rifampin and Buruli-Ulcer

Buruli ulcer is caused by

Topics: Africa, Western; Anti-Bacterial Agents; Buruli Ulcer; Clarithromycin; Humans; Macrolides; Mycobacterium Infections; Mycobacterium ulcerans; Neglected Diseases; Polymerase Chain Reaction; Rifampin; Skin Diseases, Bacterial; Streptomycin

Buruli ulcer is a necrotizing cutaneous infection caused by infection with Mycobacterium ulcerans bacteria that occurs mainly in tropical and subtropical regions. The infection progresses from nodules under the skin to deep ulcers, often on the upper and lower limbs or on the face. If left undiagnosed and untreated, it can lead to lifelong disfigurement and disabilities. It is often treated with drugs and surgery.. To summarize the evidence of drug treatments for treating Buruli ulcer.. We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE (PubMed); Embase (Ovid); and LILACS (Latin American and Caribbean Health Sciences Literature; BIREME). We also searched the US National Institutes of Health Ongoing Trials Register (clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en/). All searches were run up to 19 December 2017. We also checked the reference lists of articles identified by the literature search, and contacted leading researchers in this topic area to identify any unpublished data.. We included randomized controlled trials (RCTs) that compared antibiotic therapy to placebo or alternative therapy such as surgery, or that compared different antibiotic regimens. We also included prospective observational studies that evaluated different antibiotic regimens with or without surgery.. Two review authors independently applied the inclusion criteria, extracted the data, and assessed methodological quality. We calculated the risk ratio (RR) for dichotomous data with 95% confidence intervals (CI). We assessed the certainty of the evidence using the GRADE approach.. We included a total of 18 studies: five RCTs involving a total of 319 participants, ranging from 12 participants to 151 participants, and 13 prospective observational studies, with 1665 participants. Studies evaluated various drugs usually in addition to surgery, and were carried out across eight countries in areas with high Buruli ulcer endemicity in West Africa and Australia. Only one RCT reported adequate methods to minimize bias. Regarding monotherapy, one RCT and one observational study evaluated clofazimine, and one RCT evaluated sulfamethoxazole/trimethoprim. All three studies had small sample sizes, and no treatment effect was demonstrated. The remaining studies examined combination therapy.Rifampicin combined with streptomycinWe found one RCT and six observational studies which evaluated rifampicin combined with streptomycin for different lengths of treatment (2, 4, 8, or 12 weeks) (941 participants). The RCT did not demonstrate a difference between the drugs added to surgery compared with surgery alone for recurrence at 12 months, but was underpowered (RR 0.12, 95% CI 0.01 to 2.51; 21 participants; very low-certainty evidence).An additional five single-arm observational studies with 828 participants using this regimen for eight weeks with surgery (given to either all participants or to a select group) reported healing rates ranging from 84.5% to 100%, assessed between six weeks and one year. Four observational studies reported healing rates for participants who received the regimen alone without surgery, reporting healing rates ranging from 48% to 95% assessed between eight weeks and one year.Rifampicin combined with clarithromycinTwo observational studies administered combined rifampicin and clarithromycin. One study evaluated the regimen alone (no surgery) for eight weeks and reported a healing rate of 50% at 12 months (30 participants). Another study evaluated the regimen administered for various durations (as determined by the clinicians, durations unspecified) with surgery and reported a healing rate of 100% at 12 months (21 participants).Rifampicin with streptomycin initially, changing to rifampicin with clarithromycin in consolidation phaseOne RCT evaluated this regimen (four weeks in each phase) against continuing with rifampicin and streptomycin in the consolidation phase (total eight weeks). All included participants had small lesions, and healing rates were above 90% in both groups without surgery (healing rate at 12 months RR 0.94, 9. While the antibiotic combination treatments evaluated appear to be effective, we found insufficient evidence showing that any particular drug is more effective than another. How different sizes, lesions, and stages of the disease may contribute to healing and which kind of lesions are in need of surgery are unclear based on the included studies. Guideline development needs to consider these factors in designing practical treatment regimens. Forthcoming trials using clarithromycin with rifampicin and other trials of new regimens that also address these factors will help to identify the best regimens.

Topics: Anti-Bacterial Agents; Buruli Ulcer; Clarithromycin; Clofazimine; Drug Therapy, Combination; Humans; Mycobacterium ulcerans; Observational Studies as Topic; Randomized Controlled Trials as Topic; Rifampin; Streptomycin; Trimethoprim, Sulfamethoxazole Drug Combination

Buruli ulcer (BU) disease is a chronic ulcerative skin disease caused by Mycobacterium ulcerans, which can lead to extensive destruction of the skin, soft tissues and occasionally of bones. Although several antibiotics have demonstrated bactericidal activity against M. ulcerans in vitro, no consensus on their clinical efficacy against M. ulcerans in humans has been reached.. The objective of the systematic review was to examine the clinical effectiveness of various antibiotic regimens for the treatment of BUs.. The current review considered trials that included patients of all ages with BUs.. The current review considered trials that evaluated antibiotic regimens compared to no antibiotics or surgery in patients with BUs.. The current review considered randomized and non-randomized controlled trials (RCTs). In the absence of RCTs, other research designs such as before and after trials and clinical trials with only an intervention arm were considered for inclusion in a narrative summary.. The primary outcome of interest were the treatment success rates among the various antibiotics used. Secondary outcomes included changes in lesion size, recurrence of ulcers and incidence of adverse events.. The search strategy aimed to find both published and unpublished trials. A three-step search strategy was utilized in this review and included English language trials published after 1990. A search across the major databases was conducted up to December 2014.. Using the Joanna Briggs Institute (JBI) standardized appraisal tool, two reviewers independently assessed the methodological quality of the trials. A third independent reviewer was available to appraise trials if the two original reviewers disagreed in their assessments. There were no disagreements in findings between the two independent reviewers.. Data were extracted using the standardized JBI data extraction instruments.. Statistical pooling was not possible due to heterogeneity, hence results have been presented in the narrative form.. Seven studies involving a total of 712 patients were included in the final review. Higher treatment success rates ranging from 96% to 100% at the six months follow-up were reported among patients treated with rifampicin-streptomycin for eight weeks (RS8) in two studies. Treatment success with rifampicin-streptomycin for 12 weeks, with surgery at the 12 weeks follow-up, was 91%. In the two studies that investigated the effect of rifampicin-streptomycin for two weeks followed by rifampicin-clarithromycin for six weeks and rifampicin-streptomycin for four weeks followed by rifampicin-clarithromycin for four weeks, treatment success was reported to be 93% and 91%, respectively, at the 12 months follow-up. A significant decrease in the median lesion size at the eight weeks follow-up was reported in patients who were treated with RS8, and a 10-30% decrease in lesion size was reported in those treated with RS12 at the four weeks follow-up.. Treatment success and reduction in lesion size were higher in patients treated with RS8 in the only RCT that compared rifampicin-streptomycin for four weeks followed by rifampicin-clarithromycin for six weeks to RS8, and there was no difference in outcomes, which indicates that local preferences could dictate the treatment option. Evidence obtained from this systematic review indicates that surgery will remain necessary for some ulcers; however, detection of early lesions and treatment with antibiotics would have a greater impact on the control of M. ulcerans disease. Further large multicenter RCTs investigating the type and optimal duration of oral antibiotic treatment for patients with M. ulcerans disease are urgently needed.

Topics: Administration, Oral; Anti-Bacterial Agents; Buruli Ulcer; Drug Administration Schedule; Drug Therapy, Combination; Humans; Mycobacterium ulcerans; Rifampin; Streptomycin; Treatment Outcome

Until 2004, the skin disease known as Buruli ulcer, caused by Mycobacterium ulcerans, could only be treated by surgery and skin grafting. Although this worked reasonably well on early lesions typically found in patients in Australia, the strategy was usually impractical on large lesions resulting from diagnostic delay in patients in rural West Africa. Based on promising preclinical studies, treatment trials in West Africa have shown that a combination of rifampin and streptomycin administered daily for 8 weeks can kill M. ulcerans bacilli, arrest the disease, and promote healing without relapse or reduce the extent of surgical excision. Improved treatment options are the focus of research that has increased tremendously since the WHO began its Global Buruli Ulcer Initiative in 1998.

Topics: Adolescent; Animals; Anti-Bacterial Agents; Buruli Ulcer; Clinical Trials as Topic; Disease Models, Animal; Drug Therapy, Combination; Female; Humans; Mice; Mycobacterium ulcerans; Rifampin; Streptomycin; Treatment Outcome; Young Adult

Buruli ulcer (BU), caused by Mycobacterium ulcerans infection, has become one of the most rapidly emerging diseases in West Africa in recent decades. Until recently, the definitive treatment involved wide surgical excision. Recent data suggest that antibiotic therapy with rifampin and streptomycin may reduce the extent or prevent excision when initiated during the early phases of the disease. New strategies for BU control are needed, emphasizing early detection and increasing public awareness about the disease and treatment. Here we review current knowledge about BU and examine clinical, public health and anthropological research in the context of this new treatment paradigm to identify potential strategies for more effective control of this disease.. A comprehensive literature search for articles in English or French using the Medline and INIST databases, World Health Organization publications, and bibliographical references was undertaken using key words Buruli ulcer. Mycobacterium ulcerans, community surveillance, and public health.. Studies to identify factors contributing to delayed presentation indicate that awareness of the disease is generally good in endemic regions, but wide variation exists in perceived cause of the disease, and the role of sorcery in its transmission and treatment. The use of traditional healers as first line therapy also contributes to delayed treatment, as do lack of awareness about the availability of effective treatment and financial concerns. Epidemiological data from existing BU control programs indicate that active public awareness campaigns are succcessful in increasing understanding and decreasing treatment delay and disease progression. Community-based surveillance and health education modeled after the village health worker programs used in the eradication of Guinea worm may be successfully applied in BU endemic areas.

Topics: Africa, Western; Anti-Bacterial Agents; Buruli Ulcer; Drug Therapy, Combination; Early Diagnosis; Humans; Mycobacterium ulcerans; Rifampin; Streptomycin; Treatment Outcome

Buruli ulcer (BU) is a neglected tropical disease caused by Mycobacterium ulcerans that affects skin, soft tissues, and bones, causing long-term morbidity, stigma, and disability. The recommended treatment for BU requires 8 weeks of daily rifampicin and clarithromycin together with wound care, physiotherapy, and sometimes tissue grafting and surgery. Recovery can take up to 1 year, and it may pose an unbearable financial burden to the household. Recent in vitro studies demonstrated that beta-lactams combined with rifampicin and clarithromycin are synergistic against M. ulcerans. Consequently, inclusion of amoxicillin/clavulanate in a triple oral therapy may potentially improve and shorten the healing process. The BLMs4BU trial aims to assess whether co-administration of amoxicillin/clavulanate with rifampicin and clarithromycin could reduce BU treatment from 8 to 4 weeks.. We propose a randomized, controlled, open-label, parallel-group, non-inferiority phase II, multi-centre trial in Benin with participants stratified according to BU category lesions and randomized to two oral regimens: (i) Standard: rifampicin plus clarithromycin therapy for 8 weeks; and (ii) Investigational: standard plus amoxicillin/clavulanate for 4 weeks. The primary efficacy outcome will be lesion healing without recurrence and without excision surgery 12 months after start of treatment (i.e. cure rate). Seventy clinically diagnosed BU patients will be recruited per arm. Patients will be followed up over 12 months and managed according to standard clinical care procedures. Decision for excision surgery will be delayed to 14 weeks after start of treatment. Two sub-studies will also be performed: a pharmacokinetic and a microbiology study.. If successful, this study will create a new paradigm for BU treatment, which could inform World Health Organization policy and practice. A shortened, highly effective, all-oral regimen will improve care of BU patients and will lead to a decrease in hospitalization-related expenses and indirect and social costs and improve treatment adherence. This trial may also provide information on treatment shortening strategies for other mycobacterial infections (tuberculosis, leprosy, or non-tuberculous mycobacteria infections).. ClinicalTrials.gov NCT05169554 . Registered on 27 December 2021.

