Comprehensive Case-Control Study of Protective and Risk Factors for Buruli Ulcer, Southeastern Australia.

To examine protective and risk factors for Buruli ulcer (BU), we conducted a case-control study of 245 adult BU cases and 481 postcode-matched controls across BU-endemic areas of Victoria, Australia. We calculated age- and sex-adjusted odds ratios for socio-environmental, host, and behavioral factors associated with BU by using conditional logistic regression. Odds of BU were >2-fold for persons with diabetes mellitus and persons working outdoors who had soil contact in BU-endemic areas (compared with indoor work) but were lower among persons who had bacillus Calmette-Guérin vaccinations. BU was associated with increasing numbers of possums and with ponds and bore water use at residences. Using insect repellent, covering arms and legs outdoors, and immediately washing wounds were protective; undertaking multiple protective behaviors was associated with the lowest odds of BU. Skin hygiene/protection behaviors and previous bacillus Calmette-Guérin vaccination might provide protection against BU in BU-endemic areas.

AngioVac Aspiration Thrombectomy of Right Atrial Thrombus is Safe and Effective in Cancer Patients.

OBJECTIVES: The aim of this study was to test the hypothesis that endovascular aspiration thrombectomy of right atrial thrombus (RAT) using the AngioVac device is as safe and effective in patients with cancer as those without cancer. BACKGROUND: RAT is a uniquely challenging clinical presentation of venous thromboembolism due to its low incidence and historically high-risk of mortality due to thrombus propagation into the pulmonary arteries. There is a lack of consensus regarding management, particularly in high-risk cancer patients. Endovascular aspiration thrombectomy utilizing the AngioVac device is effective in removal of right atrial thrombus and may be a safer option for patients with cancer in whom avoidance of higher-risk intervention is preferred. METHODS: This was an institutional review board-approved retrospective single-center case control study of patients with RAT who underwent AngioVac aspiration thrombectomy between August 2013 and July 2020. Analysis of patient demographics and clinical characteristics, thrombus-related factors, and operative details was performed. Primary endpoints included survival, safety, and technical success. RESULTS: A total of 44 patients met inclusion criteria, 20 of whom with active malignancy. The oncology group had a significantly higher Charlson comorbidity index (P = 0.01). Comparative outcomes between the oncology and non-oncology group showed no difference in survival (P = 0.8) or technical success (OR 3, 95% CI 0.83-10.9). There were 9 complications, including 6 minor, 1 moderate, 1 severe, and 1 death. CONCLUSIONS: AngioVac aspiration thrombectomy of RAT is as safe and effective in patients with cancer as those without cancer.

Six vs Eight Weeks of Antibiotics for Small Mycobacterium ulcerans Lesions in Australian Patients.

BACKGROUND: Antibiotics are highly effective in curing Mycobacterium ulcerans lesions, but are associated with significant toxicity. In those not undergoing surgery, we compared 6 weeks with the currently recommended 8 weeks of combination antibiotic therapy for small M. ulcerans lesions. METHODS: Mycobacterium ulcerans cases from an observational cohort at Barwon Health, Victoria, treated with antibiotics alone from 1 October 2010 to 31 March 2018 were included. The 6-week antibiotic group received ≥28 days and ≤42 days and the 8-week antibiotic group received ≥56 days of antibiotic therapy, respectively. Only World Health Organization category 1 lesions were included. RESULTS: 207 patients were included; 53 (25.6%) in the 6-week group and 154 (74.4%) in the 8-week group. The median age of patients was 53 years (interquartile range [IQR], 33-69 years) and 100 (48.3%) were female. Lesions were ≤900 mm2 in size in 79.7% of patients and 93.2% were ulcerative. Fifty-three patients (100%) achieved treatment cure in the 6-week group compared with 153 (99.4%) in the 8-week group (P = .56). No patients died or were lost to follow-up during the study. Median time to heal was 70 days (IQR, 60-96 days) in the 6-week group and 128 days (IQR, 95-173 days) in the 8-week group (P < .001). Two (3.8%) patients in the 6-week group experienced a paradoxical reaction compared with 39 (25.3%) patients in the 8-week group (P = .001). CONCLUSIONS: For selected small M. ulcerans lesions, 6 weeks may be as effective as 8 weeks of combined antibiotic therapy in curing lesions without surgery.

Risk Factors Associated with Antibiotic Treatment Failure of Buruli Ulcer.

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.

Paediatric Buruli ulcer in Australia.

