scholarly journals Clinical and Bacteriological Efficacy of Rifampin-Streptomycin Combination for Two Weeks followed by Rifampin and Clarithromycin for Six Weeks for Treatment of Mycobacterium ulcerans Disease

2013 ◽  
Vol 58 (2) ◽  
pp. 1161-1166 ◽  
Author(s):  
Richard O. Phillips ◽  
Fred S. Sarfo ◽  
Mohammed K. Abass ◽  
Justice Abotsi ◽  
Tuah Wilson ◽  
...  
Keyword(s):  
Bacterial Load ◽  
Buruli Ulcer ◽  
Positive Culture ◽  
Mycobacterium Ulcerans ◽  
Tissue Samples ◽  
Content Type ◽  
Western Africa ◽  
Apparent Loss ◽  
Before And After ◽  
Tropical Areas

ABSTRACTBuruli ulcer, an ulcerating skin disease caused byMycobacterium ulceransinfection, is common in tropical areas of western Africa. We determined the clinical and microbiological responses to administration of rifampin and streptomycin for 2 weeks followed by administration of rifampin and clarithromycin for 6 weeks in 43 patients with small laboratory-confirmed Buruli lesions and monitored for recurrence-free healing. Bacterial load in tissue samples before and after treatment for 6 and 12 weeks was monitored by semiquantitative culture. The success rate was 93%, and there was no recurrence after a 12-month follow-up. Eight percent had a positive culture 4 weeks after antibiotic treatment, but their lesions went on to heal. The findings indicate that rifampin and clarithromycin can replace rifampin and streptomycin for the continuation phase after rifampin and streptomycin administration for 2 weeks without any apparent loss of efficacy.

scholarly journals Protective Efficacy of a DNA Vaccine Encoding Antigen 85A from Mycobacterium bovis BCG against Buruli Ulcer

2001 ◽  
Vol 69 (9) ◽  
pp. 5403-5411 ◽  
Author(s):  
Audrey Tanghe ◽  
Jean Content ◽  
Jean-Paul Van Vooren ◽  
Françoise Portaels ◽  
Kris Huygen
Keyword(s):  
Protective Efficacy ◽  
Bacterial Load ◽  
Buruli Ulcer ◽  
Skin Lesions ◽  
Protective Role ◽  
Mycobacterium Ulcerans ◽  
Mycobacterial Antigen ◽  
Dna Encoding ◽  
Major Health Problem ◽  
Western Africa

ABSTRACT Buruli ulcer, caused by Mycobacterium ulcerans, is characterized by deep and necrotizing skin lesions, mostly on the arms and legs. Together with tuberculosis and leprosy, this mycobacterial disease has become a major health problem in tropical and subtropical regions, particularly in central and western Africa. No specific vaccine is available for Buruli ulcer. There is, however, evidence in the literature that suggests a cross-reactive protective role of the tuberculosis vaccine M. bovis BCG. To identify potential mechanisms for this cross-protection, we identified and characterized the M. ulcerans homologue of the important protective mycobacterial antigen 85 (Ag85A) from BCG. The homologue is well conserved in M. ulcerans, showing 84.1% amino acid sequence identity and 91% conserved residues compared to the sequence from BCG. This antigen was sufficiently conserved to allow cross-reactive protection, as demonstrated by the ability of M. ulcerans- infected mice to exhibit strong cellular immune responses to both BCG and its purified Ag85 complex. To further address the mechanism of cross-reactive protection, we demonstrate here that prior vaccination with either BCG or plasmid DNA encoding BCG Ag85A is capable of significantly reducing the bacterial load in the footpads ofM. ulcerans- infected mice, as determined by Ziehl-Neelsen staining and by actual counting of CFU on 7H11 Middlebrook agar. Together, the results reported here support the potential of a cross-protective Ag85-based future vaccine against tuberculosis, Buruli ulcer, and leprosy.

scholarly journals High-Dose Rifamycins Enable Shorter Oral Treatment in a Murine Model ofMycobacterium ulceransDisease

2018 ◽  
Vol 63 (2) ◽  
pp. e01478-18 ◽  
Author(s):  
Till F. Omansen ◽  
Deepak Almeida ◽  
Paul J. Converse ◽  
Si-Yang Li ◽  
Jin Lee ◽  
...  
Keyword(s):  
Oral Treatment ◽  
Buruli Ulcer ◽  
Indirect Costs ◽  
Ceiling Effect ◽  
Mycobacterium Ulcerans ◽  
High Dose ◽  
Current Standard ◽  
Standard Regimen ◽  
Content Type ◽  
Dose Dependent