Topics: Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Benin; Buruli Ulcer; Clarithromycin; Clinical Trials, Phase II as Topic; Humans; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Rifampin; Treatment Outcome

Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare 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 that of RS8 for treatment of early Buruli ulcer lesions.. We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437.. Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10-29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, -0·5% (-5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1-2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts.. Fully 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.. WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac.

Topics: Administration, Oral; Adolescent; Adult; Anti-Bacterial Agents; Benin; Buruli Ulcer; Child; Clarithromycin; Delayed-Action Preparations; Drug Therapy, Combination; Female; Ghana; Humans; Male; Rifampin; Streptomycin; Wound Healing; Young Adult

Surgical debridement was the standard treatment for Mycobacterium ulcerans infection (Buruli ulcer disease) until WHO issued provisional guidelines in 2004 recommending treatment with antimicrobial drugs (streptomycin and rifampicin) in addition to surgery. These recommendations were based on observational studies and a small pilot study with microbiological endpoints. We investigated the efficacy of two regimens of antimicrobial treatment in early-stage M ulcerans infection.. In this parallel, open-label, randomised trial undertaken in two sites in Ghana, patients were eligible for enrolment if they were aged 5 years or older and had early (duration <6 months), limited (cross-sectional diameter <10 cm), M ulcerans infection confirmed by dry-reagent-based PCR. Eligible patients were randomly assigned to receive intramuscular streptomycin (15 mg/kg once daily) and oral rifampicin (10 mg/kg once daily) for 8 weeks (8-week streptomycin group; n=76) or streptomycin and rifampicin for 4 weeks followed by rifampicin and clarithromycin (7.5 mg/kg once daily), both orally, for 4 weeks (4-week streptomycin plus 4-week clarithromycin group; n=75). Randomisation was done by computer-generated minimisation for study site and type of lesion (ulceration or no ulceration). The randomly assigned allocation was sent from a central site by cell-phone text message to the study coordinator. The primary endpoint was lesion healing at 1 year after the start of treatment without lesion recurrence or extensive surgical debridement. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00321178.. Four patients were lost to follow-up (8-week streptomycin, one; 4-week streptomycin plus 4-week clarithromycin, three). Since these four participants had healed lesions at their last assessment, they were included in the analysis for the primary endpoint. 73 (96%) participants in the 8-week streptomycin group and 68 (91%) in the 4-week streptomycin plus 4-week clarithromycin group had healed lesions at 1 year (odds ratio 2.49, 95% CI 0.66 to infinity; p=0.16, one-sided Fisher's exact test). No participants had lesion recurrence at 1 year. Three participants had vestibulotoxic events (8-week streptomycin, one; 4-week streptomycin plus 4-week clarithromycin, two). One participant developed an injection abscess and two participants developed an abscess close to the initial lesion, which was incised and drained (all three participants were in the 4-week streptomycin plus 4-week clarithromycin group).. Antimycobacterial treatment for M ulcerans infection is effective in early, limited disease. 4 weeks of streptomycin and rifampicin followed by 4 weeks of rifampicin and clarithromycin has similar efficacy to 8 weeks of streptomycin and rifampicin; however, the number of injections of streptomycin can be reduced by switching to oral clarithromycin after 4 weeks.. European Union (EU FP6 2003-INCO-Dev2-015476) and Buruli Ulcer Groningen Foundation.

Topics: Administration, Oral; Adolescent; Adult; Anti-Bacterial Agents; Buruli Ulcer; Child; Clarithromycin; Drug Administration Schedule; Drug Therapy, Combination; Endpoint Determination; Female; Follow-Up Studies; Ghana; Humans; Injections, Intramuscular; Leprostatic Agents; Male; Mycobacterium ulcerans; Rifampin; Statistics, Nonparametric; Streptomycin; Time Factors; Treatment Outcome; Young Adult

We have evaluated the clinical efficacy of the combination of oral rifampin at 10 mg/kg of body weight and intramuscular streptomycin at 15 mg/kg for 8 weeks (RS8), as recommended by the WHO, in 160 PCR-confirmed cases of Mycobacterium ulcerans disease. In 152 patients (95%) with all forms of disease from early nodules to large ulcers, with or without edema, the lesions healed without recourse to surgery. Eight patients whose ulcers were healing poorly had skin grafting after completion of antibiotics. There were no recurrences among 158 patients reviewed at the 1-year follow-up. The times to complete healing ranged from 2 to 48 weeks, according to the type and size of the lesion, but the average rate of healing (rate of reduction in ulcer diameter) varied widely. Thirteen subjects had positive cultures for M. ulcerans during or after treatment, but all the lesions healed without further antibiotic treatment. Adverse events were rare. These results confirm the efficacy of RS8 delivered in a community setting.

Topics: Adolescent; Adult; Aged; Buruli Ulcer; Child; Child, Preschool; Drug Combinations; Female; Humans; Infant; Male; Middle Aged; Mycobacterium ulcerans; Rifampin; Streptomycin; Treatment Outcome; Young Adult

In a randomized controlled trial in Ghana, treatment of Mycobacterium ulcerans infection with streptomycin (SM)-rifampin (RIF) for 8 weeks was compared with treatment with SM-RIF for 4 weeks followed by treatment with RIF-clarithromycin (CLA) for 4 weeks. The extent of the interaction of RIF and CLA combined on the pharmacokinetics of the two compounds is unknown in this population and was therefore studied in a subset of patients. Patients received CLA at a dose of 7.5 mg/kg of body weight once daily, rounded to the nearest 125 mg. RIF was administered at a dose of 10 mg/kg, rounded to the nearest 150 mg. SM was given at a dose of 15 mg/kg once daily as an intramuscular injection. Plasma samples were drawn at steady state and analyzed by liquid chromatography-tandem mass spectroscopy. Pharmacokinetic parameters were calculated with the MW/Pharm (version 3.60) program. Comedication with CLA resulted in a 60% statistically nonsignificant increase in the area under the plasma concentration-time curve (AUC) for RIF of 25.8 mg x h/liter (interquartile ratio [IQR], 21.7 to 31.5 mg x h/liter), whereas the AUC of RIF was 15.2 mg x h/liter (IQR, 15.0 to 17.5 mg x h/liter) in patients comedicated with SM (P = 0.09). The median AUCs of CLA and 14-hydroxyclarithromycin (14OH-CLA) were 2.9 mg x h/liter (IQR, 1.5 to 3.8 mg x h/liter) and 8.0 mg x h/liter (IQR, 6.7 to 8.6 mg x h/liter), respectively. The median concentration of CLA was above the MIC of M. ulcerans, but that of 14OH-CLA was not. In further clinical studies, a dose of CLA of 7.5 mg/kg twice daily should be used (or with an extended-release formulation, 15 mg/kg should be used) to ensure higher levels of exposure to CLA and an increase in the time above the MIC compared to those achieved with the currently used dose of 7.5 mg/kg once daily.

Topics: Antibiotics, Antitubercular; Buruli Ulcer; Chromatography, Liquid; Clarithromycin; Humans; Microbial Sensitivity Tests; Rifampin; Tandem Mass Spectrometry

According to recommendations of the 6th WHO Advisory Committee on Buruli ulcer, directly observed treatment with the combination of rifampin and streptomycin, administered daily for 8 weeks, was recommended to 310 patients diagnosed with Buruli ulcer in Pobè, Bénin. Among the 224 (72%) eligible patients for whom treatment was initiated, 215 (96%) were categorized as treatment successes, and 9, including 1 death and 8 losses to follow-up, were treatment failures. Of the 215 successfully treated patients, 102 (47%) were treated exclusively with antibiotics and 113 (53%) were treated with antibiotics plus surgical excision and skin grafting. The size of lesions at treatment initiation was the major factor associated with surgical intervention: 73% of patients with lesions of >15 cm in diameter underwent surgery, whereas only 17% of patients with lesions of <5 cm had surgery. No patient discontinued therapy for side effects from the antibiotic treatment. One year after stopping treatment, 208 of the 215 patients were actively retrieved to assess the long-term therapeutic results: 3 (1.44%) of the 208 retrieved patients had recurrence of Mycobacterium ulcerans disease, 2 among the 107 patients treated only with antibiotics and 1 among the 108 patients treated with antibiotics plus surgery. We conclude that the WHO-recommended streptomycin-rifampin combination is highly efficacious for treating M. ulcerans disease. Chemotherapy alone was successful in achieving cure in 47% of cases and was particularly effective against ulcers of less than 5 cm in diameter.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Buruli Ulcer; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Mycobacterium ulcerans; Rifampin; Streptomycin; Survival Analysis; Treatment Outcome

Buruli ulcer (BU) is a chronic necrotizing skin disease caused by Mycobacterium ulcerans. Historically, the disease was treated by surgical excision of the skin lesions, until an 8-week combination therapy of rifampicin and streptomycin was introduced in 2004. This treatment modality was effective and reduced recurrence rates. Rifampicin is the most efficacious antibiotic for the treatment of BU and, should rifampicin-resistant M. ulcerans strains emerge, there is currently no replacement for it. As for mycobacterial diseases in general, there is a pressing need for the development of novel, fast-acting drugs. Under market economy conditions, repurposing of new tuberculosis drug candidates is the most promising avenue for alternative BU treatments. Our drug repurposing activities have led to the identification of several actives against M. ulcerans. In particular, the cytochrome bc1 complex inhibitor telacebec (Q203) is a promising drug candidate for the treatment of BU in Africa and Australia. While an active cytochrome-bd oxidase bypass limits the potency of the cytochrome-bc1-specific inhibitor telacebec against M. tuberculosis, classical lineage M. ulcerans strains rely exclusively on cytochrome-bc1 to respire. Hence, telacebec is effective at nanomolar concentration against M. ulcerans, and a high treatment efficacy in an experimental mouse infection model indicates that treatment of BU could be substantially shortened and simplified by telacebec.

Topics: Animals; Buruli Ulcer; Cytochromes; Disease Models, Animal; Drug Repositioning; Mice; Mycobacterium ulcerans; Rifampin; Tuberculosis

For the treatment of chronic wounds, acid-oxidizing solutions (AOSs) with broad-spectrum microbicidal activity without disturbing granulation tissue formation have been developed. We found AOSs to efficiently kill Mycobacterium ulcerans, the causative agent of Buruli ulcer, which is able to survive harsh decontamination treatments. Topical AOS treatment of Buruli ulcer lesions may support the recommended antibiotic therapy (oral rifampin and clarithromycin), prevent contamination of the environment by the mycobacteria, and control secondary infections, which are a prevalent wound management problem in resource-poor settings where Buruli ulcer is endemic.

Topics: Buruli Ulcer; Clarithromycin; Humans; Mycobacterium ulcerans; Oxidation-Reduction; Rifampin

Skin infection by Mycobacterium ulcerans causes Buruli ulcer (BU) disease, a serious condition that significantly impact patient' health and quality of life and can be very difficult to treat. Treatment of BU is based on daily systemic administration of antibiotics for at least 8 weeks and presents drawbacks associated with the mode and duration of drug administration and potential side effects. Thus, new therapeutic strategies are needed to improve the efficacy and modality of BU therapeutics, resulting in a more convenient and safer antibiotic regimen. Hence, we developed a dual delivery system based on poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) microparticles and a gellan gum (GG) hydrogel for delivery of rifampicin (RIF) and streptomycin (STR), two antibiotics used for BU treatment. RIF was successfully loaded into PHBV microparticles, with an encapsulation efficiency of 43%, that also revealed a mean size of 10 µm, spherical form and rough topography. These microparticles were further embedded in a GG hydrogel containing STR. The resultant hydrogel showed a porous microstructure that conferred a high water retention capability (superior to 2000%) and a controlled release of both antibiotics. Also, biological studies revealed antibacterial activity against M. ulcerans, and a good cytocompatibility in a fibroblast cell line. Thus, the proposed drug delivery system can constitute a potential topical approach for treatment of skin ulcers caused by BU disease.

