University of Groningen
Improving antimicrobial therapy for Buruli ulcer
Omansen, Till Frederik
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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 11
discussion and Future perspectives
The future of Buruli ulcer treatment
Manuscript in preparation.
Till F. Omansen1,2, Ymkje Stienstra2, Eric Nuermberger3, Tjip van der Werf2,4
1 Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine and
I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
2 Infectious Diseases Unit, Department of Internal Medicine, University of Groningen,
Groningen, The Netherlands
3 Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University,
Baltimore, Maryland, USA
4 Department of Pulmonary Diseases and Tuberculosis, University of Groningen,
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The treatment of Buruli ulcer (BU), a neglected tropical disease (NTD), has come a long way from primarily surgical care with terrible sequelae, scarring and relapse (1-3) to primarily antimicrobial therapy (4). Current WHO-recommended (5) antimicrobial regimens consist-ing of rifampin (RIF) plus either streptomycin (STR) or clarithromycin (CLR) achieve high cure rates as 8-week regimens (6-8) and patients with small lesions report good quality of life after healing (9). However, lesions vary greatly in size and in form. BU may present as ul-cerative, nodular, oedematous or plaque forms (10). Albeit mostly singular, BU lesions vary greatly in size and are defined by cross-sectional diameter. WHO category I <5cm, category II 5-15cm and category III >15cm, or any lesion on critical locations (e.g. eye, genitalia) or presence of multiple lesions (7). Preliminary results of a study (ClinicalTrials.gov Identifier: NCT01659437) investigating 8 weeks of RIF+CLR showed non-inferiority to the RIF+STR regi-men and spark the hope for soon fully replacing the oto- and nephrotoxic (11) injectable and providing all-oral 8-week therapy.
Despite these advances, further improvement of BU therapy is needed; development of efficient and oral treatment is currently the top BU research priority at WHO, besides unrav-elling the transmission mode and the development of a rapid diagnostic test (5).
Three research items should to be addressed concerning BU therapy: a) the dosing and pharmacokinetics of the current RIF+CLR regimen should be further explored and optimized, b) the treatment duration should be shortened and stratified to lesion category and c) new anti-mycobacterial agents should be evaluated for future shorter-course therapy with quick time to healing of BU lesions.
The current dosage of RIF is based on out-dated arguments about cost-effectiveness and side effects. High-dose RIF is safe in humans (12) and renders BU lesions in mice culture-negative in 4 weeks (13). The widespread availability of the drug and the ease to “double the dose and half the duration” are enticing. Nonetheless, a careful clinical study should evaluate the efficacy in BU patients and pay attention to paradoxical reactions which could arise during rapid killing of bacilli, however were not observed in mice (14). Concerning the macrolide companion, bi-directional drug-drug interactions between RIF and CLR have been noticed (15). Other macrolides such as azithromycin (AZI) (Omansen et al, in prepara-tion) or modern oxazolidinones like sutezolid or tedizolid (16) could be a better option. A recently emerged concept in the related M. tuberculosis infection is that the granulomatous lesion-microenvironment greatly affects local drug penetration and pharmacokinetics (17). Further pre-clinical research is needed to assess the lesion pharmacokinetics of drugs used to treat BU.
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In 2017, despite efforts to promote earlier diagnosis, still 31% of lesions were category III (Chapter 2). However, there are no studies or recommendations on the treatment of large lesions. Albeit it is free of charge in most countries, the long duration of BU treatment causes indirect costs for patients (18) and exposes them to potentially unnecessary side effects. In summary, “a one size fits all” approach for BU antimicrobial therapy should perhaps be reconsidered. Clinical research should evaluate treatment stratified by lesion category, ad-ministering a shorter-course regimen for WHO category I-II e.g. with high dose RIF (13) and either a macrolide companion (AZI, CLR) or another drug such as an oxazolidinone (Almeida et al, in press). Follow-up of patients who defaulted from antimicrobial therapy revealed healing with sub-8-week treatment duration with regular RIF doses, further supporting the case for shorter-course therapy (19). Management of category III lesions in contrast, should be intensified by paying special attention to wound care, physiotherapy to prevent sequelae and psychosocial counselling for stigma prevention. Clofazimine (CFZ) is an off-patent drug that is mycobacteriocidal and has been shown to have good efficacy in experimental M.
ulcerans mouse studies (20). Its availability is expected to increase as a result of its new
place in shorter-course regimen for multidrug-resistant tuberculosis recently recommended by WHO. CFZ could be administered in addition to the abovementioned two drugs. A total duration of 6-8 weeks seems necessary considering the fact that the lesions may sometimes be extensive (Table 1). All abovementioned suggestions can be implemented rather easily and rapidly as all stated drugs are marketed, well-known and available, with the exception of the newer oxazolidinones.