ABSTRACTBuruli ulcer (BU), caused byMycobacterium ulcerans, is a neglected tropical skin and soft tissue infection that is associated with disability and social stigma. The mainstay of BU treatment is an 8-week course of rifampin (RIF) at 10 mg/kg of body weight and 150 mg/kg streptomycin (STR). Recently, the injectable STR has been shown to be replaceable with oral clarithromycin (CLR) for smaller lesions for the last 4 weeks of treatment. A shorter, all-oral, highly efficient regimen for BU is needed, as the long treatment duration and indirect costs currently burden patients and health systems. Increasing the dose of RIF or replacing it with the more potent rifamycin drug rifapentine (RPT) could provide such a regimen. Here, we performed a dose-ranging experiment of RIF and RPT in combination with CLR over 4 weeks of treatment in a mouse model ofM. ulceransdisease. A clear dose-dependent effect of RIF on both clinical and microbiological outcomes was found, with no ceiling effect observed with tested doses up to 40 mg/kg. RPT-containing regimens were more effective onM. ulcerans. All RPT-containing regimens achieved culture negativity after only 4 weeks, while only the regimen with the highest RIF dose (40 mg/kg) did so. We conclude that there is dose-dependent efficacy of both RIF and RPT and that a ceiling effect is not reached with the current standard regimen used in the clinic. A regimen based on higher rifamycin doses than are currently being evaluated against tuberculosis in clinical trials could shorten and improve therapy of Buruli ulcer.

scholarly journals Buruli Ulcer: Review of a Neglected Skin Mycobacterial Disease

2017 ◽  
Vol 56 (4) ◽  
Author(s):  
Jeannette Guarner
Keyword(s):  
Clinical Presentation ◽  
Oral Treatment ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
World Health ◽  
Tissue Necrosis ◽  
Content Type ◽  
Skin Nodule ◽  
The World ◽  
Health Organization

ABSTRACTBuruli ulcer is caused byMycobacterium ulcerans. This neglected disease occurs in scattered foci around the world, with a higher concentration of cases in West Africa. The mycobacteria produce mycolactones that cause tissue necrosis. The disease presents as a painless skin nodule that ulcerates as necrosis expands. Finding acid-fast bacilli in smears or histopathology, culturing the mycobacteria, and performingM. ulceransPCR in presumptive cases confirm the diagnosis. Medical treatment with oral rifampin and intramuscular streptomycin or oral treatment with rifampin plus clarithromycin for 8 weeks is supported by the World Health Organization. This review summarizes the epidemiology, pathogenesis, clinical presentation, diagnostic tests, and advances in treatment.

scholarly journals Chemotherapy-Associated Changes of Histopathological Features of Mycobacterium ulcerans Lesions in a Buruli Ulcer Mouse Model

2011 ◽  
Vol 56 (2) ◽  
pp. 687-696 ◽  
Author(s):  
Marie-Thérèse Ruf ◽  
Daniela Schütte ◽  
Aurélie Chauffour ◽  
Vincent Jarlier ◽  
Baohong Ji ◽  
...  
Keyword(s):  
B Lymphocyte ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Infection Model ◽  
Histopathological Study ◽  
Content Type ◽  
Histopathological Features ◽  
Treatment Regimens ◽  
Mouse Infection Model ◽  
New Treatment

ABSTRACTCombination chemotherapy with rifampin and streptomycin (RIF-STR) for 8 weeks is currently recommended by the WHO as the first-line treatment forMycobacterium ulceransinfection (Buruli ulcer). To gain better insight into the mode of action of these antibiotics against establishedM. ulceransinfection foci and to characterize recovery of local immune responses during chemotherapy, we conducted a detailed histopathological study ofM. ulcerans-infected and RIF-STR-treated mice. Mice were inoculated withM. ulceransin the footpad and 11 weeks later treated with RIF-STR. Development of lesions during the first 11 weeks after infection and subsequent differences in disease progression between RIF-STR-treated and untreated mice were studied. Changes in histopathological features, footpad swelling, and number of CFU were analyzed. After inoculation withM. ulcerans, massive infiltrates dominated by polymorphonuclear leukocytes developed at the inoculation site but did not prevent bacterial multiplication. Huge clusters of extracellular bacteria located in large necrotic areas and surrounded by dead leukocytes developed in the untreated mice. Chemotherapy with RIF-STR led to a rapid drop in CFU associated with loss of solid Ziehl-Neelsen staining of acid-fast bacilli. Development of B-lymphocyte clusters and of macrophage accumulations surrounding the mycobacteria demonstrated the resolution of local immune suppression. Results demonstrate that the experimentalM. ulceransmouse infection model will be a valuable tool to investigate efficacy of new treatment regimens and of candidate vaccines.