Topics: Anti-Bacterial Agents; Buruli Ulcer; Humans; Hydrogels; Polyesters; Quality of Life; Rifampin; Streptomycin

Topics: Adult; Buruli Ulcer; Clarithromycin; Humans; Lung; Male; Mycobacterium ulcerans; Rifampin

Buruli ulcer (BU) is a skin disease caused by Mycobacterium ulcerans infection that requires long-term antibiotic treatment and/or surgical excision. In this study, we investigated the therapeutic efficacy of the rifamycin derivative, rifalazil (RLZ) (also known as KRM-1648), in an advanced M. ulcerans infection model. Six-week-old female BALB/c mice were infected with 3.25 x 104 colony-forming units (CFU) of M. ulcerans subcutaneously into the bilateral hind footpads. At 33 days post-infection, when the footpads exhibited significant redness and swelling, mice were treated orally with 5 or 10 mg/kg of RLZ for up to 15 weeks. Mice were followed for an additional 15 weeks following treatment cessation. Untreated mice exhibited a progressive increase in footpad redness, swelling, and erosion over time, and all untreated mice reached to endpoint within 5-8 weeks post-bacterial injection. In the RLZ-treated mice, footpad redness and swelling and general condition improved or completely healed, and no recurrence occurred following treatment cessation. After 3 weeks of treatment, the CFU counts from the footpads of recovered RLZ-treated mice showed a 104 decrease compared with those of untreated mice. We observed a further reduction in CFU counts to the detection limit following 6 to 15 weeks of treatment, which did not increase 15 weeks after discontinuing the treatment. Histopathologically, bacteria in the treated mice became fragmented one week after RLZ-treatment. At the final point of the experiment, all the treated mice (5mg/kg/day; n = 6, 10mg/kg/day; n = 7) survived and had no signs of M. ulcerans infection. These results indicate that the rifamycin analogue, RLZ, is efficacious in the treatment of an advanced M. ulcerans infection mouse model.

Topics: Animals; Anti-Bacterial Agents; Buruli Ulcer; Disease Models, Animal; Drug Therapy, Combination; Female; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Rifampin; Rifamycins

Mycobacterium ulcerans, the opportunistic pathogen causing Buruli ulcer, is reported to affect rural populations in 36 tropical countries. We report one case of Buruli ulcer in a peri-urban area in Côte d'Ivoire, confirmed by whole genome sequencing which indicated a M. ulcerans genotype previously unreported in Côte d'Ivoire.

Topics: Anti-Bacterial Agents; Azithromycin; Buruli Ulcer; Cities; Cote d'Ivoire; Genome, Bacterial; Genotype; Humans; Male; Middle Aged; Mycobacterium ulcerans; Phylogeny; Rifampin; Whole Genome Sequencing

Topics: Antibiotics, Antitubercular; Arm; Buruli Ulcer; Child; Cote d'Ivoire; Drug Therapy, Combination; Humans; Male; Mass Screening; Mycobacterium ulcerans; Neglected Diseases; Rifampin; School Health Services; Skin; Streptomycin; Treatment Outcome

Topics: Anti-Bacterial Agents; Buruli Ulcer; Clarithromycin; Humans; Rifampin; Streptomycin

Topics: Adolescent; Aged; Antibiotics, Antitubercular; Buruli Ulcer; Clarithromycin; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Mycobacterium ulcerans; Rifampin; Victoria

Buruli ulcer (BU), caused by Mycobacterium ulcerans, is currently treated with a daily combination of rifampin and either injectable streptomycin or oral clarithromycin. An intermittent oral regimen would facilitate treatment supervision. We first evaluated the bactericidal activity of newer antimicrobials against M. ulcerans using a BU animal model. The imidazopyridine amine telacebec (Q203) exhibited high bactericidal activity whereas tedizolid (an oxazolidinone closely related to linezolid), selamectin and ivermectin (two avermectine compounds) and the benzothiazinone PBTZ169 were not active. Consequently, telacebec was evaluated for its bactericidal and sterilizing activities in combined intermittent regimens. Telacebec given twice a week in combination with a long-half-life compound, either rifapentine or bedaquiline, sterilized mouse footpads in 8 weeks, i.e. after a total of only 16 doses, and prevented relapse during a period of 20 weeks after the end of treatment. These results are very promising for future intermittent oral regimens which would greatly simplify BU treatment in the field.

Topics: Animals; Antitubercular Agents; Buruli Ulcer; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Female; Imidazoles; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Oxazolidinones; Piperidines; Pyridines; Rifampin; Tetrazoles

Rifampin (RIF) plus clarithromycin (CLR) for 8 weeks is now the standard of care for Buruli ulcer (BU) treatment, but CLR may not be an ideal companion for rifamycins due to bidirectional drug-drug interactions. The oxazolidinone linezolid (LZD) was previously shown to be active against

Topics: Animals; Anti-Bacterial Agents; Buruli Ulcer; Clarithromycin; Disease Models, Animal; Female; Linezolid; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Oxazolidinones; Rifampin; Tetrazoles

The potential use of clinically approved beta-lactams for Buruli ulcer (BU) treatment was investigated with representative classes analyzed in vitro for activity against Mycobacterium ulcerans. Beta-lactams tested were effective alone and displayed a strong synergistic profile in combination with antibiotics currently used to treat BU, i.e. rifampicin and clarithromycin; this activity was further potentiated in the presence of the beta-lactamase inhibitor clavulanate. In addition, quadruple combinations of rifampicin, clarithromycin, clavulanate and beta-lactams resulted in multiplicative reductions in their minimal inhibitory concentration (MIC) values. The MIC of amoxicillin against a panel of clinical isolates decreased more than 200-fold within this quadruple combination. Amoxicillin/clavulanate formulations are readily available with clinical pedigree, low toxicity, and orally and pediatric available; thus, supporting its potential inclusion as a new anti-BU drug in current combination therapies.

Topics: Administration, Oral; Amoxicillin; beta-Lactamase Inhibitors; beta-Lactamases; Buruli Ulcer; Clarithromycin; Clavulanic Acid; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Humans; Microbial Sensitivity Tests; Mycobacterium ulcerans; Rifampin

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Buruli Ulcer; Clarithromycin; Clofazimine; Disease Models, Animal; Drug Resistance, Bacterial; Drug Therapy, Combination; Electron Transport; Humans; Imidazoles; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mycobacterium ulcerans; Piperidines; Pyridines; Rifampin; Streptomycin

Buruli ulcer caused by Mycobacterium ulcerans is endemic in parts of West Africa and is most prevalent among the 5-15 years age group; Buruli ulcer is uncommon among neonates. The mode of transmission and incubation period of Buruli ulcer are unknown. We report two cases of confirmed Buruli ulcer in human immunodeficiency virus-unexposed, vaginally delivered term neonates in Ghana.. Patient 1: Two weeks after hospital delivery, a baby born to natives of the Ashanti ethnic group of Ghana was noticed by her mother to have a papule with associated edema on the right anterior chest wall and neck that later ulcerated. There was no restriction of neck movements. The diagnosis of Buruli ulcer was confirmed on the basis of a swab sample that had a positive polymerase chain reaction result for the IS2404 repeat sequence of M. ulcerans. Patient 2: This patient, from the Ashanti ethnic group in Ghana, had the mother noticing a swelling in the baby's left gluteal region 4 days after birth. The lesion progressively increased in size to involve almost the entire left gluteal region. Around the same time, the mother noticed a second, smaller lesion on the forehead and left side of neck. The diagnosis of Buruli ulcer was confirmed by polymerase chain reaction when the child was aged 4 weeks. Both patients 1 and 2 were treated with oral rifampicin and clarithromycin at recommended doses for 8 weeks in addition to appropriate daily wound dressing, leading to complete healing. Our report details two cases of polymerase chain reaction-confirmed Buruli ulcer in children whose lesions appeared at ages 14 and 4 days, respectively. The mode of transmission of M. ulcerans infection is unknown, so the incubation period is difficult to estimate and is probably dependent on the infective dose and the age of exposure. In our study, lesions appeared 4 days after birth in patient 2. Unless the infection was acquired in utero, this would be the shortest incubation period ever recorded.. Buruli ulcer should be included in the differential diagnosis of neonates who present with characteristic lesions. The incubation period of Buruli ulcer in neonates is probably shorter than is reported for adults.

Topics: Administration, Oral; Antibiotics, Antitubercular; Buruli Ulcer; Clarithromycin; Drug Therapy, Combination; Ghana; Humans; Infant, Newborn; Infectious Disease Incubation Period; Mycobacterium ulcerans; Polymerase Chain Reaction; Rifampin

Mycobacterium ulcerans infection, commonly known as Buruli ulcer (BU), is a debilitating neglected tropical disease. Its management remains complex and has three main components: antibiotic treatment combining rifampicin and streptomycin for 56 days, wound dressings and skin grafts for large ulcerations, and physical therapy to prevent functional limitations after care. In Benin, BU patient care is being integrated into the government health system. In this paper, we report on an innovative pilot program designed to introduce BU decentralization in Ouinhi district, one of Benin's most endemic districts previously served by centralized hospital-based care.. We conducted intervention-oriented research implemented in four steps: baseline study, training of health district clinical staff, outreach education, outcome and impact assessments. Study results demonstrated that early BU lesions (71% of all detected cases) could be treated in the community following outreach education, and that most of the afflicted were willing to accept decentralized treatment. Ninety-three percent were successfully treated with antibiotics alone. The impact evaluation found that community confidence in decentralized BU care was greatly enhanced by clinic staff who came to be seen as having expertise in the care of most chronic wounds.. This study documents a successful BU outreach and decentralized care program reaching early BU cases not previously treated by a proactive centralized BU program. The pilot program further demonstrates the added value of integrated wound management for NTD control.

Topics: Anti-Bacterial Agents; Benin; Buruli Ulcer; Community Health Services; Disease Management; Early Medical Intervention; Female; Health Impact Assessment; Health Plan Implementation; Humans; Male; Mycobacterium ulcerans; Rifampin; Streptomycin

Topics: Anti-Bacterial Agents; Benin; Buruli Ulcer; Humans; Mycobacterium ulcerans; Rifampin

Mycobacterium ulcerans is the causative agent of Buruli ulcer, a neglected tropical skin disease that is most commonly found in children from West and Central Africa. Despite the severity of the infection, therapeutic options are limited to antibiotics with severe side effects. Here, we show that M. ulcerans is susceptible to the anti-tubercular drug Q203 and related compounds targeting the respiratory cytochrome bc

Topics: Africa; Animals; Antibiotics, Antitubercular; Australia; Buruli Ulcer; Disease Models, Animal; Electron Transport Complex III; Electron Transport Complex IV; Female; Humans; Imidazoles; Inhibitory Concentration 50; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Neglected Diseases; Piperidines; Pyridines; Rifampin; Treatment Outcome

Buruli ulcer (BU) is a necrotizing infection of subcutaneous tissue that is caused by Mycobacterium ulcerans and is responsible for disfiguring skin lesions. The disease is endemic to specific geographic regions in the state of Victoria in southeastern Australia. Growing evidence of the effectiveness of antibiotic therapy for M. ulcerans disease has evolved our practice to the use of primarily oral medical therapy. An observational cohort study was performed on all confirmed M. ulcerans cases treated with primary rifampin-based medical therapy at Barwon Health between October 2010 and December 2014 and receiving 12 months of follow-up. One hundred thirty-two patients were managed with primary medical therapy. The median age of patients was 49 years, and nearly 10% had diabetes mellitus. Lesions were ulcerative in 83.3% of patients and at WHO stage 1 in 78.8% of patients. The median duration of therapy was 56 days, with 22 patients (16.7%) completing fewer than 56 days of antimicrobial treatment. Antibiotic-associated complications requiring cessation of one or more antibiotics occurred in 21 (15.9%) patients. Limited surgical debridement was performed on 30 of these medically managed patients (22.7%). Cure was achieved, with healing within 12 months, in 131 of 132 patients (99.2%), and cosmetic outcomes were excellent. Primary rifampin-based oral medical therapy for M. ulcerans disease, combined with either clarithromycin or a fluoroquinolone, has an excellent rate of cure and an acceptable toxicity profile in Australian patients. We advocate for further research to determine the optimal and safest minimum duration of medical therapy for BU.

