to Mycobacterium marinum, Mycobacterium tuberculosis, and Mycobacterium leprae, which are all susceptible to antimycobacterial antibiotics, so it was curious that M ulcerans appeared not to be, at least in early field studies.4Espey DK Djomand G Diomande I et al.A pilot study of treatment of Buruli ulcer with rifampin and dapsone.Int J Infect Dis. 2002; 6: 60-65Summary Full Text PDF PubMed Scopus (41) Google Scholar Part of the reason for this perception might have been paradoxical worsening of the appearance of lesions during treatment.5O’Brien DP Robson ME Callan PP McDonald AH “Paradoxical” immune-mediated reactions to Mycobacterium ulcerans during antibiotic treatment: a result of treatment success, not failure.Med J Aust. 2009; 191: 564-566Crossref PubMed Scopus (75) Google Scholar, 6Nienhuis WA Stienstra Y Abass KM et al.Paradoxical responses after start of antimicrobial treatment in Mycobacterium ulcerans infection.Clin Infect Dis. 2012; 54: 519-526Crossref PubMed Scopus (69) Google Scholar However, a key pilot study sponsored by WHO in a small group of people in Ghana with early Buruli lesions7Etuaful S Carbonnelle B Grosset J et al.Efficacy of the combination rifampin-streptomycin in preventing growth of Mycobacterium ulcerans in early lesions of Buruli ulcer in humans.Antimicrob Agents Chemother. 2005; 49: 3182-3186Crossref PubMed Scopus (179) Google Scholar showed that rifampicin and streptomycin could microbiologically sterilise early Buruli lesions, leading to provisional WHO advice for the medical management of Buruli ulcer.8WHORole of specific antibiotics in Mycobacterium ulcerans (Buruli ulcer) management provisional guidelines. 2004.https://www.who.int/buruli/information/antibiotics/en/Date accessed: February 15, 2020Google Scholar Experience built confidence in this regimen9Chauty A Ardant MF Adeye A et al.Promising clinical efficacy of streptomycin-rifampin combination for treatment of buruli ulcer (Mycobacterium ulcerans disease).Antimicrob Agents Chemother. 2007; 51: 4029-4035Crossref PubMed Scopus (161) Google Scholar and some centres in Africa also reported promising results when oral rifampicin was combined with oral clarithromycin, sometimes without any surgery being required.10Chauty A Ardant MF Marsollier L et al.Oral treatment for Mycobacterium ulcerans infection: results from a pilot study in Benin.Clin Infect Dis. 2011; 52: 94-96Crossref PubMed Scopus (70) Google Scholar In Australia, intramuscular streptomycin was not used, but it became apparent that rifampicin-based fully oral regimens reduced relapse after surgery11O’Brien DP McDonald A Callan P et al.Successful outcomes with oral fluoroquinolones combined with rifampicin in the treatment of Mycobacterium ulcerans: an observational cohort study.PLoS Negl Trop Dis. 2012; 6e1473Crossref PubMed Scopus (46) Google Scholar, 12Jenkin GA Smith M Fairley M Johnson PD Acute, oedematous Mycobacterium ulcerans infection in a farmer from far north Queensland.Med J Aust. 2002; 176: 180-181Crossref PubMed Scopus (30) Google Scholar and could often replace surgery as definitive treatment.13Friedman ND Athan E Hughes AJ et al.Mycobacterium ulcerans disease: experience with primary oral medical therapy in an Australian cohort.PLoS Negl Trop Dis. 2013; 7e2315Crossref PubMed Scopus (31) Google Scholar, 14Gordon CL Buntine JA Hayman JA et al.All-oral antibiotic treatment for Buruli ulcer: a report of four patients.PLoS Negl Trop Dis. 2010; 4e770Crossref PubMed Scopus (35) Google Scholar Now, Phillips and colleagues have shown that rifampicin combined with clarithromycin is non-inferior to RS8, and is safer. 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. Healing of Buruli lesions is a slow process. 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.15Wadagni AC Barogui YT Johnson RC et al.Delayed versus standard assessment for excision surgery in patients with Buruli ulcer in Benin: a randomised controlled trial.Lancet Infect Dis. 2018; 18: 650-656Summary Full Text Full Text PDF PubMed Scopus (20) Google Scholar However, we now know that we can trust oral antibiotics for Buruli ulcer, even if this might not be clinically apparent at 8 weeks. One of the limitations of the study is that the study did not enrol the originally planned number of participants because of slow recruitment, reflecting a general reduction in the incidence of Buruli ulcer in west Africa for reasons that are not clear. Questions remain as to whether we need 8 weeks of treatment or if 4–6 weeks might be sufficient in some cases, whether steroids could reduce inflammatory reactions and improve outcomes, and whether 2 weeks of some of the new antimycobacterial agents in development could suffice.16Converse PJ Almeida DV Tyagi S Xu J Nuermberger EL Shortening Buruli ulcer treatment with combination therapy targeting the respiratory chain and exploiting Mycobacterium ulcerans gene decay.Antimicrob Agents Chemother. 2019; 63: e00426-e00519Crossref PubMed Scopus (16) Google Scholar The change in incidence in time and place of Buruli ulcer makes it hard to study and it is a tribute to all involved in this trial that they saw it through, providing clinicians with the key evidence needed to assist people with Buruli ulcer to resume their lives and to put the disease behind them. I declare no competing interests. Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions: a randomised, open-label, non-inferiority phase 3 trialFully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer. Full-Text PDF Open Access