scholarly journals Comparative Genomics Shows ThatMycobacterium ulceransMigration and Expansion Preceded the Rise of Buruli Ulcer in Southeastern Australia

2018 ◽  
Vol 84 (8) ◽  
pp. e02612-17 ◽  
Author(s):  
Andrew H. Buultjens ◽  
Koen Vandelannoote ◽  
Conor J. Meehan ◽  
Miriam Eddyani ◽  
Bouke C. de Jong ◽  
...  
Keyword(s):  
Buruli Ulcer ◽  
Population Expansion ◽  
Mycobacterium Ulcerans ◽  
Disease Spread ◽  
Whole Genome Sequence ◽  
Sequence Comparisons ◽  
Content Type ◽  
Continental Scale ◽  
Southeastern Australia ◽  
East End

ABSTRACTSince 2000, cases of the neglected tropical disease Buruli ulcer, caused by infection withMycobacterium ulcerans, have increased 100-fold around Melbourne (population 4.4 million), the capital of Victoria, in temperate southeastern Australia. The reasons for this increase are unclear. Here, we used whole-genome sequence comparisons of 178M. ulceransisolates obtained primarily from human clinical specimens, spanning 70 years, to model the population dynamics of this pathogen from this region. Using phylogeographic and advanced Bayesian phylogenetic approaches, we found that there has been a migration of the pathogen from the east end of the state, beginning in the 1980s, 300 km west to the major human population center around Melbourne. This move was then followed by a significant increase inM. ulceranspopulation size. These analyses inform our thinking around Buruli ulcer transmission and control, indicating thatM. ulceransis introduced to a new environment and then expands, rather than it being from the awakening of a quiescent pathogen reservoir.IMPORTANCEBuruli ulcer is a destructive skin and soft tissue infection caused byMycobacterium ulceransand is characterized by progressive skin ulceration, which can lead to permanent disfigurement and long-term disability. Despite the majority of disease burden occurring in regions of West and central Africa, Buruli ulcer is also becoming increasingly common in southeastern Australia. Major impediments to controlling disease spread are incomplete understandings of the environmental reservoirs and modes of transmission ofM. ulcerans. The significance of our research is that we used genomics to assess the population structure of this pathogen at the Australian continental scale. We have then reconstructed a historical bacterial spread and modeled demographic dynamics to reveal bacterial population expansion across southeastern Australia. These findings provide explanations for the observed epidemiological trends with Buruli ulcer and suggest possible management to control disease spread.

scholarly journals Mycobacterium ulcerans Population Genomics To Inform on the Spread of Buruli Ulcer across Central Africa

mSphere ◽  
2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Koen Vandelannoote ◽  
Delphin Mavinga Phanzu ◽  
Kapay Kibadi ◽  
Miriam Eddyani ◽  
Conor J. Meehan ◽  
...  
Keyword(s):  
Disease Control ◽  
Population Genomics ◽  
Demographic History ◽  
Buruli Ulcer ◽  
Central Africa ◽  
Mycobacterium Ulcerans ◽  
Evolutionary Trajectory ◽  
Content Type ◽  
Mode Of Transmission ◽  
The Impact