Topics: Administration, Oral; Adult; Aged; Anti-Bacterial Agents; Australia; Buruli Ulcer; Clarithromycin; Cohort Studies; Female; Fluoroquinolones; Humans; Male; Middle Aged; Mycobacterium ulcerans; Prospective Studies; Rifampin; Victoria; Young Adult

Buruli ulcer (BU) is a tropical skin disease caused by infection with Mycobacterium ulcerans, which is currently treated with 8 weeks of streptomycin and rifampicin. The evidence to treat BU for a duration of 8 weeks is limited; a recent retrospective study from Australia suggested that a shorter course of antimicrobial therapy might be equally effective. We studied the outcomes of BU in a cohort of Ghanaian patients who defaulted from treatment and as such received less than 8 weeks of antimicrobial therapy.. A number of days of antimicrobial therapy and patient and lesion characteristics were recorded from charts from a cohort of BU patients treated at Nkawie-Toase hospital between 2008 and 2012. Patients who defaulted from treatment were retrieved, and lesion characteristics and functional limitations were recorded.. About 54% of patients defaulted from therapy or wound care. Forty-seven defaulters with follow-up completed had received <56 days of antibiotics. 84% of these patients healed after 32 days or less of antibiotics. There appeared to be an increased rate of healing in smaller lesions; 94% of WHO category I lesions had healed after 32 days or less of antibiotics.. Although numbers were small, and a potential for bias exists, our findings suggest that a reduction in the duration of antimicrobial therapy in BU in small, early lesions is feasible. These findings can serve as a basis for future well-designed studies.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Buruli Ulcer; Cohort Studies; Drug Administration Schedule; Drug Therapy, Combination; Female; Ghana; Hospitals; Humans; Male; Medication Adherence; Middle Aged; Mycobacterium ulcerans; Rifampin; Streptomycin; Treatment Outcome; Wound Healing; Young Adult

The treatment of Buruli ulcer (BU) that is caused by Mycobacterium ulcerans, is currently based on a daily administration of rifampin and streptomycin (RIF-STR). A fully oral intermittent regimen would greatly simplify its treatment on the field.. The objective of this study was to assess the bactericidal and sterilizing activities of intermittent oral regimens in a murine model of established M. ulcerans infection. Regimens combining rifapentine (RFP 20 mg/kg) with either moxifloxacin (MXF 200 mg/kg), clarithromycin (CLR 100 mg/kg) or bedaquiline (BDQ 25 mg/kg) were administrated twice (2/7) or three (only for RFP-CLR 3/7) times weekly during 8 weeks. The bactericidal but also the sterilizing activities of these four intermittent oral regimens were at least as good as those obtained with control weekdays regimens, i.e. RFP-CLR 5/7 or RIF-STR 5/7. A single mouse from the RFP-MFX 2/7 group had culture-positive relapse at the end of the 28 weeks following treatment completion among the 157 mice treated with one of the four intermittent regimens (40 RFP-CLR 2/7, 39 RFP-CLR 3/7, 39 RFP-MXF 2/7, 39 RFP-BDQ 2/7).. These results open the door for a fully intermittent oral drug regimen for BU treatment avoiding intramuscular injections and facilitating supervision by health care workers.

Topics: Animals; Anti-Bacterial Agents; Buruli Ulcer; Clarithromycin; Diarylquinolines; Drug Therapy, Combination; Female; Fluoroquinolones; Humans; Mice; Mice, Inbred BALB C; Moxifloxacin; Mycobacterium ulcerans; Rifampin

Buruli ulcer (BU), caused by Mycobacterium ulcerans, is a neglected tropical disease frequently leading to permanent disabilities. The ulcers are treated with rifampicin and streptomycin, wound care and, if necessary surgical intervention. Professionals have exclusively shaped the research agenda concerning management and control, while patients' perspective on priorities and preferences have not explicitly been explored or addressed.. To get insight into patient perception of the management and control of Buruli ulcer a mixed methods research design was applied with a questionnaire and focus group discussions among former BU patients. Data collection was obtained in collaboration with a local team of native speakers in Ghana. A questionnaire was completed by 60 former patients and four focus group discussions were conducted with eight participants per group. Former patients positively evaluated both the effectiveness of the treatment and the financial contribution received for the travel costs to the hospitals. Pain experienced during treatment procedures, in particular wound care and the streptomycin injections, and the side-effects of the treatment were negatively evaluated. Former patients considered the development of preventive measures and knowledge on the transmission as priorities. Additionally, former patients asked for improved accessibility of health services, counselling and economic support.. These findings can be used to improve clinical management and to guide the international research agenda.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Buruli Ulcer; Female; Focus Groups; Ghana; Humans; Interviews as Topic; Male; Middle Aged; Mycobacterium ulcerans; Patient Preference; Rifampin; Streptomycin; Surveys and Questionnaires; Treatment Outcome; Young Adult

Buruli ulcer (BU) is an infectious skin disease, caused by Mycobacterium ulcerans, endemic in more than 30 countries worldwide especially Africa. Brong-Ahafo Region implemented WHO recommended daily treatment with streptomycin and rifampicin for eight weeks (SR8). Yet limited assessment of therapy exists. This study seeks to determine the outcome of SR8 therapy on BU in two endemic districts in Brong-Ahafo.. Longitudinal study was done with laboratory confirmed Buruli ulcer patients selected consecutively and put on SR8. Patient follow-up involved daily administration of SR8 and Bi-Weekly monitoring of treatment in the form of measurement of wound size and taking photographs.. The mean age of participants was 34.6 ± 16.6 years with minimum and maximum ages of 10 to 65 respectively. Those in the 10-19year age group 13 (26%) were most affected. Majority, 26 (52%) had no formal education and 27 (54.0%) were peasant farmers. Thirty-eight (76.0%) had previously used traditional treatment. Forty completed treatment and of these, 28 (70.0%) healed completely and 12 (30. 0%) improved by 80%-90%. Duration of lesion before seeking healthcare (P =0.04), use of traditional treatment P < 0.001, clinical form of lesion P = 0.04, lesion category (p = 0.01), significantly affected healing. Mean time to healing, was 7.7 weeks (95% CI, 7.3 - 7.9).. Though SR8 is effective in curing BU, late reporting, use of herbs and access to health care impeded wound healing. This calls for provision of accessible health care and education to improve early reporting.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Buruli Ulcer; Child; Drug Therapy, Combination; Female; Follow-Up Studies; Ghana; Humans; Longitudinal Studies; Male; Middle Aged; Mycobacterium ulcerans; Rifampin; Streptomycin; Time Factors; Treatment Outcome; Wound Healing; Young Adult

Mycobacterium ulcerans (M. ulcerans) is a necrotizing skin infection endemic to the Bellarine Peninsula, Australia. Current treatment recommendations include 8 weeks of combination antibiotics, with adjuvant surgery if necessary. However, antibiotic toxicity often results in early treatment cessation and local experience suggests that shorter antibiotic courses may be effective with concurrent surgery. We report the outcomes of patients in the Barwon Health M. ulcerans cohort who received shorter courses of antibiotic therapy than 8 weeks.. A retrospective analysis was performed of all M. ulcerans infections treated at Barwon Health from March 1, 1998 to July 31, 2013. Sixty-two patients, with a median age of 65 years, received < 56 days of antibiotics and 51 (82%) of these patients underwent concurrent surgical excision. Most received a two-drug regimen of rifampicin combined with either ciprofloxacin or clarithromycin for a median 29 days (IQR 21-41 days). Cessation rates were 55% for adverse events and 36% based on clinician decision. The overall success rate was 95% (98% with concurrent surgery; 82% with antibiotics alone) with a 50% success rate for those who received < 14 days of antibiotics increasing to 94% if they received 14-27 days and 100% for 28-55 days (p<0.01). A 100% success rate was seen for concurrent surgery and 14-27 days of antibiotics versus 67% for concurrent surgery and < 14 days of antibiotics (p = 0.12). No previously identified risk factors for treatment failure with surgery alone were associated with reduced treatment success rates with < 56 days of antibiotics.. In selected patients, antibiotic treatment durations for M. ulcerans shorter than the current WHO recommended 8 weeks duration may be associated with successful outcomes.

Topics: Adjuvants, Immunologic; Adult; Aged; Antibiotics, Antitubercular; Australia; Buruli Ulcer; Ciprofloxacin; Clarithromycin; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Mycobacterium ulcerans; Retrospective Studies; Rifampin; Risk Factors; Treatment Outcome; Withholding Treatment

Mycobacterium ulcerans causes Buruli ulcer (BU), a debilitating infection of subcutaneous tissue. There is a WHO-recommended antibiotic treatment requiring an 8-week course of streptomycin and rifampicin. This regime has revolutionized the treatment of BU but there are problems that include reliance on daily streptomycin injections and side effects such as ototoxicity. Trials of all-oral treatments for BU show promise but additional drug combinations that make BU treatment safer and shorter would be welcome. Following on from reports that avermectins have activity against Mycobacterium tuberculosis, we tested the in-vitro efficacy of ivermectin and moxidectin on M. ulcerans. We observed minimum inhibitory concentrations of 4-8 μg/ml and time-kill assays using wild type and bioluminescent M. ulcerans showed a significant dose-dependent reduction in M. ulcerans viability over 8-weeks. A synergistic killing-effect with rifampicin was also observed. Avermectins are well tolerated, widely available and inexpensive. Based on our in vitro findings we suggest that avermectins should be further evaluated for the treatment of BU.

Topics: Administration, Oral; Buruli Ulcer; Ivermectin; Microbial Sensitivity Tests; Mycobacterium ulcerans; Rifampin; Streptomycin

Buruli ulcer (BU) is a refractory skin ulcer caused by Mycobacterium ulcerans or M. ulcerans ssp. shinshuense, a subspecies thought to have originated in Japan or elsewhere in Asia. Although BU occurs most frequently in tropical and subtropical areas such as Africa and Australia, the occurrence in Japan has gradually increased in recent years. The World Health Organization recommends multidrug therapy consisting of a combination of oral rifampicin (RFP) and i.m. streptomycin (SM) for the treatment of BU. However, surgical interventions are often required when chemotherapy alone is ineffective. As a first step in developing a standardized regimen for BU treatment in Japan, we analyzed detailed records of treatments and prognoses in 40 of the 44 BU cases that have been diagnosed in Japan. We found that a combination of RFP (450 mg/day), levofloxacin (LVFX; 500 mg/day) and clarithromycin (CAM; at a dose of 800 mg/day instead of 400 mg/day) was superior to other chemotherapies performed in Japan. This simple treatment with oral medication increases the probability of patient adherence, and may often eliminate the need for surgery.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Buruli Ulcer; Child; Child, Preschool; Clarithromycin; Drug Therapy, Combination; Female; Humans; Japan; Levofloxacin; Male; Middle Aged; Rifampin; Young Adult

Severe oedematous forms of Buruli ulcer (BU) often result in extensive tissue destruction, even with the institution of appropriate antibiotic treatment, leading to reconstructive surgery and long-term disability. We report a case of a patient with severe oedematous BU, which describes for the first time the pre-emptive use of prednisolone therapy commenced at the time of antibiotic initiation aimed at limiting the ongoing tissue destruction and its secondary sequelae.. A 91-year-old Australian-born Caucasian woman presented with a WHO category 3 oedematous BU lesion on the anterior aspect of her right ankle that she had first noticed three weeks earlier. Treatment was commenced with an antibiotic combination of rifampicin and ciprofloxacin. At the same time, pre-emptive prednisolone was commenced (a dose of 0.5mg/kg daily). Treatment resulted in rapid and significant reduction in the size of the induration associated with the lesion, and no significant increase in the size of the skin ulceration. Antibiotics were continued for 56 days and prednisolone therapy ceased 130 days after antibiotics commenced. No surgery was required. The wound healed completely after 10 months and there was no long-term limitation of movement at the ankle joint.. Pre-emptive corticosteroid therapy may prevent further progressive tissue necrosis and the need for secondary reconstructive surgery that commonly occurs during the antibiotic treatment of severe odematous forms of BU.