Research for new anti-mycobacterial agents, especially for the treatment of M. tuberculosis infection has produced several compounds that could be applied for the therapy of BU in the future, specifically Q203, bedaquiline (BDQ), its newer analogues 587 and TBAJ-876, and an injectable long-acting formulation of BDQ (LA-BDQ). Q203 is an inhibitor of the cytochrome bc1 complex (specifically, the QcrB component), a 4-gene complex in the mycobacterial electron transport chain responsible for oxidative phosphorylation (21). M.
tuberculosis is able to circumvent this mechanism by changing to a different metabolism,
namely the use of bd oxidase; in M. ulcerans genes encoding for the bd oxidase are non-functional pseudogenes. The MIC of Q203 against M. ulcerans is 0.000078-0.00015 μg/ml (22) and the compound has been shown to be highly bactericidal against M. ulcerans in mice using monotherapy (23); combination regimens e.g. with high-dose rifampin or other drugs prove to be very efficient (24). The rapid microbiological killing of M. ulcerans by Q203 is only surpassed by its rapid reduction of lesion swelling, possibly owing to secondary anti-inflammatory properties of the compound (21,24). BDQ is an inhibitor of the mycobacterial ATP synthase employed in the therapy of tuberculosis (25). BDQ is also highly active against
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M. ulcerans with an MIC of 0.06-0.125 µg/ml (22), comparable to its MIC against M. tuber-culosis. The newer BDQ analogues TBAJ-587 and TBAJ-876 exhibit the 4-8x greater potency
compared to BDQ against M. tuberculosis and are thus of interest for further exploration in BU, too. In an effort to develop short and efficient BU therapy options we are currently testing the use of both oral and LAI-BDQ. LAI-BDQ is a slow-release, i.m. injectable formu-lation. Antibacterial activity could still be observed 12 weeks after a single injection in a mouse model of latent tuberculosis infection (26). Contemplation of shorter-course, highly efficient BU therapy comes with the realization that mycobacterial killing alone does not heal an ulcer instantaneously; culture-negativity is a success from a microbiological view-point but adequate healing without stigmatizing scarring and impairment of locomotion (27) must be the primary endpoint of BU therapy. Perhaps, the use of anti-inflammatory agents as adjuvants can be considered, so lesion healing can be matched by bacterial kill-ing. Although macrolides have been shown to exhibit immunomodulatory effects (28), no differences in sequelae could be detected in an earlier randomized study (7); that study was obviously not designed or powered to detect such immunomodulatory effects. Adjunct anti-inflammatory therapy is considered in M. tuberculosis infection (ClinicalTrials.gov Identifier: NCT03160638). Although some authors have argued in favour of corticosteroids to treat the paradoxical inflammatory response in BU (29), the natural course of these paradoxical responses is usually benign and self-limiting (30).
Lastly, efficient antimicrobial therapy must be accompanied by adequate non-medical treat-ment, such as physiotherapy to prevent sequelae, psychosocial counselling to reduce the burden of stigma, especially for cases with large lesions or lesions in visible critical locations, such as the face, as well as by efficient pain management (31). Integration of the care for BU with other NTDs will offer opportunities for joint engagement of skin NTDs (32,33).
Even though surgery has been shown to be unnecessary in many cases of BU (34), which we hypothesize will be even more so with the advent of new highly active drugs, it should not be neglected but, rather, carefully used in complicated and very advanced cases.
M. ulcerans is an environmental pathogen with an unknown niche and supposedly multiple
transmission pathways (10); the changing epidemiology of BU obeys unknown environmen-tal drivers (35). It is paramount to thus realise that BU will likely never be eradicated, yet it can be controlled well. Fast, reliable and efficient antimicrobial therapy is a key element for efficient disease control in BU and research should focus on improving it. Drug development is a costly process and it is difficult to gain funding for NTD research. Clinical trials for BU are further complicated by the declining global burden of BU and its occurrence in isolated
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foci, even though local epidemics arise such as in Australia (Chapter 2). International col-laboration between researchers and clinicians, coordination and support through WHO, as well as engagement of NGOs and industry partners will be indispensable to translate the promising aforementioned pre-clinical findings into the clinical setting to form the future of Buruli ulcer treatment.
Table 1: Suggested future treatment algorithm for Buruli ulcer; therapy stratified by lesion category with high-dose
rifampin plus either macrolide or oxazolidinone for category I-II and for category III lesions addition of clofazimine. Overview of potential drug candidates worthy of further clinical investigation for Buruli ulcer treatment. RIF, ri-fampin, CFZ, clofazimine, BDQ, Bedaquiline.
lesion category antimicrobial therapy non-medical treatment WhO I – II 2-4 weeks
High-dose RIF + macrolide/ oxazolidinone
Wound care Pain management Physiotherapy as needed
WhO III 8 weeks
High-dose RIF + macrolide/ oxazolidinone + CFZ
Advanced wound care Pain management
Surgery if necessary Intensified Physiotherapy Psychosocial counselling
Future drug candidates
Q203 Cytochrome bc1 inhibitor, MIC 0.000078-0.00015 µg/ml
BdQ and analogues Diarylquinolines, BDQ MIC 0.06-0.125 µg/ml, newer analogues have 4-8x more potent activity
long-acting injectable BdQ One-time i.m. injections offer up to 12 weeks slow release and antibacterial activity
149 Discussion and Future Perspectives
Ch ap te r 1 1 reFerenCes
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