University of Groningen
Improving antimicrobial therapy for Buruli ulcer
Omansen, Till Frederik
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Publication date: 2019
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Omansen, T. F. (2019). Improving antimicrobial therapy for Buruli ulcer: Pre-clinical studies towards highly efficient, short-course therapy. University of Groningen.
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Chapter 3
Treatment for Buruli ulcer: the long and
winding road to antimicrobials-first
Cochrane Database Syst Rev. 2018 Dec 17;12:ED000128.
Till F. Omansen1, Ymkje Stienstra1, Tjip S. van der Werf1,2
1 Infectious Diseases Unit, Department of Internal Medicine, University of Groningen,
Groningen, The Netherlands
2 Department of Pulmonary Diseases and Tuberculosis, University of Groningen,
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Treatment for Buruli ulcer: the long and winding road to antimicrobials-first
TreaTMenT FOr BurulI ulCer: The lOng and WIndIng rOad TO anTIMICrOBIals-FIrsT
Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans that affects mainly children under the age of 15 in sub Saharan Africa and people of any age in Australia (1). The infection manifests as skin nodule, edematous lesion, plaque or ulcer. Lesions are categorized by cross-sectional diameter, category I, less than 5 cm; category II, 5–15 cm; category III, more than 15 cm, or disseminated disease. Although transmission of Buruli ulcer is not entirely understood, different insects, aquatic and mosquitoes, have been linked to disease transmission depending on the settings. It is clear, however, that puncturing injury and introduction of the environmental pathogen into the skin causes disease (2). If the bacteria are actually thriving within a vector before they are transmitted (biological transmission) or if they are merely transported and injected by them (mechanical transmis-sion) is yet to be elucidated. The presence of M. ulcerans on the host skin and introduction e.g. following insect bite or minor trauma is another hypothesis.
The pathogenesis in Buruli ulcer is mediated by a large plasmid, that encodes the toxin mycolactone. Mycolactone not only causes extensive tissue damage, but also profoundly impairs the host immune response and tissue repair (3). Despite several research efforts, there is no vaccine available for Buruli ulcer. The main management of Buruli ulcer now is chemotherapy and wound care. Surgery is performed on some lesions depending on the ex-tent of the disease and the local practice. Yotsu et al. included and discussed 5 randomized controlled trials, as well as 13 prospective observational studies in their systematic review on drug to treat Buruli ulcer (4). The treatment for Buruli ulcer has made an enormous shift over the past two decades. Prior to chemotherapy, wide surgical resection was the mainstay of treatment. Large resection areas resulted in extensive scarring, causing social stigma and disability (5). Failure and relapse following surgery alone were considerable - reportedly between 6-47% (6) and were probably caused by presence of bacteria outside of the usual wide resection margin. In vitro and animal experiments (7) suggested however that several antimicrobial agents are active against M. ulcerans - rifamycins, aminoglycosides, macrolides and fluoroquinolones. The first proof-of-principle landmark study in human Buruli ulcer pa-tients showed, that a combination regimen of streptomycin and rifampicin administered for at least 4 weeks resulted in a sterilizing effect in patients with small lesions (8). Subsequent studies evaluated drug treatment for 8 weeks without surgery in patients with early, limited (WHO category I-II) lesions. Healing in Buruli ulcer is a long process only initiated upon reduction to a critically low lesion bacterial load and subsequent declining mycolactone levels. This allows for re-institution of local host immunity. In fact, this re-institution can lead
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to a local, transient hyper-inflammatory response that worsens the clinical aspect of the lesion, called paradoxical reaction (9). The delayed healing following antimicrobial therapy of Buruli ulcer is believed to have led to an underappreciation of the value of antimicrobial in Buruli ulcer management in earlier clinical practice or treatment, when knowledge of Buruli ulcer pathology was limited. As our understanding of the unique pathobiology and the role of mycolactone in M. ulcerans infection improved, slow healing after completion of antimicrobial therapy was not seen as failure and it was appreciated that the vast majority of such lesions are actually free of bacteria and proceed to heal within several weeks. Mi-crobiological outcomes, such as reduction or absence of viable bacteria in lesions were thus favored over clinical healing assessed during treatment or early afterwards in the design of future studies (10,11).