Topics: Aged, 80 and over; Anti-Bacterial Agents; Anti-Inflammatory Agents; Buruli Ulcer; Ciprofloxacin; Drug Therapy, Combination; Edema; Female; Humans; Prednisolone; Rifampin

Treatment of Buruli ulcer, or Mycobacterium ulcerans disease, has shifted from surgical excision and skin grafting to antibiotic therapy usually with 8 weeks of daily rifampin (RIF) and streptomycin (STR). Although the results have been highly favorable, administration of STR requires intramuscular injection and carries the risk of side effects, such as hearing loss. Therefore, an all-oral, potentially less toxic, treatment regimen has been sought and encouraged by the World Health Organization. A combination of RIF plus clarithromycin (CLR) has been successful in patients first administered RIF+STR for 2 or 4 weeks. Based on evidence of efficacy of clofazimine (CFZ) in humans and mice with tuberculosis, we hypothesized that the combination of RIF+CFZ would be effective against M. ulcerans in the mouse footpad model of M. ulcerans disease because CFZ has similar MIC against M. tuberculosis and M. ulcerans. For comparison, mice were also treated with the gold standard of RIF+STR, the proposed RIF+CLR alternative regimen, or CFZ alone. Treatment was initiated after development of footpad swelling, when the bacterial burden was 4.64±0.14log10 CFU. At week 2 of treatment, the CFU counts had increased in untreated mice, remained essentially unchanged in mice treated with CFZ alone, decreased modestly with either RIF+CLR or RIF+CFZ, and decreased substantially with RIF+STR. At week 4, on the basis of footpad CFU counts, the combination regimens were ranked as follows: RIF+STR>RIF+CLR>RIF+CFZ. At weeks 6 and 8, none of the mice treated with these regimens had detectable CFU. Footpad swelling declined comparably with all of the combination regimens, as did the levels of detectable mycolactone A/B. In mice treated for only 6 weeks and followed up for 24 weeks, there were no relapses in RIF+STR treated mice, one (5%) relapse in RIF+CFZ-treated mice, but >50% in RIF+CLR treated mice. On the basis of these results, RIF+CFZ has potential as a continuation phase regimen for treatment of M. ulcerans disease.

Topics: Animals; Buruli Ulcer; Clarithromycin; Clofazimine; Colony Count, Microbial; Drug Evaluation, Preclinical; Drug Therapy, Combination; Foot; Macrolides; Mice; Microbial Sensitivity Tests; Rifampin; Streptomycin; Survival Analysis; Time Factors; Treatment Outcome

The synergy between Mycobacterium tuberculosis infection and human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome is well established but not so in Buruli ulcer (BU). We screened confirmed BU cases for HIV infection and followed seven BU/HIV-coinfected patients. Management of BU/HIV was based on the World Health Organization guidelines and patient condition. The HIV positivity among BU patients (8.2%; 11/134) was higher compared with that of general patients attending the facility (4.8%; 718/14,863; P = 0.07) and that of pregnant women alone (2.5%; 279/11,125; P = 0.001). All seven BU/HIV-coinfected cases enrolled in the study presented with very large (category III) lesions with four having multiple lesions compared with 54.5% of category III lesions among HIV-negative BU patients. During the recommended BU treatment with streptomycin and rifampicin (SR) all patients developed immune infiltrates including CD4 T cells in their lesions. However, one patient who received antiretroviral therapy (ART) 1 week after beginning SR treatment developed four additional lesions during antibiotic treatment, while two out of the four who did not receive ART died. Further evidence is required to ascertain the most appropriate time to commence ART in relation to SR treatment to minimize paradoxical reactions.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Antiretroviral Therapy, Highly Active; Buruli Ulcer; Child; Child, Preschool; Coinfection; Disease Management; Female; Ghana; HIV Infections; Humans; Male; Middle Aged; Mycobacterium ulcerans; Rifampin; Streptomycin; World Health Organization; Young Adult

Mycobacterium ulcerans (MU) produces mycolactone toxin when infected with a plasmid. Toxin is cytotoxic and immunosuppressive, causing extensive destruction of tissues, leading to large ulcers on exposed parts of the body. Spontaneous healing by secondary intention leads to contractures, subluxation of joints, disuse atrophy, distal lymphedema and other complications. The disease is endemic in some communities within the middle belt of Ghana.. To document the clinical and epidemiological features of MU disease in the middle belt of Ghana and the outcome of treatment.. Patients with lesions suspected to MU disease were screened by community workers. Lesions were confirmed by any of the following: direct smear examination, culture, polymerase chain reaction (PCR), or histopathology. Patients were treated with rifampicin (10mg/kg orally) and streptomycin (15 mg/kg IM) combination for eight weeks. Patients selected for surgical treatment included cases where medical treatment had failed, cases where medical treatment is contraindicated, cases presenting late with complications and recurrent cases.. 258 patients were seen in the Ahafo Ano, Amansie Central, Amansie West, Asunafo, Asutifi, and Upper Denkyira districts of Ghana between 2005 and 2012. Their ages ranged from 1 year 3 months to 98 years, with a mean age of 29.8 (SD 20.4). The clinical forms of MU disease seen were: papule (0.5%), nodule (1.5%), chronic osteomyelitis (1.5%), contracture (1.5%), edematous lesion (3%), and ulcer (92%). Uncommon complications include subluxation of knee joint, salivary gland fistula and Marjolin's ulcer. The lesions were distributed as follows: head and neck (6.8%), upper limb (20.3%), trunk (1.7%), and lower limb (71.2%).. MU disease in the middle belt of Ghana can be controlled by early case detection and adequate curative treatment.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Buruli Ulcer; Child; Endemic Diseases; Female; Ghana; Humans; Male; Mycobacterium ulcerans; Rifampin; Streptomycin; Young Adult

Buruli ulcer, an ulcerating skin disease caused by Mycobacterium ulcerans infection, 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.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Buruli Ulcer; Child; Child, Preschool; Clarithromycin; Drug Synergism; Drug Therapy, Combination; Female; Ghana; Humans; Middle Aged; Mycobacterium ulcerans; Rifampin; Skin; Streptomycin; Treatment Outcome

This study evaluates a novel assay for detecting rifampin resistance in clinical Mycobacterium ulcerans isolates. Although highly susceptible for PCR inhibitors in 50% of the samples tested, the assay was 100% M. ulcerans specific and yielded >98% analyzable sequences with a lower limit of detection of 100 to 200 copies of the target sequence.

Topics: Anti-Bacterial Agents; Buruli Ulcer; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Molecular Diagnostic Techniques; Mycobacterium ulcerans; Rifampin; Sensitivity and Specificity

• Guidelines reflecting contemporary clinical practice in the management of Buruli ulcer (Mycobacterium ulcerans infection) in Australia were published in 2007. • Management has continued to evolve, as new evidence has become available from randomised trials, case series and increasing clinical experience with oral antibiotic therapy. • Therefore, guidelines on the diagnosis, treatment and prevention of Buruli ulcer in Australia have been updated. They include guidance on the new role of antibiotics as first-line therapy; the shortened duration of antibiotic treatment and the use of all-oral antibiotic regimens; the continued importance, timing and role of surgery; the recognition and management of paradoxical reactions during antibiotic treatment; and updates on the prevention of disease.

Topics: Anti-Bacterial Agents; Australia; Buruli Ulcer; Debridement; Drug Therapy, Combination; Hot Temperature; Humans; Mycobacterium ulcerans; Practice Guidelines as Topic; Rifampin; Streptomycin

Topics: Adolescent; Adult; Anti-Bacterial Agents; Buruli Ulcer; Child; Child, Preschool; Congo; Epidemiological Monitoring; Female; Humans; Male; Mycobacterium ulcerans; Neglected Diseases; Rifampin; Streptomycin

Topics: Anti-Bacterial Agents; Buruli Ulcer; Clarithromycin; Female; Humans; Mycobacterium ulcerans; Rifampin; Streptomycin

Topics: Anti-Bacterial Agents; Buruli Ulcer; Clarithromycin; Female; Humans; Mycobacterium ulcerans; Rifampin; Streptomycin

Since 2004, treatment of Mycobacterium ulcerans disease, or Buruli ulcer, has shifted from surgery to daily treatment with streptomycin (STR) + rifampin (RIF) for 8 weeks. For shortening treatment duration, we tested the potential of daily rifapentine (RPT), a long-acting rifamycin derivative, as a substitute for RIF.. BALB/c mice were infected with M. ulcerans in the right hind footpad and treated either daily (7/7) with STR+RIF or five days/week (5/7) with STR+RIF or STR+RPT for 4 weeks, beginning 28 days after infection when CFU counts were 4.88±0.51. The relative efficacy of the drug treatments was compared by footpad CFU counts during treatment and median time to footpad swelling after treatment cessation as measure of sterilizing activity. All drug treatments were bactericidal. After 1 week of treatment, the decline in CFU counts was significantly greater in treated mice but not different between the three treated groups. After 2 weeks of treatment, the decline in CFU was greater in mice treated with STR+RPT 5/7 than in mice treated with STR+RIF 7/7 and STR+RIF 5/7. After 3 and 4 weeks of treatment, CFU counts were nil in mice treated with STR+RPT and reduced by more than 3 and 4 logs in mice treated with STR+RIF 5/7 and STR+RIF 7/7, respectively. In sharp contrast to the bactericidal activity, the sterilizing activity was not different between all drug regimens although it was in proportion to the treatment duration.. The better bactericidal activity of daily STR+RIF and especially of STR+RPT did not translate into better prevention of relapse, possibly because relapse-freecure after treatment of Buruli ulcer is more related to the reversal of mycolactone-induced local immunodeficiency by drug treatment rather than to the bactericidal potency of drugs.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Buruli Ulcer; Colony Count, Microbial; Disease Models, Animal; Drug Therapy, Combination; Female; Mice; Mice, Inbred BALB C; Microbial Viability; Mycobacterium ulcerans; Rifampin; Secondary Prevention; Streptomycin; Treatment Outcome

Mycobacterium ulcerans infection causes a neglected tropical disease known as Buruli ulcer that is now found in poor rural areas of West Africa in numbers that sometimes exceed those reported for another significant mycobacterial disease, leprosy, caused by M. leprae. Unique among mycobacterial diseases, M. ulcerans produces a plasmid-encoded toxin called mycolactone (ML), which is the principal virulence factor and destroys fat cells in subcutaneous tissue. Disease is typically first manifested by the appearance of a nodule that eventually ulcerates and the lesions may continue to spread over limbs or occasionally the trunk. The current standard treatment is 8 weeks of daily rifampin and injections of streptomycin (RS). The treatment kills bacilli and wounds gradually heal. Whether RS treatment actually stops mycolactone production before killing bacilli has been suggested by histopathological analyses of patient lesions. Using a mouse footpad model of M. ulcerans infection where the time of infection and development of lesions can be followed in a controlled manner before and after antibiotic treatment, we have evaluated the progress of infection by assessing bacterial numbers, mycolactone production, the immune response, and lesion histopathology at regular intervals after infection and after antibiotic therapy. We found that RS treatment rapidly reduced gross lesions, bacterial numbers, and ML production as assessed by cytotoxicity assays and mass spectrometric analysis. Histopathological analysis revealed that RS treatment maintained the association of the bacilli with (or within) host cells where they were destroyed whereas lack of treatment resulted in extracellular infection, destruction of host cells, and ultimately lesion ulceration. We propose that RS treatment promotes healing in the host by blocking mycolactone production, which favors the survival of host cells, and by killing M. ulcerans bacilli.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Buruli Ulcer; Cell Survival; Disease Models, Animal; Histocytochemistry; Macrolides; Mass Spectrometry; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Rifampin; Streptomycin

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Aza Compounds; Buruli Ulcer; Debridement; Fluoroquinolones; Glucocorticoids; Humans; Male; Moxifloxacin; Mycobacterium ulcerans; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prednisolone; Quinolines; Rifampin; Young Adult

