Risk Factors Associated with Antibiotic Treatment Failure of Buruli Ulcer

ABSTRACT Combination antibiotic therapy is highly effective in curing Buruli ulcer (BU) caused by Mycobacterium ulcerans. Treatment failures have been uncommonly reported with the recommended 56 days of antibiotics, and little is known about risk factors for treatment failure. We analyzed treatment failures among BU patients treated with ≥56 days of antibiotics from a prospective observational cohort at Barwon Health, Victoria, from 1 January 1998 to 31 December 2018. Treatment failure was defined as culture-positive recurrence within 12 months of commencing antibiotics under the following conditions: (i) following failure to heal the initial lesion or (ii) a new lesion developing at the original or at a new site. A total of 430 patients received ≥56 days of antibiotic therapy, with a median duration of 56 days (interquartile range [IQR], 56 to 80). Seven (1.6%) patients experienced treatment failure. For six adult patients experiencing treatment failure, all were male, weighed >90 kg, did not have surgery, and received combination rifampin-clarithromycin (median rifampin dose, 5.6 mg per kg of body weight per day; median clarithromycin dose, 8.1 mg/kg/day). When compared to those who did not fail treatment on univariate analysis, treatment failure was significantly associated with a weight of >90 kg (P < 0.001), male gender (P = 0.02), immune suppression (P = 0.04), and a first-line regimen of rifampin-clarithromycin compared to a regimen of rifampin-fluoroquinolone (P = 0.05). There is a low rate of treatment failure in Australian BU patients treated with rifampin-based oral combination antibiotic therapy. Our study raises the possibility that treatment failure risk may be increased in males, those with a body weight of >90 kg, those with immune suppression, and those taking rifampin-clarithromycin antibiotic regimens, but future pharmacokinetic and pharmacodynamics studies are required to determine the validity of these hypotheses.

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Increasing Experience with Primary Oral Medical Therapy for Mycobacterium ulcerans Disease in an Australian Cohort

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02853-15 ◽

2016 ◽

Vol 60 (5) ◽

pp. 2692-2695 ◽

Cited By ~ 22

Author(s):

N. Deborah Friedman ◽

Eugene Athan ◽

Aaron L. Walton ◽

Daniel P. O'Brien

Keyword(s):

Medical Therapy ◽

Subcutaneous Tissue ◽

Buruli Ulcer ◽

Skin Lesions ◽

Antimicrobial Treatment ◽

Mycobacterium Ulcerans ◽

Content Type ◽

Southeastern Australia ◽

Observational Cohort ◽

Stage 1

ABSTRACTBuruli ulcer (BU) is a necrotizing infection of subcutaneous tissue that is caused byMycobacterium ulceransand 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 forM. ulceransdisease has evolved our practice to the use of primarily oral medical therapy. An observational cohort study was performed on all confirmedM. ulceranscases 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 forM. ulceransdisease, 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.

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Efficacy of the Combination Rifampin-Streptomycin in Preventing Growth of Mycobacterium ulcerans in Early Lesions of Buruli Ulcer in Humans

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.8.3182-3186.2005 ◽

2005 ◽

Vol 49 (8) ◽

pp. 3182-3186 ◽

Cited By ~ 167

Author(s):

S. Etuaful ◽

B. Carbonnelle ◽

J. Grosset ◽

S. Lucas ◽

C. Horsfield ◽

...

Keyword(s):

Body Weight ◽

Antibiotic Therapy ◽

Antibiotic Treatment ◽

Buruli Ulcer ◽

Surgical Excision ◽

Skin Lesions ◽

Mycobacterium Ulcerans ◽

Early Lesions ◽

Culture Positive ◽

Culture Negative

ABSTRACT Mycobacterium ulcerans disease is common in some humid tropical areas, particularly in parts of West Africa, and current management is by surgical excision of skin lesions ranging from early nodules to extensive ulcers (Buruli ulcer). Antibiotic therapy would be more accessible to patients in areas of Buruli ulcer endemicity. We report a study of the efficacy of antibiotics in converting early lesions (nodules and plaques) from culture positive to culture negative. Lesions were excised either immediately or after treatment with rifampin orally at 10 mg/kg of body weight and streptomycin intramuscularly at 15 mg/kg of body weight daily for 2, 4, 8, or 12 weeks and examined by quantitative bacterial culture, PCR, and histopathology for M. ulcerans. Lesions were measured during treatment. Five lesions excised without antibiotic treatment and five lesions treated with antibiotics for 2 weeks were culture positive, whereas three lesions treated for 4 weeks, five treated for 8 weeks, and three treated for 12 weeks were culture negative. No lesions became enlarged during antibiotic treatment, and most became smaller. Treatment with rifampin and streptomycin for 4 weeks or more inhibited growth of M. ulcerans in human tissue, and it provides a basis for proceeding to a trial of antibiotic therapy as an alternative to surgery for early M. ulcerans disease.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01478-18 ◽

2018 ◽

Vol 63 (2) ◽

pp. e01478-18 ◽

Cited By ~ 4

Author(s):

Till F. Omansen ◽

Deepak Almeida ◽

Paul J. Converse ◽

Si-Yang Li ◽

Jin Lee ◽

...