As a next step, the use of primarily oral therapeutics was evaluated compared to the use of injectable antibiotics. Oral therapy is fundamentally important for a disease like Buruli ulcer that mostly occurs in rural areas. It enables outpatient management, is more practical and less traumatizing than daily injections, especially for children. Streptomycin, the most widely used injectable, also caused toxicity (12). A first randomized controlled trial evalu-ated a regimen with rifampin, where the companion drug, streptomycin, was switched to clarithromycin after four of the eight total weeks of treatment (10). Following the favorable outcome of that study, a next study assessed fully-oral, eight-week rifampin and clarithro-mycin treatment over the entire 8-week duration the treatment. The results and analysis are currently pending (ClinicalTrials.gov Identifier: NCT01659437). Circumstantial evidence from observational studies however suggests, that fully oral treatment is highly effective (13,14).
The systematic review by Yotsu et al (4) is the first of its kind to formally assess the available evidence for drug treatment of Buruli ulcer. The advantage of this formal evaluation of all peer-reviewed, published literature is, that the many flaws in methodology are highlighted and suggestions for future, improved BU drug trials are made. Despite the great success of antimicrobial therapy for Buruli ulcer, mitigated by the advancing understanding of Buruli ulcer pathobiology, many questions on the treatment of this condition remain unanswered. As Yotsu et al. point out, most studies enrolled patients with limited, WHO category I-II lesions only. Also there are currently no specific recommendations on how to treat Buruli ul-cer lesions of different sizes (4). Further studies should aim at stratifying patients by disease extent treating small lesions with a short-course regimen, while addressing large lesions with an intensified, perhaps 3-drug regimen. This would help to achieve maximal efficacy
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and healing in large lesions, while reducing unnecessary long treatment for smaller lesions. Some patients who defaulted from the regular 8-week treatment and who could still be con-tacted for follow-up appeared to have healed despite incomplete treatment (15). Another important area of future study should be pharmacokinetics in Buruli ulcer chemotherapy. Substantial drug-drug interactions are noted in the rifampin-clarithromycin regimen (16). Also, Buruli ulcers are histologically complex, granulomatous lesions; in M. tuberculosis infection such structures are known to greatly affect drug tissue penetration and hence efficacy (17). The design of the different published studies, the majority being observational without comparator, precludes clear answers to these important questions. Recent labora-tory studies demonstrated the applicability of new, highly potent antibiotic drug regimens for the treatment of Buruli ulcer. Intermittent regimens e.g. containing rifapentine have been shown to sterilize lesions in mice (18); high-dose rifampin and rifapentine in combina-tion with clofazimine rendered lesions culture negative in only four weeks of continuous treatment (19). Perhaps another companion-drug than clarithromycin with its inherent drug-drug interaction with rifampicin deserves attention in future studies. Drug research for M. tuberculosis produced a repertoire of new, highly active anti-mycobacterial agents such as diarylquinolines and imidazopyridine amides, benzothiazinones, and oxazolidinones that could be repurposed and trialed for use in Buruli ulcer therapy in the future. Although most national programs now adhere to the WHO-recommended antimicrobial treatment, in some areas, the role of surgery has remained dominant. In a randomized study in Benin, standard-decisions about surgery around the end of week 8, at completion of antimicrobial treatment were compared to postponing that decision to week 14. Postponing the decision to perform surgery many times resulted in no surgery: it reduced the proportion of patients operated to 48%, versus 67% in the standard care group safeguarding patients from general risks associated with surgery and offering better overall outcomes in terms of time to heal-ing without affectheal-ing residual functional limitations(20).
The review by Yotsu et al. describes the past decades of Buruli ulcer clinical chemotherapy research. It provides an important clinical research agenda for the time to come; and it certainly helps clinicians to share current evidence with their patients for shared decision making. These studies represent the long and winding road from surgical to predominantly antimicrobial treatment. Maintaining high quality standards of clinical trial design, including auditing and monitoring is a moral imperative that should not be undermined by short-comings in resources directed to Neglected Tropical Diseases such as Buruli ulcer in future studies.
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lITeraTure
1. World Health Organization. Buruli ulcer. www.who.int/buruli (accessed 5 November 2018).
2. Wallace JR, Mangas KM, Porter JL, Marcsisin R, Pidot SJ, Howden BO, et al. Mycobacterium ulcerans low infectious dose and atypical mechanical transmission support insect bites and puncturing injuries in the spread of Buruli ulcer. bioRxiv. Cold Spring Harbor Labs Journals; 2016 Aug 27; : 071753.
3. Coutanceau E, Decalf J, Martino A, Babon A, Winter N, Cole ST, et al. Selective suppression of dendritic cell functions by Mycobacterium ulcerans toxin mycolactone. J Exp Med. 2007 Jun 11; 204(6): 1395–403. 4. Yotsu RR, Richardson M, Ishii N. Drugs for treating Buruli ulcer (Mycobacterium ulcerans disease). Cochrane
Infectious Diseases Group, editor. Cochrane Database Syst Rev. 2018 Aug 23; 8(4): CD012118.