Buruli ulcer (BU), caused by Mycobacterium ulcerans is a chronic necrotizing skin disease. It usually starts with a subcutaneous nodule or plaque containing large clusters of extracellular acid-fast bacilli. Surrounding tissue is destroyed by the cytotoxic macrolide toxin mycolactone produced by microcolonies of M. ulcerans. Skin covering the destroyed subcutaneous fat and soft tissue may eventually break down leading to the formation of large ulcers that progress, if untreated, over months and years. Here we have analyzed the bacterial flora of BU lesions of three different groups of patients before, during and after daily treatment with streptomycin and rifampicin for eight weeks (SR8) and determined drug resistance of the bacteria isolated from the lesions. Before SR8 treatment, more than 60% of the examined BU lesions were infected with other bacteria, with Staphylococcus aureus and Pseudomonas aeruginosa being the most prominent ones. During treatment, 65% of all lesions were still infected, mainly with P. aeruginosa. After completion of SR8 treatment, still more than 75% of lesions clinically suspected to be infected were microbiologically confirmed as infected, mainly with P. aeruginosa or Proteus miriabilis. Drug susceptibility tests revealed especially for S. aureus a high frequency of resistance to the first line drugs used in Ghana. Our results show that secondary infection of BU lesions is common. This could lead to delayed healing and should therefore be further investigated.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacteria; Buruli Ulcer; Child; Child, Preschool; Coinfection; Drug Resistance, Bacterial; Female; Ghana; Humans; Male; Middle Aged; Rifampin; Streptomycin; Wound Infection; Young Adult

Topics: Antibiotics, Antitubercular; Buruli Ulcer; Female; Humans; Mycobacterium ulcerans; Rifampin

Mycobacterium ulcerans (MU) is responsible for disfiguring skin lesions and is endemic on the Bellarine peninsula of southeastern Australia. Antibiotics have been shown to be highly effective in sterilizing lesions and preventing disease recurrences when used alone or in combination with surgery. Our practice has evolved to using primarily oral medical therapy.. From a prospective cohort of MU patients managed at Barwon Health, we describe those treated with primary medical therapy defined as treatment of a M. ulcerans lesion with antimicrobials either alone or in conjunction with limited surgical debridement.. From 1/10/2010 through 31/12/11, 43 patients were treated with exclusive medical therapy, of which 5 (12%) also underwent limited surgical debridement. The median patient age was 50.2 years, and 86% had WHO category 1 and 91% ulcerative lesions. Rifampicin was combined with ciprofloxacin in 30 (70%) and clarithromycin in 12 (28%) patients. The median duration of antibiotic therapy was 56 days, with 7 (16%) receiving less than 56 days. Medication side effects requiring cessation of one or more antibiotics occurred in 7 (16%) patients. Forty-two (98%) patients healed without recurrence within 12 months, and 1 patient (2%) experienced a relapse 4 months after completion of 8 weeks of antimicrobial therapy.. Our experience demonstrates the efficacy and safety of primary oral medical management of MU infection with oral rifampicin-based regimens. Further research is required to determine the optimal and minimum durations of antibiotic therapy, and the most effective antibiotic dosages and formulations for young children.

Topics: Administration, Oral; Adult; Aged; Anti-Bacterial Agents; Australia; Buruli Ulcer; Ciprofloxacin; Clarithromycin; Cohort Studies; Debridement; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Mycobacterium ulcerans; Retrospective Studies; Rifampin; Treatment Outcome

Buruli ulcer (BU) denotes a cutaneous infection by Mycobacterium ulcerans endemic in certain tropical and subtropical regions. Treatment may be either medical and surgical or else purely medical for early lesions. The literature contains reports of several cases of transient aggravation of BU following initiation of medical treatment. We report a case observed in the Ivory Coast, one of the areas with the highest prevalence of BU worldwide. The distinguishing features of our case are the early onset of this paradoxical reaction and the multiple cephalic site of lesions.. A 4-year-old child with no prior medical history was referred for two painless ulcerative cutaneous nodules. Incubation of samples from the edges of these lesions revealed the presence of acid-alcohol resistant bacilli (AARB), which were shown by PCR to be M. ulcerans, the causative agent in BU. Treatment consisted of levofloxacin (100mg/d) and rifampicin (150mg/d) for 8weeks. After 7days of medical treatment, seven painless nodules appeared on the patient's scalp. Further PCR for these lesions confirmed the presence of M. ulcerans. The same medical therapy was maintained and after 54days of treatment, all lesions had been healed.. The originality of this case rests on two features: the bifocal aspect of the lesions, which is uncommon, and the early development of cephalic predominance that occurred after the start of drug treatment. While cases of lesions secondary to initiation of medical therapy have already been described, such lesions generally occurred after at least 2months of treatment and did not involve the head.

Topics: Anti-Bacterial Agents; Buruli Ulcer; Child, Preschool; Chin; Cicatrix; Cote d'Ivoire; Drug Therapy, Combination; Endemic Diseases; Facial Dermatoses; Female; Humans; Leg; Levofloxacin; Mycobacterium ulcerans; Ofloxacin; Rifampin; Scalp Dermatoses; Time Factors

Buruli ulcer is an indolent disease that needs aggressive curettage of caseous subcutaneous tissue beneath the undermined skin. We report the successful treatment of an 18-day-old baby.

Topics: Adult; Antibiotics, Antitubercular; Buruli Ulcer; Female; Humans; Infant, Newborn; Mycobacterium ulcerans; Rifampin; Skin; Skin Diseases, Bacterial; Treatment Outcome

Combination chemotherapy with rifampin and streptomycin (RIF-STR) for 8 weeks is currently recommended by the WHO as the first-line treatment for Mycobacterium ulcerans infection (Buruli ulcer). To gain better insight into the mode of action of these antibiotics against established M. ulcerans infection foci and to characterize recovery of local immune responses during chemotherapy, we conducted a detailed histopathological study of M. ulcerans-infected and RIF-STR-treated mice. Mice were inoculated with M. ulcerans in 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 with M. 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 experimental M. ulcerans mouse infection model will be a valuable tool to investigate efficacy of new treatment regimens and of candidate vaccines.

Topics: Animals; Anti-Bacterial Agents; Buruli Ulcer; Colony Count, Microbial; Disease Models, Animal; Drug Therapy, Combination; Female; Foot; Humans; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Rifampin; Streptomycin; Treatment Outcome

Topics: Anti-Bacterial Agents; Asian People; Buruli Ulcer; Clarithromycin; Drug Therapy, Combination; Face; Female; Humans; Middle Aged; Mycobacterium ulcerans; Ofloxacin; Pain; Rifampin

The World Health Organization currently recommends combined streptomycin and rifampicin antibiotic treatment as first-line therapy for Mycobacterium ulcerans infections. Alternatives are needed when these are not tolerated or accepted by patients, contraindicated, or neither accessible nor affordable. Despite in vitro effectiveness, clinical evidence for fluoroquinolone antibiotic use against Mycobacterium ulcerans is lacking. We describe outcomes and tolerability of fluoroquinolone-containing antibiotic regimens for Mycobacterium ulcerans in south-eastern Australia.. Analysis was performed of prospectively collected data including all primary Mycobacterium ulcerans infections treated at Barwon Health between 1998 and 2010. Medical treatment involved antibiotic use for more than 7 days; surgical treatment involved surgical excision of a lesion. Treatment success was defined as complete lesion healing without recurrence at 12 months follow-up. A complication was defined as an adverse event attributed to an antibiotic that required its cessation. A total of 133 patients with 137 lesions were studied. Median age was 62 years (range 3-94 years). 47 (34%) had surgical treatment alone, and 90 (66%) had combined surgical and medical treatment. Rifampicin and ciprofloxacin comprised 61% and rifampicin and clarithromycin 23% of first-line antibiotic regimens. 13/47 (30%) treated with surgery alone failed treatment compared to 0/90 (0%) of those treated with combination medical and surgical treatment (p<0.0001). There was no difference in treatment success rate for antibiotic combinations containing a fluoroquinolone (61/61 cases; 100%) compared with those not containing a fluoroquinolone (29/29 cases; 100%). Complication rates were similar between ciprofloxacin and rifampicin (31%) and rifampicin and clarithromycin (33%) regimens (OR 0.89, 95% CI 0.27-2.99). Paradoxical reactions during treatment were observed in 8 (9%) of antibiotic treated cases.. Antibiotics combined with surgery may significantly increase treatment success for Mycobacterium ulcerans infections, and fluoroquinolone combined with rifampicin-containing antibiotic regimens can provide an effective and safe oral treatment option.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Australia; Buruli Ulcer; Child; Child, Preschool; Cohort Studies; Drug Therapy, Combination; Female; Fluoroquinolones; Humans; Male; Middle Aged; Mycobacterium ulcerans; Rifampin; Treatment Outcome; Young Adult

Buruli ulcer (BU) is a neglected necrotizing disease of the skin, subcutaneous tissue and bone, caused by Mycobacterium ulcerans. BU pathogenesis is associated with mycolactone, a lipidic exotoxin with cytotoxic and immunosuppressive properties. Since 2004, the World Health Organization recommends the treatment of BU with a combination of rifampicin and streptomycin (RS). Histological analysis of human tissue samples suggests that such antibiotic treatment reverses the mycolactone-induced local immunosuppression, leading to increased inflammatory infiltrations and phagocytosis of bacilli.. We used a mouse model of M. ulcerans footpad infection, followed by combined RS treatment. Time-lapsed analyses of macroscopic lesions, bacterial burdens, histology and immunohistochemistry were performed in footpads. We also performed CFU counts, histology and immunohistochemistry in the popliteal draining lymph nodes (DLN). We observed a shift in the cellular infiltrates from a predominantly neutrophilic/macrophagic to a lymphocytic/macrophagic profile in the infected footpads of antibiotic-treated mice. This shift occurred before the elimination of viable M. ulcerans organisms, which were ultimately eradicated as demonstrated by the administration of dexamethasone. This reduction of bacillary loads was accompanied by an increased expression of inducible nitric oxide synthase (NOS2 or iNOS). Predominantly mononuclear infiltrates persisted in the footpads during and after treatment, coincident with the long persistence of non-viable poorly stained acid-fast bacilli (AFB). We additionally observed that antibiotherapy prevented DLN destruction and lymphocyte depletion, which occurs during untreated experimental infections.. Early RS treatment of M. ulcerans mouse footpad infections results in the rapid elimination of viable bacilli with pathogen eradication. However, non-viable AFB persisted for several months after lesion sterilization. This RS regimen prevented DLN destruction, allowing the rapid re-establishment of local and regional cell mediated immune responses associated with macrophage activation. Therefore it is likely that this re-establishment of protective cellular immunity synergizes with antibiotherapy.

Topics: Animals; Anti-Bacterial Agents; Buruli Ulcer; Dexamethasone; Disease Models, Animal; Disease Progression; Drug Therapy, Combination; Female; Flow Cytometry; Immunity, Cellular; Immunosuppressive Agents; Inflammation; Lymphocytes; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Rifampin; Streptomycin

Topics: Buruli Ulcer; Communicable Disease Control; Drug Therapy, Combination; Early Diagnosis; Ghana; Humans; National Health Programs; Rifampin; Streptomycin; World Health Organization

The diagnosis of Buruli ulcer should be considered in all painless undermined ulcers in the tropics. The diagnosis and treatment are a challenge in rural settings despite the well established tuberculosis programmes. Immediate commencement on rifampicin and streptomycin is essential to halt the progression of disease and to, hopefully, reverse it. Surgery is indicated in those with complex ulcers or with complications. We report the case of a nine-month-old boy presenting to visiting British surgeons in a district hospital in Uganda with multiple ulcers to the right forearm.