Keyword(s):

Oral Treatment ◽

Buruli Ulcer ◽

Indirect Costs ◽

Ceiling Effect ◽

Mycobacterium Ulcerans ◽

High Dose ◽

Current Standard ◽

Standard Regimen ◽

Content Type ◽

Dose Dependent

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

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Treatment Duration for Uncomplicated Staphylococcus aureus Bacteremia To Prevent Relapse: Analysis of a Prospective Observational Cohort Study

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01021-12 ◽

2012 ◽

Vol 57 (3) ◽

pp. 1150-1156 ◽

Cited By ~ 58

Author(s):

Yong Pil Chong ◽

Song Mi Moon ◽

Kyung-Mi Bang ◽

Hyun Jung Park ◽

So-Youn Park ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Cohort Study ◽

Antibiotic Therapy ◽

Treatment Failure ◽

Practice Guidelines ◽

Observational Cohort Study ◽

Care Hospital ◽

Prospective Observational Cohort Study ◽

Short Course ◽

Observational Cohort

ABSTRACTPractice guidelines recommend at least 14 days of antibiotic therapy for uncomplicatedStaphylococcus aureusbacteremia (SAB). However, these recommendations have not been formally evaluated in clinical studies. To evaluate the duration of therapy for uncomplicated SAB, we analyzed data from our prospective cohort of patients with SAB. A prospective observational cohort study was performed in patients with SAB at a tertiary-care hospital in Korea between August 2008 and September 2010. All adult patients with SAB were prospectively enrolled and observed over a 12-week period. Uncomplicated SAB was defined as follows: negative results of follow-up blood cultures at 2 to 4 days, defervescence within 72 h of therapy, no evidence of metastatic infection, and catheter-related bloodstream infection or primary bacteremia without evidence of endocarditis on echocardiography. Of 483 patients with SAB, 111 met the study criteria for uncomplicated SAB. Fifty-three (47.7%) had methicillin-resistant SAB. When short-course therapy (<14 days) and intermediate-course therapy (≥14 days) were compared, the treatment failure rates (10/38 [26.3%] versus 16/73 [21.9%]) and crude mortality (7/38 [18.4%] versus 16/73 [21.9%]) did not differ significantly between the two groups. However, short-course therapy was significantly associated with relapse (3/38 [7.9%] versus 0/73;P= 0.036). In multivariate analysis, primary bacteremia was associated with a trend toward increased treatment failure (P= 0.06). Therefore, in the treatment of uncomplicated SAB, it seems reasonable to consider at least 14 days of antibiotic therapy to prevent relapse, as practice guidelines recommend. Because of its poor prognosis, primary bacteremia, even with a low risk of complication, should not be treated with short-course therapy.

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Buruli Ulcer: Review of a Neglected Skin Mycobacterial Disease

Journal of Clinical Microbiology ◽

10.1128/jcm.01507-17 ◽

2017 ◽

Vol 56 (4) ◽

Cited By ~ 8

Author(s):

Jeannette Guarner

Keyword(s):

Clinical Presentation ◽

Oral Treatment ◽

Buruli Ulcer ◽

Mycobacterium Ulcerans ◽

World Health ◽

Tissue Necrosis ◽

Content Type ◽

Skin Nodule ◽

The World ◽

Health Organization

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

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Carbapenem-Resistant Pseudomonas aeruginosa Bacteremia: Risk Factors for Mortality and Microbiologic Treatment Failure

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01243-16 ◽

2016 ◽

Vol 61 (1) ◽

Cited By ~ 26

Author(s):

Deanna J. Buehrle ◽

Ryan K. Shields ◽

Lloyd G. Clarke ◽

Brian A. Potoski ◽

Cornelius J. Clancy ◽

...

