Randomised Trial to Compare Clarithromycin (Extended Release)-Rifampicin and Streptomycin-Rifampicin for Early, Limited Lesions of  &lt;i&gt;M. Ulcerans&lt;/i&gt; Infection

Phillips, Richard Odame; Robert, Jérôme; Abass, Kabiru Mohamed; Thompson, W. A.

doi:10.2139/ssrn.3458507

Cited by 2 publications

(3 citation statements)

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“…As a result, there has been a recent increase in BU cases in several areas, including Australia and Nigeria (4,5). However, timeliness of therapeutic intervention can help to decrease the severity of the disease, since early stages of BU can be treated with antibiotics, but advanced stages require surgery and antibiotic therapy in a hospital (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Serum lipoproteins and lipoarabinomannan suppress the inflammatory response induced by the mycolactone toxin

Jakhar¹,

Lenz²,

Jacobsen³

et al. 2022

Preprint

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Mycobacterium ulcerans is the causative agent of the chronic and debilitating neglected tropical disease Buruli ulcer (BU) that mostly affects children. The early detection and treatment of M. ulcerans infections can significantly minimize life-long disability resulting from surgical intervention. However, the disease is characterized by relatively few systemic symptoms due to complex host-pathogen interactions that have yet to be fully characterized, which has limited the development of both diagnostic and therapeutic approaches to treat BU. In this work, we study the interactions of the host immune system with two principle M. ulcerans virulence factors: mycolactone, an amphiphilic macrolide toxin, and lipoarabinomannan (LAM), a cell wall component of most mycobacterial pathogens. We observe that human lipoproteins have a profound effect on the interaction of both mycolactone and LAM with the immune system. Individually, both molecules are pro-inflammatory in the absence of serum and immunosuppressive in the presence of serum. When combined, mycolactone and LAM are immunosuppressive regardless of serum conditions. We also show that Toll-like receptor 2 (TLR2), a macrophage pathogen pattern recognition receptor, is critical for LAM immune stimulation but aids in mycolactone immunosuppression. These findings are a critical step towards unraveling mycolactone-mediated immunosuppression during BU disease and may facilitate the development of effective diagnostics and therapeutics in the future.

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Section: Introductionmentioning

confidence: 99%

Serum lipoproteins and lipoarabinomannan suppress the inflammatory response induced by the mycolactone toxin

Jakhar¹,

Lenz²,

Jacobsen³

et al. 2022

Preprint

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“…The neglected tropical disease Buruli ulcer (BU), which is caused by Mycobacterium ulcerans and which primarily causes skin and soft tissue lesions, is treated following WHO guidelines by a combination of 10 mg/kg rifampin (RIF, R) and 15-30 mg/kg clarithromycin (CLR, C) daily for 8 weeks, a long and burdensome treatment for the patients (1)(2)(3)(4)(5). This newer regimen, compared to the earlier regimen of RIF in combination with 15 mg/kg streptomycin (STR) daily for 8 weeks, avoids the risk of oto-and nephrotoxicity as well as the need for daily injections for 56 days.…”

Section: Introductionmentioning

confidence: 99%

“…Nonetheless, the RIF+CLR treatment has disadvantages, such as frequent gastrointestinal intolerance, reduced CLR exposure due to a drug-drug interaction with RIF (6-9), and no reduction in the treatment duration of 8 weeks. Accordingly, even though RIF+CLR is a clinically proven effective therapy for BU (4,5), the search for a shorter oral treatment for BU is a priority for improved control of BU.…”

Section: Introductionmentioning

confidence: 99%

Ultrashort treatment with telacebec alone and with companion drugs in immunocompetent and immunosuppressed mouse footpad models of Buruli ulcer

Almeida

et al. 2021

Preprint

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The antimicrobial treatment of Mycobacterium ulcerans infection, or Buruli ulcer (BU), has a long duration and is therefore burdensome and linked to indirect costs for affected patients. The new antimycobacterial drug telacebec (Q203) has previously shown promising treatment-shortening potential in mouse models of BU. In the present study, we investigated the potential of Q203 to reduce the treatment duration further. The first experiment investigated the possibility of cure by one, three or five doses of Q203 (2 mg/kg) with or without a companion drug (bedaquiline, BDQ, clofazimine, CFZ, or clarithromycin, CLR) in immunocompetent BALB/c mice. The second experiment assessed the effect of five doses of Q203 with or without BDQ or CFZ on Mycobacterium ulcerans infection of immunocompromised SCID-beige mice with the aim to evaluate the contribution of host immunity to treatment efficacy. In BALB/c mice, a treatment duration as short as 3 days was sufficient to prevent relapse in nearly all footpads and a single dose of Q203 with or without BDQ or CFZ prevented relapse in approximately 50% of footpads. Unlike in BALB/c mice, a small percentage of SCID-beige mouse footpads were culture-positive after a treatment duration of five days, highlighting an important role of host immunity for M. ulcerans clearance. Our results confirm the marked potency and prolonged bactericidal and sterilizing effects of Q203, even in immunocompromised SCID-beige mice.

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Randomised Trial to Compare Clarithromycin (Extended Release)-Rifampicin and Streptomycin-Rifampicin for Early, Limited Lesions of <i>M. Ulcerans</i> Infection

Cited by 2 publications

References 0 publications

Serum lipoproteins and lipoarabinomannan suppress the inflammatory response induced by the mycolactone toxin

Serum lipoproteins and lipoarabinomannan suppress the inflammatory response induced by the mycolactone toxin

Ultrashort treatment with telacebec alone and with companion drugs in immunocompetent and immunosuppressed mouse footpad models of Buruli ulcer

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