Topics: Antitubercular Agents; Buruli Ulcer; Forearm; Humans; Infant; Male; Rifampin; Streptomycin

Buruli ulcer (BU) is a necrotizing disease of the skin, subcutaneous tissue and bone caused by Mycobacterium ulcerans. It has been suggested that the immune response developed during the recommended rifampicin/streptomycin (RS) antibiotherapy is protective, contributing to bacterial clearance. On the other hand, paradoxical reactions have been described during or after antibiotherapy, characterized by pathological inflammatory responses. This exacerbated inflammation could be circumvented by immunosuppressive drugs. Therefore, it is important to clarify if the immune system contributes to bacterial clearance during RS antibiotherapy and if immunosuppression hampers the efficacy of the antibiotic regimen.. We used the M. ulcerans infection footpad mouse model. Corticosteroid-induced immunosuppression was achieved before experimental infection and maintained during combined RS antibiotherapy by the administration of dexamethasone (DEX). Time-lapsed analyses of macroscopic lesions, bacterial burdens, histology and immunohistochemistry were performed in M. ulcerans-infected footpads. We show here that corticosteroid-immunosuppressed mice are more susceptible to M. ulcerans, with higher bacterial burdens and earlier ulceration. Despite this, macroscopic lesions remised during combined antibiotic/DEX treatment and no viable bacteria were detected in the footpads after RS administration. This was observed despite a delayed kinetics in bacterial clearance, associated with a local reduction of T cell and neutrophil numbers, when compared with immunocompetent RS-treated mice. In addition, no relapse was observed following an additional 3 month period of DEX administration.. These findings reveal a major role of the RS bactericidal activity for the resolution of M. ulcerans experimental infections even during immunosuppression, and support clinical investigation on the potential use of corticosteroids or other immunosuppressive/anti-inflammatory drugs for the management of BU patients undergoing paradoxical reactions.

Topics: Adrenal Cortex Hormones; Animals; Anti-Bacterial Agents; Buruli Ulcer; Disease Models, Animal; Female; Foot; Histocytochemistry; Immunohistochemistry; Immunosuppressive Agents; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Rifampin; Streptomycin; Treatment Outcome

Mycobacterium ulcerans causes Buruli ulcer, a potentially disabling ulcerative skin disease. Only recently was antimicrobial therapy proven effective. Treatment for 2 months with rifampin plus streptomycin was first proposed after experiments in the mouse footpad model demonstrated bactericidal activity. This treatment is now considered the treatment of choice, although larger ulcers may require adjunctive surgery. Shorter, oral regimens are desired, but evaluating drug activity in mice is hampered by the very slow growth of M. ulcerans, which takes 3 months to produce countable colonies. We created a recombinant bioluminescent M. ulcerans strain expressing luxAB from Vibrio harveyi for real-time evaluation of antimicrobial effects in vivo. Mouse footpads were injected with wild-type M. ulcerans 1059 (WtMu) or the recombinant bioluminescent strain (rMu). Two weeks later, mice received rifampin plus streptomycin, kanamycin alone (to which rMu is resistant), or streptomycin alone for 4 weeks and were observed for footpad swelling (preventive model). Untreated controls and kanamycin-treated rMu-infected mice received rifampin plus streptomycin for 4 weeks after developing footpad swelling (curative model). Compared to WtMu, rMu exhibited similar growth and virulence in vivo and similar drug susceptibility. A good correlation was observed between luminescence (measured as relative light units) and number of viable bacteria (measured by CFU) in footpad homogenates. Proof of concept was also shown for serial real-time evaluation of drug activity in live mice. These results indicate the potential of bioluminescence as a real-time surrogate marker for viable bacteria in mouse footpads to accelerate the identification of new treatments for Buruli ulcer.

Topics: Animals; Anti-Bacterial Agents; Buruli Ulcer; Female; Kanamycin; Luminescence; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Rifampin; Streptomycin

Mycobacterium ulcerans infection is responsible for severe skin lesions in sub-Saharan Africa. We enrolled 30 Beninese patients with Buruli ulcers in a pilot study to evaluate efficacy of an oral chemotherapy using rifampicin plus clarithromycin during an 8-week period. The treatment was well tolerated, and all patients were healed by 12 months after initiation of therapy without relapse.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anti-Bacterial Agents; Benin; Buruli Ulcer; Child; Child, Preschool; Clarithromycin; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Mycobacterium ulcerans; Pilot Projects; Rifampin; Treatment Outcome; Young Adult

treatment of Mycobacterium ulcerans disease, or Buruli ulcer (BU), has shifted from surgery to treatment with streptomycin(STR)+rifampin(RIF) since 2004 based on studies in a mouse model and clinical trials. We tested two entirely oral regimens for BU treatment, rifampin(RIF)+clarithromycin(CLR) and rifapentine(RPT)+clarithromycin(CLR) in the mouse model.. BALB/c mice were infected in the right hind footpad with M. ulcerans strain 1059 and treated daily (5 days/week) for 4 weeks, beginning 11 days after infection. Treatment groups included an untreated control, STR+RIF as a positive control, and test regimens of RIF, RPT, STR and CLR given alone and the RIF+CLR and RPT+CLR combinations. The relative efficacy of the drug treatments was compared on the basis of footpad CFU counts and median time to footpad swelling. Except for CLR, which was bacteriostatic, treatment with all other drugs reduced CFU counts by approximately 2 or 3 log(10). Median time to footpad swelling after infection was 5.5, 16, 17, 23.5 and 36.5 weeks in mice receiving no treatment, CLR alone, RIF+CLR, RIF alone, and STR alone, respectively. At the end of follow-up, 39 weeks after infection, only 48%, 26.4% and 16.3% of mice treated with RPT+CLR, RPT alone and STR+RIF had developed swollen footpads. An in vitro checkerboard assay showed the interaction of CLR and RIF to be indifferent. However, in mice, co-administration with CLR resulted in a roughly 25% decrease in the maximal serum concentration (Cmax) and area under the serum concentration-time curve (AUC) of each rifamycin. Delaying the administration of CLR by one hour restored Cmax and AUC values of RIF to levels obtained with RIF alone.. these results suggest that an entirely oral daily regimen of RPT+CLR may be at least as effective as the currently recommended combination of injected STR+oral RIF.

Topics: Animals; Anti-Bacterial Agents; Buruli Ulcer; Clarithromycin; Disease Models, Animal; Drug Therapy, Combination; Female; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Rifampin; Treatment Outcome

The neglected tropical disease Buruli ulcer (BU) caused by Mycobacterium ulcerans is an infection of the subcutaneous tissue leading to chronic ulcerative skin lesions. Histopathological features are progressive tissue necrosis, extracellular clusters of acid fast bacilli (AFB) and poor inflammatory responses at the site of infection. After the recommended eight weeks standard treatment with rifampicin and streptomycin, a reversal of the local immunosuppression caused by the macrolide toxin mycolactone of M. ulcerans is observed.. We have conducted a detailed histopathological and immunohistochemical analysis of tissue specimens from two patients developing multiple new skin lesions 12 to 409 days after completion of antibiotic treatment. Lesions exhibited characteristic histopathological hallmarks of Buruli ulcer and AFB with degenerated appearance were found in several of them. However, other than in active disease, lesions contained massive leukocyte infiltrates including large B-cell clusters, as typically found in cured lesions.. Our histopathological findings demonstrate that the skin lesions emerging several months after completion of antibiotic treatment were associated with M. ulcerans infection. During antibiotic therapy of Buruli ulcer development of new skin lesions may be caused by immune response-mediated paradoxical reactions. These seem to be triggered by mycobacterial antigens and immunostimulators released from clinically unrecognized bacterial foci. However, in particular the lesions that appeared more than one year after completion of antibiotic treatment may have been associated with new infection foci resolved by immune responses primed by the successful treatment of the initial lesion.

Topics: Antibiotics, Antitubercular; Antigens, CD; Buruli Ulcer; Child; Humans; Immunohistochemistry; Leukocytes; Male; Mycobacterium ulcerans; Necrosis; Neglected Diseases; Rifampin; Skin; Streptomycin; Treatment Outcome

Buruli ulcer (BU) caused by Mycobacterium ulcerans is a necrotizing skin disease usually starting with a subcutaneous nodule or plaque, which may ulcerate and progress, if untreated, over months and years. During the currently recommended antibiotic treatment with rifampicin/streptomycin plaque lesions tend to ulcerate, often associated with retarded wound healing and prolonged hospital stays.. Included in this study were twelve laboratory reconfirmed, HIV negative BU patients presenting with plaque lesions at the CDTUB in Allada, Benin. Punch biopsies for histopathological and immunohistochemical analysis were taken before start of treatment and after four to five weeks of treatment. Where excision or wound debridement was clinically indicated, the removed tissue was also analyzed. Based on clinical judgment, nine of the twelve patients enrolled in this study received limited surgical excision seven to 39 days after completion of chemotherapy, followed by skin grafting. Lesions of three patients healed without further intervention. Before treatment, plaque lesions were characterized by a destroyed subcutis with extensive necrosis without major signs of infiltration. After completion of antibiotic treatment partial infiltration of the affected tissue was observed, but large necrotic areas remained unchanged.. Our histopathological analyses show that ulceration of plaque lesions during antibiotic treatment do not represent a failure to respond to antimycobacterial treatment. Based on our results we suggest formal testing in a controlled clinical trial setting whether limited surgical excision of necrotic tissue favours wound healing and can reduce the duration of hospital stays.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Benin; Biopsy; Buruli Ulcer; Child; Child, Preschool; Debridement; Drug Therapy; Female; Histocytochemistry; Humans; Immunohistochemistry; Male; Microscopy; Middle Aged; Mycobacterium ulcerans; Rifampin; Skin; Streptomycin; Treatment Outcome; Young Adult

The introduction of antibiotic therapy as first-line treatment of Buruli ulcer underlines the importance of laboratory confirmation of clinical diagnosis. Because smear microscopy has very limited sensitivity, the technically demanding and more expensive IS2404 diagnostic polymerase chain reaction (PCR) has become the main method for confirmation. By optimization of the release of mycobacteria from swab specimen and concentration of bacterial suspensions before smearing, we were able to improve the detection rate of acid-fast bacilli by microscopy after Ziehl-Neelsen staining. Compared with IS2404 PCR, which is the gold standard diagnostic method, the sensitivity and specificity of microscopy with 100 concentrated specimens were 58.4% and 95.7%, respectively. We subsequently evaluated a stepwise laboratory confirmation algorithm with detection of AFB as first-line method and IS2404 PCR performed only with those samples that were negative in microscopic analysis. This stepwise approach reduced unit cost by more than 50% to $5.41, and the total costs were reduced from $917 to $433.

Topics: Anti-Bacterial Agents; Biopsy, Fine-Needle; Buruli Ulcer; Ghana; Health Care Costs; Humans; Microscopy; Mycobacterium ulcerans; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Streptomycin

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-Bacterial Agents; Antibiotics, Antitubercular; Buruli Ulcer; Drug Therapy, Combination; Humans; Male; Rifampin; Streptomycin

Topics: Animals; Anti-Bacterial Agents; Buruli Ulcer; Clarithromycin; Drug Therapy, Combination; Ghana; Humans; Mice; Rifampin; Streptomycin

Topics: Administration, Oral; Adult; Anti-Bacterial Agents; Buruli Ulcer; Clarithromycin; Drug Therapy, Combination; France; Humans; Leg Ulcer; Male; Mali; Mycobacterium ulcerans; Pain; Rifampin; Travel; Treatment Outcome

The World Health Organization (WHO) advises treatment of Mycobacterium ulcerans disease, also called "Buruli ulcer" (BU), with a combination of the antibiotics rifampicin and streptomycin (R+S), whether followed by surgery or not. In endemic areas, a clinical case definition is recommended. We evaluated the effectiveness of this strategy in a series of patients with large ulcers of > or =10 cm in longest diameter in a rural health zone of the Democratic Republic of Congo (DRC).. A cohort of 92 patients with large ulcerated lesions suspected to be BU was enrolled between October 2006 and September 2007 and treated according to WHO recommendations. The following microbiologic data were obtained: Ziehl-Neelsen (ZN) stained smear, culture and PCR. Histopathology was performed on a sub-sample. Directly observed treatment with R+S was administered daily for 12 weeks and surgery was performed after 4 weeks. Patients were followed up for two years after treatment.. Out of 92 treated patients, 61 tested positive for M. ulcerans by PCR. PCR negative patients had better clinical improvement than PCR positive patients after 4 weeks of antibiotics (54.8% versus 14.8%). For PCR positive patients, the outcome after 4 weeks of antibiotic treatment was related to the ZN positivity at the start. Deterioration of the ulcers was observed in 87.8% (36/41) of the ZN positive and in 12.2% (5/41) of the ZN negative patients. Deterioration due to paradoxical reaction seemed unlikely. After surgery and an additional 8 weeks of antibiotics, 98.4% of PCR positive patients and 83.3% of PCR negative patients were considered cured. The overall recurrence rate was very low (1.1%).. Positive predictive value of the WHO clinical case definition was low. Low relapse rate confirms the efficacy of antibiotics. However, the need for and the best time for surgery for large Buruli ulcers requires clarification. We recommend confirmation by ZN stain at the rural health centers, since surgical intervention without delay may be necessary on the ZN positive cases to avoid progression of the disease. PCR negative patients were most likely not BU cases. Correct diagnosis and specific management of these non-BU ulcers cases are urgently needed.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacteriological Techniques; Buruli Ulcer; Child; Child, Preschool; Cohort Studies; Democratic Republic of the Congo; Female; Histocytochemistry; Humans; Male; Middle Aged; Mycobacterium ulcerans; Prospective Studies; Rifampin; Streptomycin; Treatment Outcome; Young Adult

Buruli ulcer (BU), a disease caused by Mycobacterium ulcerans, leads to the destruction of skin and sometimes bone. Here, we report a case of severe multifocal BU with osteomyelitis in a 6-year-old human immunodeficiency virus (HIV)-negative boy. Such disseminated forms are poorly documented and generally occur in patients with HIV co-infection. The advent of antibiotic treatment with streptomycin (S) and rifampin (R) raised hope that these multifocal BU cases could be reduced. The present case raises two relevant points about multifocal BU: the mechanism of dissemination that leads to the development of multiple foci and the difficulties of treatment of multifocal forms of BU. Biochemical (hypoproteinemia), hematological (anemia), clinical (traditional treatment), and genetic factors are discussed as possible risk factors for dissemination.