5. Stienstra Y, van Roest MHG, van Wezel MJ, Wiersma IC, Hospers IC, Dijkstra PU, et al. Factors associated with functional limitations and subsequent employment or schooling in Buruli ulcer patients. Trop Med Int Health. 2005 Dec; 10(12): 1251–7.
6. Debacker M, Aguiar J, Steunou C, Zinsou C, Meyers WM, Portaels F. Buruli ulcer recurrence, Benin. Emerg-ing Infect Dis. 2005 Apr; 11(4): 584–9.
7. Dega H, Robert J, Bonnafous P, Jarlier V, Grosset J. Activities of several antimicrobials against Mycobacte-rium ulcerans infection in mice. Antimicrob Agents Chemother. American Society for Microbiology (ASM); 2000 Sep; 44(9): 2367–72.
8. Etuaful S, Carbonnelle B, Grosset J, Lucas S, Horsfield C, Phillips R, 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. American Society for Microbiology; 2005 Aug; 49(8): 3182–6. 9. Nienhuis WA, Stienstra Y, Abass KM, Tuah W, Thompson WA, Awuah PC, et al. Paradoxical responses after
start of antimicrobial treatment in Mycobacterium ulcerans infection. Clin Infect Dis. 2012 Feb 15; 54(4): 519–26.
10. Nienhuis WA, Stienstra Y, Thompson WA, Awuah PC, Abass KM, Tuah W, et al. Antimicrobial treatment for early, limited Mycobacterium ulcerans infection: a randomised controlled trial. Lancet. 2010 Feb 20; 375(9715): 664–72.
11. Sarfo FS, Phillips R, Asiedu K, Ampadu E, Bobi N, Adentwe E, et al. Clinical efficacy of combination of ri-fampin and streptomycin for treatment of Mycobacterium ulcerans disease. Antimicrob Agents Chemother. 2010 Sep; 54(9): 3678–85.
12. Klis S, Stienstra Y, Phillips RO, Abass KM, Tuah W, van der Werf TS. Long term streptomycin toxicity in the treatment of Buruli Ulcer: follow-up of participants in the BURULICO drug trial. Johnson C, editor. PLoS Negl Trop Dis. 2014 Mar; 8(3): e2739.
13. Friedman ND, Athan E, Walton AL, O’Brien DP. Increasing Experience with Primary Oral Medical Therapy for Mycobacterium ulcerans Disease in an Australian Cohort. Antimicrob Agents Chemother. 2016 May; 60(5): 2692–5.
14. Chauty A, Ardant M-F, Marsollier L, Pluschke G, Landier J, Adeye A, et al. Oral treatment for Mycobacterium ulcerans infection: results from a pilot study in Benin. Clin Infect Dis. 2011 Jan 1; 52(1): 94–6.
15. Klis S, Kingma RA, Tuah W, van der Werf TS, Stienstra Y. Clinical outcomes of Ghanaian Buruli ulcer patients who defaulted from antimicrobial therapy. Trop Med Int Health. 2016 Sep; 21(9): 1191–6.
16. Alffenaar JWC, Nienhuis WA, de Velde F, Zuur AT, Wessels AMA, Almeida D, et al. Pharmacokinetics of Rifampin and Clarithromycin in Patients Treated for Mycobacterium ulcerans Infection. Antimicrob Agents Chemother. American Society for Microbiology; 2010 Sep 1; 54(9): 3878–83.
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17. Prideaux B, Via LE, Zimmerman MD, Eum S, Sarathy J, O’Brien P, et al. The association between sterilizing activity and drug distribution into tuberculosis lesions. Nat Med. 2015 Oct; 21(10): 1223–7.
18. Chauffour A, Robert J, Veziris N, Aubry A, Jarlier V. Sterilizing Activity of Fully Oral Intermittent Regimens against Mycobacterium Ulcerans Infection in Mice. Small PLC, editor. PLoS Negl Trop Dis. Public Library of Science; 2016 Oct; 10(10): e0005066.
19. Converse PJ, Almeida DV, Tasneen R, Saini V, Tyagi S, Ammerman NC, et al. Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer. Small PLC, editor. PLoS Negl Trop Dis. 2018 Aug 13; 12(8): e0006728.
20. Wadagni AC, Barogui YT, Johnson RC, Sopoh GE, Affolabi D, van der Werf TS, et al. Delayed versus standard assessment for excision surgery in patients with Buruli ulcer in Benin: a randomised controlled trial. Lancet Infect Dis. 2018 Jun; 18(6): 650–6.