ABSTRACT Buruli ulcer is a neglected tropical disease of skin and subcutaneous tissue caused by infection with the pathogen Mycobacterium ulcerans. Many critical issues for disease control, such as understanding the mode of transmission and identifying source reservoirs of M. ulcerans, are still largely unknown. Here, we used genomics to reconstruct in detail the evolutionary trajectory and dynamics of M. ulcerans populations at a central African scale and at smaller geographical village scales. Whole-genome sequencing (WGS) data were analyzed from 179 M. ulcerans strains isolated from all Buruli ulcer foci in the Democratic Republic of the Congo, The Republic of Congo, and Angola that have ever yielded positive M. ulcerans cultures. We used both temporal associations and the study of the mycobacterial demographic history to estimate the contribution of humans as a reservoir in Buruli ulcer transmission. Our phylogeographic analysis revealed one almost exclusively predominant sublineage of M. ulcerans that arose in Central Africa and proliferated in its different regions of endemicity during the Age of Discovery. We observed how the best sampled endemic hot spot, the Songololo territory, became an area of endemicity while the region was being colonized by Belgium (1880s). We furthermore identified temporal parallels between the observed past population fluxes of M. ulcerans from the Songololo territory and the timing of health policy changes toward control of the Buruli ulcer epidemic in that region. These findings suggest that an intervention based on detecting and treating human cases in an area of endemicity might be sufficient to break disease transmission chains, irrespective of other reservoirs of the bacterium. IMPORTANCE Buruli ulcer is a destructive skin and soft tissue infection caused by Mycobacterium ulcerans. The disease is characterized by progressive skin ulceration, which can lead to permanent disfigurement and long-term disability. Currently, the major hurdles facing disease control are incomplete understandings of both the mode of transmission and environmental reservoirs of M. ulcerans. As decades of spasmodic environmental sampling surveys have not brought us much closer to overcoming these hurdles, the Buruli ulcer research community has recently switched to using comparative genomics. The significance of our research is in how we used both temporal associations and the study of the mycobacterial demographic history to estimate the contribution of humans as a reservoir in Buruli ulcer transmission. Our approach shows that it might be possible to use bacterial population genomics to assess the impact of health interventions, providing valuable feedback for managers of disease control programs in areas where health surveillance infrastructure is poor.

scholarly journals Shortening Buruli Ulcer Treatment with Combination Therapy Targeting the Respiratory Chain and Exploiting Mycobacterium ulcerans Gene Decay

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Paul J. Converse ◽  
Deepak V. Almeida ◽  
Sandeep Tyagi ◽  
Jian Xu ◽  
Eric L. Nuermberger
Keyword(s):  
Buruli Ulcer ◽  
Oxidase Inhibitor ◽  
Mycobacterium Ulcerans ◽  
Infection Model ◽  
Synergistic Activity ◽  
Content Type ◽  
Drug Regimens ◽  
Long Acting ◽  
Synthase Inhibitor

ABSTRACT Buruli ulcer is treatable with antibiotics. An 8-week course of rifampin (RIF) and either streptomycin (STR) or clarithromycin (CLR) cures over 90% of patients. However, STR requires injections and may be toxic, and CLR shares an adverse drug-drug interaction with RIF and may be poorly tolerated. Studies in a mouse footpad infection model showed that increasing the dose of RIF or using the long-acting rifamycin rifapentine (RPT), in combination with clofazimine (CFZ), a relatively well-tolerated antibiotic, can shorten treatment to 4 weeks. CFZ is reduced by a component of the electron transport chain (ETC) to produce reactive oxygen species toxic to bacteria. Synergistic activity of CFZ with other ETC-targeting drugs, the ATP synthase inhibitor bedaquiline (BDQ) and the bc1:aa3 oxidase inhibitor Q203 (now named telacebec), was recently described against Mycobacterium tuberculosis. Recognizing that M. tuberculosis mutants lacking the alternative bd oxidase are hypersusceptible to Q203 and that Mycobacterium ulcerans is a natural bd oxidase-deficient mutant, we tested the in vitro susceptibility of M. ulcerans to Q203 and evaluated the treatment-shortening potential of novel 3- and 4-drug regimens combining RPT, CFZ, Q203, and/or BDQ in a mouse footpad model. The MIC of Q203 was extremely low (0.000075 to 0.00015 μg/ml). Footpad swelling decreased more rapidly in mice treated with Q203-containing regimens than in mice treated with RIF and STR (RIF+STR) and RPT and CFZ (RPT+CFZ). Nearly all footpads were culture negative after only 2 weeks of treatment with regimens containing RPT, CFZ, and Q203. No relapse was detected after only 2 weeks of treatment in mice treated with any of the Q203-containing regimens. In contrast, 15% of mice receiving RIF+STR for 4 weeks relapsed. We conclude that it may be possible to cure patients with Buruli ulcer in 14 days or less using Q203-containing regimens rather than currently recommended 56-day regimens.

scholarly journals Evaluation of a Multiplex Real-Time PCR Assay for Detecting Major Bacterial Enteric Pathogens in Fecal Specimens: Intestinal Inflammation and Bacterial Load Are Correlated in Campylobacter Infections