Keyword(s):

Risk Factors ◽

Pseudomonas Aeruginosa ◽

Treatment Failure ◽

Antimicrobial Therapy ◽

Multiple Drug ◽

Drug Resistant ◽

Active Therapy ◽

Content Type ◽

Carbapenem Resistant ◽

Multiple Drug Resistant

ABSTRACT We reviewed 37 patients treated for bacteremia due to carbapenem-resistant (CR) Pseudomonas aeruginosa. Although 65% of isolates were multiple-drug resistant, therapeutic options were available, as all were susceptible to ≥1 antibiotic. A total of 92% of patients received active antimicrobial therapy, but only 57% received early active therapy (within 48 h). Fourteen-day mortality was 19%. Microbiologic failure occurred in 29%. The Pitt bacteremia score (P = 0.046) and delayed active therapy (P = 0.027) were predictive of death and microbiologic failure, respectively.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05543-11 ◽

2011 ◽

Vol 56 (2) ◽

pp. 687-696 ◽

Cited By ~ 18

Author(s):

Marie-Thérèse Ruf ◽

Daniela Schütte ◽

Aurélie Chauffour ◽

Vincent Jarlier ◽

Baohong Ji ◽

...

Keyword(s):

B Lymphocyte ◽

Buruli Ulcer ◽

Mycobacterium Ulcerans ◽

Infection Model ◽

Histopathological Study ◽

Content Type ◽

Histopathological Features ◽

Treatment Regimens ◽

Mouse Infection Model ◽

New Treatment

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

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

Applied and Environmental Microbiology ◽

10.1128/aem.02612-17 ◽

2018 ◽

Vol 84 (8) ◽

pp. e02612-17 ◽

Cited By ~ 16

Author(s):

Andrew H. Buultjens ◽

Koen Vandelannoote ◽

Conor J. Meehan ◽

Miriam Eddyani ◽

Bouke C. de Jong ◽

...

Keyword(s):

Buruli Ulcer ◽

Population Expansion ◽

Mycobacterium Ulcerans ◽

Disease Spread ◽

Whole Genome Sequence ◽

Sequence Comparisons ◽

Content Type ◽

Continental Scale ◽

Southeastern Australia ◽

East End

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

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Incidence and Risk Factors for Ventilator-Associated Pneumonia in Kathmandu University Hospital

Kathmandu University Medical Journal ◽

10.3126/kumj.v9i1.6258 ◽

2012 ◽

Vol 9 (1) ◽

pp. 28-31 ◽

Cited By ~ 3

Author(s):

S Ranjit ◽

B Bhattarai

Keyword(s):

Risk Factors ◽

Intensive Care Unit ◽

Intensive Care ◽

Univariate Analysis ◽

University Hospital ◽

Ventilator Associated Pneumonia ◽

Chi Square ◽

H2 Blockers ◽

Observational Cohort ◽

Level Of Significance

Background Ventilator associated pneumonia is a major cause of morbidity in the intensive care unit. Difficulties in identification of the risk factors, in diagnosing and in prevention, have intensified the problem. Objectives To measure the incidence of ventilator associated pneumonia in intensive care unit and to identify the risk factors associated. Methods A prospective observational cohort study of 69 patients who were mechanically ventilated for more than 48 hours were evaluated to find out the development of nosocomial pneumonia and presence or absence of risk factors. Data were subjected to univariate analysis using chi-square and t-test. Level of significance was set at 0.05. Results Twenty two (31.88%) out of 69 patients developed ventilator associated pneumonia, majority of them between four days to 14 days. Reintubation, invasive lines, H2 blockers and low PaO2/FiO2 were identified as major risk factors in our study. Enteral feeding via nasogastric tube and use of steroids was not associated with development of ventilator associated pneumonia. The patients with ventilator associated pneumonia had significantly longer duration of mechanical ventilation (18.88±7.7 days vs 7.36±4.19 days) and stay (29±17.8 days vs 9.22±5.14 days). The morality was similar for both the groups with or without ventilator associated pneumonia. ConclusionThe incidence of ventilator pneumonia is high. Patients requiring prolonged ventilation, re-intubation, more invasive lines and H2 blockers, are at high risk and need special attention towards prevention.http://dx.doi.org/10.3126/kumj.v9i1.6258 Kathmandu Univ Med J 2011;9(1):28-31

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

mSphere ◽

10.1128/msphere.00472-18 ◽

2019 ◽

Vol 4 (1) ◽

Cited By ~ 6

Author(s):

Koen Vandelannoote ◽

Delphin Mavinga Phanzu ◽

Kapay Kibadi ◽

Miriam Eddyani ◽

Conor J. Meehan ◽

...

Keyword(s):

Disease Control ◽

Population Genomics ◽

Demographic History ◽

Buruli Ulcer ◽

Central Africa ◽

Mycobacterium Ulcerans ◽

Evolutionary Trajectory ◽

Content Type ◽

Mode Of Transmission ◽

The Impact

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

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