Topics: Anti-Bacterial Agents; Buruli Ulcer; Child; Humans; Male; Osteomyelitis; Rifampin; Streptomycin

Topics: Adolescent; Age Distribution; Aged; AIDS-Related Opportunistic Infections; Amikacin; Anti-Infective Agents; Buruli Ulcer; Child; Combined Modality Therapy; Debridement; Drug Therapy, Combination; Female; Humans; Metronidazole; Mycobacterium ulcerans; Osteomyelitis; Rifampin; Streptomycin

Buruli ulcers result from an initial skin infection that often leads to extensive tissue necrosis. The causative agent is Mycobacterium ulcerans, a bacterium prevalent in humid, rural tropical areas. Several thousand people are infected each year, especially in Africa, where Buruli ulcers are a source of major disability. A combination of oral rifampicin and injectable streptomycin is effective. Surgical treatment and functional rehabilitation are often necessary. Diagnostic tests suitable for use in primary care settings are needed, along with well-tolerated, effective oral treatments.

Topics: Antitubercular Agents; Buruli Ulcer; Drug Therapy, Combination; Humans; Rifampin; Streptomycin; Water Microbiology

We have studied the evolution of the gamma interferon (IFN-gamma) and interleukin 10 (IL-10) responses after Mycobacterium ulcerans sonicate stimulation of whole blood from patients with early M. ulcerans lesions during treatment with rifampin and streptomycin for 8 weeks. Among the 26 patients, secretion of IFN-gamma increased during treatment, with a significant increase at 4 weeks and a further increase after 8 weeks overall. The increase was more rapid in patients with large or ulcerative lesions, becoming significant by 4 weeks. For small lesions, there was only a minor increase, which did not reach significance. There was no significant change in the median IL-10 response during antibiotic therapy, and there was no inverse correlation between IFN-gamma and IL-10 responses. These results demonstrate that an IFN-gamma secretory response to M. ulcerans developed, independently of IL-10 secretion, in patients whose M. ulcerans disease healed during antibiotic therapy.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Buruli Ulcer; Child; Female; Humans; Interferon-gamma; Interleukin-10; Male; Middle Aged; Mycobacterium ulcerans; Rifampin; Streptomycin

Infection with Mycobacterium ulcerans involves a devastating skin disease called Buruli ulcer (BU). Currently, dual therapy with rifampicin and streptomycin (R/S) for 8 weeks as well as surgery are the standard treatments.. To elucidate the processes taking place in BU lesions in the course of chemotherapy we performed an in-depth histological analysis of lesions after 4 weeks of R/S treatment and compared results with findings in untreated lesions and lesions treated for 8 weeks.. Tissue specimens were collected from patients who had no treatment and from patients after 4 and 8 weeks of R/S treatment. The main features evaluated were local immune responses, histopathological alterations and bacterial distribution.. After 4 weeks of R/S treatment we observed a large proportion of mycobacteria inside macrophages, occasionally forming globus-like aggregations. While distinct bands of inflammatory leucocytes surrounded the necrotic core in an ulcer and early granuloma formation was apparent in the healthy-appearing margins, acute cellular infiltration covering the whole lesion had developed in a nodular lesion. In contrast, ulcerative lesions after 8 weeks of chemotherapy showed intra- and extracellular bacterial debris as well as the presence of extensive chronic infiltrates forming huge granulomas.. R/S treatment of BU results in a rapid onset of local cellular immune responses associated with phagocytosis of the extracellular M. ulcerans. This may be related to declining levels of the macrolide toxin mycolactone in the tissue, thus leading to an enhanced chemotherapy-induced clearance of the infection.

Topics: Adolescent; Anti-Bacterial Agents; Buruli Ulcer; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Child; Drug Therapy, Combination; Female; Granuloma; Humans; Macrophages; Male; Middle Aged; Phagocytosis; Rifampin; Streptomycin; Treatment Outcome

Because of operational limitations, a significant proportion of the health centers at the peripheral level are able to provide treatment to Buruli ulcer patients with the combination rifampin (rifampicin)-streptomycin (RIF-STR) only five times weekly (5/7) instead of seven times weekly (7/7), as recommended. The objective of this experiment is to assess the impacts of various dosing frequencies of the combination on its bactericidal and sterilizing activities against Mycobacterium ulcerans in mice. The results demonstrate that the bactericidal activities did not differ significantly among five dosing frequencies of the combination, ranging from seven times to twice weekly, whereas the sterilizing activities differed widely. RIF-STR 7/7 was the only regimen that was able to sterilize the infection after 4 to 8 weeks of treatment; the sterilizing activities associated with reduced dosing frequencies were significantly diminished, and 8 weeks of 5/7 administration yielded a relapse rate greater than the generally accepted level of 5%. We recommend that the duration of treatment with 5/7 administration be prolonged beyond 8 weeks and that additional experiments with mice be carried out, with sufficient statistical power to compare the relapse rates of M. ulcerans infection between 8 weeks of 7/7 administration and 10 and 12 weeks of 5/7 administration of RIF-STR.

Topics: Animals; Anti-Bacterial Agents; Buruli Ulcer; Drug Therapy, Combination; Female; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Rifampin; Streptomycin; Treatment Outcome

Topics: Adult; Antibiotics, Antitubercular; Benin; Buruli Ulcer; Clarithromycin; Female; Humans; Mycobacterium ulcerans; Pregnancy; Pregnancy Complications, Infectious; Rifampin; Skin Transplantation

We report 3 patients with laboratory-confirmed Buruli ulcer in Kafufu/Luremo, Angola, and Kasongo-Lunda, Democratic Republic of Congo. These villages are near the Kwango/Cuango River, which flows through both countries. Further investigation of artisanal alluvial mining as a risk factor for Buruli ulcer is recommended.

Topics: Adolescent; Adult; Angola; Antibiotics, Antitubercular; Biopsy; Buruli Ulcer; Democratic Republic of the Congo; Diamond; Disease Reservoirs; Female; Humans; Male; Mining; Mycobacterium ulcerans; Rifampin; Risk Factors; Rivers; Skin; Streptomycin; Treatment Outcome

Infection due to Mycobacterium ulcerans or Buruli ulcer usually occurs on the limbs (70%) or trunk (20%). Involvement of the head and neck region is less frequent but can lead to serious sequels. The purpose of this report is to describe 8 patients including 7 children who were treated for Buruli ulcers on the head in the dermatology department of the University Hospital Center in Abidjan, Cote d'Ivoire. Eye lesions and visual impairment were the most frequent sequels.

Topics: Adolescent; Anti-Bacterial Agents; Anticoagulants; Buruli Ulcer; Child; Child, Preschool; Cote d'Ivoire; Enoxaparin; Eye Infections, Bacterial; Face; Female; Humans; Male; Ofloxacin; Rifampin; Severity of Illness Index; Soft Tissue Infections; Young Adult

The author reports a case of pleuritis associated with a large homolateral Buruli thorax ulcer in a nine-year old female patient, in the Democratic Republic of Congo. Smears on Ziehl-Neelsen revealed acid-alcohol-resistant bacilli. The pathological histology confirmed a Mycobacterium ulcerans infection (Buruli ulcer). The treatment was surgical (excision-dressing-grafting) associated to antibiotic therapy (Rifater, Pyrazynamide, and Myambutol). After six years of follow up, no relapse was observed.

Topics: Anti-Bacterial Agents; Buruli Ulcer; Child; Chloramines; Combined Modality Therapy; Drug Combinations; Drug Therapy, Combination; Ethambutol; Female; Follow-Up Studies; Humans; Isoniazid; Mastectomy; Metronidazole; Mycobacterium ulcerans; Nitrofurantoin; Pleurisy; Prednisolone; Pyrazinamide; Recurrence; Rifampin; Skin Transplantation

Buruli ulcer caused by Mycobacterium ulcerans is an infection of the subcutaneous tissue leading to chronic necrotising skin ulcers. The pathogenesis is associated with the cytocidal and immunosuppressive activities of a macrolide toxin. Histopathological hallmark of progressing disease is a poor inflammatory response despite of clusters of extracellular bacilli. While traditionally wide excision of the infected tissue was the standard treatment, provisional WHO guidelines now recommend an eight week pre-treatment with streptomycin and rifampicin.. We conducted a detailed immunohistochemical analysis of tissue samples from Buruli patients who received antibiotic treatment. Cellular immune response along with bacterial load and distribution were monitored. We demonstrate that this treatment leads to the development of highly organized cellular infiltration surrounding areas of coagulative necrosis. Diffuse infiltrates, granulomas and dense lymphocyte aggregation close to vessels were observed. Mycobacterial material was primarily located inside mononuclear phagocytes and microcolonies consisting of extracellular rod-shaped mycobacteria were no longer found. In observational studies some patients showed no clinical response to antibiotic treatment. Corresponding to that, one of five lesions analysed presented with huge clusters of rod-shaped bacilli but no signs of infiltration.. Results signify that eight weeks of antibiotic treatment reverses local immunosuppression and leads to an active inflammatory process in different compartments of the skin. Structured leukocyte infiltrates with unique signatures indicative for healing processes developed at the margins of the lesions. It remains to be analysed whether antibiotic resistance of certain strains of M. ulcerans, lacking patient compliance or poor drug quality are responsible for the absent clinical responses in some patients. In future, analysis of local immune responses could serve as a suitable surrogate marker for the efficacy of alternative treatment strategies.

Topics: Anti-Bacterial Agents; Buruli Ulcer; Child; Ghana; Granuloma; Humans; Immunohistochemistry; Lymphocytes; Mycobacterium; Mycobacterium Infections; Rifampin; Streptomycin

We report a case of a four-year-old Angolan boy with the edematous form of Buruli ulcer on the face and scalp, who was treated at a rural hospital in the Bas-Congo Province, Democratic Republic of Congo. Treatment consisted of a series of surgical interventions and antimycobacterial chemotherapy (rifampin and ciprofloxacin) for two months. This case demonstrates the diagnostic and management difficulties of an edematous lesion of BU on the face and suggests an enhancement of healing and limitation of extent of excision by specific antibiotherapy. The outcome in this patient also underscores the importance of prompt referral of suspected cases and training of health professionals in the early diagnosis of BU.

Topics: Angola; Anti-Bacterial Agents; Buruli Ulcer; Child, Preschool; Ciprofloxacin; Edema; Humans; Male; Mycobacterium ulcerans; Necrosis; Rifampin; Treatment Outcome