2016 ◽  
Vol 54 (9) ◽  
pp. 2262-2266 ◽  
Author(s):  
Nadia Wohlwend ◽  
Sacha Tiermann ◽  
Lorenz Risch ◽  
Martin Risch ◽  
Thomas Bodmer
Keyword(s):  
Real Time ◽  
Real Time Pcr ◽  
Bacterial Load ◽  
Positive Culture ◽  
Fecal Calprotectin ◽  
Enteric Pathogens ◽  
Significant Linear Trend ◽  
Content Type ◽  
Culture Positive ◽  
Culture Negative

A total of 1,056 native or Cary-Blair-preserved stool specimens were simultaneously tested by conventional stool culturing and by enteric bacterial panel (EBP) multiplex real-time PCR forCampylobacter jejuni,Campylobacter coli,Salmonellaspp., and shigellosis disease-causing agents (Shigellaspp. and enteroinvasiveEscherichia coli[EIEC]). Overall, 143 (13.5%) specimens tested positive by PCR for the targets named above; 3 coinfections and 109 (10.4%)Campylobacterspp., 17 (1.6%)Salmonellaspp., and 20 (1.9%)Shigellaspp./EIEC infections were detected. The respective positive stool culture rates were 75 (7.1%), 14 (1.3%), and 7 (0.7%). The median threshold cycle (CT) values of culture-positive specimens were significantly lower than those of culture-negative ones (CTvalues, 24.3 versus 28.7;P< 0.001), indicating that the relative bacterial load per fecal specimen was significantly associated with the culture results. InCampylobacterinfections, the respective median fecal calprotectin concentrations in PCR-negative/culture-negative (n =40), PCR-positive/culture-negative (n =14), and PCR-positive/culture-positive (n =15) specimens were 134 mg/kg (interquartile range [IQR], 30 to 1,374 mg/kg), 1,913 mg/kg (IQR, 165 to 3,813 mg/kg), and 5,327 mg/kg (IQR, 1,836 to 18,213 mg/kg). Significant differences were observed among the three groups (P< 0.001), and a significant linear trend was identified (P< 0.001). Furthermore, the fecal calprotectin concentrations andCTvalues were found to be correlated (r= −0.658). Our results demonstrate that molecular screening ofCampylobacterspp.,Salmonellaspp., andShigellaspp./EIEC using the BD Max EBP assay will result in timely diagnosis and improved sensitivity. The determination of inflammatory markers, such as calprotectin, in fecal specimens may aid in the interpretation of PCR results, particularly for enteric pathogens associated with mucosal damage and colonic inflammation.

scholarly journals Whole-Genome Sequence of Mycobacterium ulcerans CSURP7741, a French Guianan Clinical Isolate

2019 ◽  
Vol 8 (29) ◽  
Author(s):  
Jamal Saad ◽  
Marine Combe ◽  
Nassim Hammoudi ◽  
Pierre Couppié ◽  
Romain Blaizot ◽  
...  
Keyword(s):  
Clinical Isolate ◽  
Genome Sequence ◽  
Buruli Ulcer ◽  
Gc Content ◽  
Mycobacterium Ulcerans ◽  
Whole Genome Sequence ◽  
Whole Genome ◽  
Protein Coding ◽  
Content Type ◽  
Rna Genes

Combined Nanopore and Illumina whole-genome sequencing of a French Guianan Mycobacterium ulcerans (Buruli ulcer agent) clinical isolate yielded a 5.12-Mbp genome with a 65.5% GC content, 5,215 protein-coding genes, and 51 predicted RNA genes. This publicly available M. ulcerans whole-genome sequence from a strain isolated in South America is closely related to M. ulcerans subsp. liflandii.

scholarly journals Draft Genome Sequence of Mycobacterium ulcerans S4018 Isolated from a Patient with an Active Buruli Ulcer in Benin, Africa

2017 ◽  
Vol 5 (17) ◽  
Author(s):  
Stanimir Kambarev ◽  
Stéphane Corvec ◽  
Annick Chauty ◽  
Estelle Marion ◽  
Laurent Marsollier ◽  
...  
Keyword(s):  
Genome Sequence ◽  
Causative Agent ◽  
Cutaneous Lesion ◽  
Draft Genome ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Tropical Disease ◽  
Draft Genome Sequence ◽  
Content Type

ABSTRACT Currently, there are only two publicly available genomes of Mycobacterium ulcerans—the causative agent of the neglected, but devastating, tropical disease Buruli ulcer. Here, we report the draft genome sequence of isolate S4018, recovered from an active cutaneous lesion of a patient with Buruli ulcer in Benin, Africa.

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