AIM: This study describes an Australian cohort of paediatric Buruli ulcer (BU) patients and compares them with adult BU patients. METHODS: Analysis of a prospective cohort of all BU cases managed at Barwon Health, Victoria, from 1 January 1998 to 31 May 2018 was performed. Children were defined as ≤15 years of age. RESULTS: A total of 565 patients were included: 52 (9.2%) children, 289 (51.2%) adults aged 16-64 years and 224 (39.6%) adults aged ≥65 years. Among children, half were female and the median age was 8.0 years (interquartile range 4.8-12.3 years). Six (11.5%) cases were diagnosed from 2001 to 2006, 14 (26.9%) from 2007 to 2012 and 32 (61.5%) from 2013 to 2018. Compared to adults, children had a significantly higher proportion of non-ulcerative lesions (32.7%, P < 0.001) and a higher proportion of severe lesions (26.9%, P < 0.01). The median duration of symptoms prior to diagnosis was shorter for children compared with adults aged 16-64 years (42 vs. 56 days, P = 0.04). Children were significantly less likely to experience antibiotic complications (6.1%) compared with adults (20.6%, P < 0.001), but had a significantly higher rate of paradoxical reactions (38.8%) compared with adults aged 16-64 (19.2%) (P < 0.001). Paradoxical reactions in children occurred significantly earlier than in adults (median 17 vs. 56 days, P < 0.01). Cure rates were similarly high for children compared to adults treated with antibiotics alone or with antibiotics and surgery. CONCLUSIONS: Paediatric BU cases in Australia are increasing and represent an important but stable proportion of Australian BU cohorts. Compared with adults, there are significant differences in clinical presentation and treatment outcomes.

Increased Severity and Spread of Mycobacterium ulcerans, Southeastern Australia.

Reported cases of Mycobacterium ulcerans disease (Buruli ulcer) have been increasing in southeastern Australia and spreading into new geographic areas. We analyzed 426 cases of M. ulcerans disease during January 1998-May 2017 in the established disease-endemic region of the Bellarine Peninsula and the emerging endemic region of the Mornington Peninsula. A total of 20.4% of cases-patients had severe disease. Over time, there has been an increase in the number of cases managed per year and the proportion associated with severe disease. Risk factors associated with severe disease included age, time period (range of years of diagnosis), and location of lesions over a joint. We highlight the changing epidemiology and pathogenicity of M. ulcerans disease in Australia. Further research, including genomic studies of emergent strains with increased pathogenicity, are urgently needed to improve the understanding of disease to facilitate implementation of effective public health measures to halt its spread.

Exposure Risk for Infection and Lack of Human-to-Human Transmission of Mycobacterium ulcerans Disease, Australia.

We conducted epidemiologic and genetic analyses of family clusters of Mycobacterium ulcerans (Buruli ulcer) disease in southeastern Australia. We found that the incidence of M. ulcerans disease in family members was increased. However, the risk for exposure appeared short-term and not related to human-human transmission.

Antibiotic complications during the treatment of Mycobacterium ulcerans disease in Australian patients.

BACKGROUND: Antibiotics are the recommended first-line treatment for Mycobacterium ulcerans disease. Antibiotic toxicity is common in Australian patients, yet antibiotic complication rates and their risk factors have not been determined. AIM: To determine the incidence rate and risk factors for antibiotic toxicity in Australian patients treated for M. ulcerans disease. METHODS: An analysis of severe antibiotic complications was performed using data from a prospective cohort of M. ulcerans cases managed at Barwon Health from 1 January 1998 to 30 June 2016. A severe antibiotic complication was defined as an antibiotic adverse event that required its cessation. Antibiotic complication rates and their associations were assessed using a Poisson regression model. RESULTS: A total of 337 patients was included; 184 (54.6%) males and median age 57 years (interquartile range (IQR) 36-73 years). Median antibiotic treatment duration was 56 days (IQR 49-76 days). Seventy-five (22.2%) patients experienced severe antibiotic complications after a median 28 days (IQR 17-45 days) at a rate of 141.53 per 100 person-years (95% confidence interval (CI) 112.86-177.47). Eleven (14.7%) patients required hospitalisation. Compared with rifampicin/clarithromycin combinations, severe complication rates were not increased for rifampicin/ciprofloxacin (rate ratio (RR) 1.49, 95% CI 0.89-2.50, P = 0.13) or rifampicin/moxifloxacin (RR 2.54, 95% CI 0.76-8.50, P = 0.13) combinations, but were significantly increased for 'other' combinations (RR 2.53, 95% CI 1.13-5.68, P = 0.03). In a multivariable analysis, severe complication rates were significantly increased with reduced estimated glomerular filtration rates (EGFR) (adjusted rate ratio (aRR) 2.65, 95% CI 1.24-5.65 for EGFR 60-89 mL/min and aRR 1.31, 95% CI 0.49-3.53 for EGFR 0-59 mL/min compared with EGFR ≥90 mL/min, P < 0.01) and female gender (aRR 2.15, 95% CI 1.38-3.30, P < 0.01). CONCLUSIONS: Severe antibiotic complications during M. ulcerans treatment are high with increased rates independently associated with reduced renal function and female gender.

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

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.

Risk factors for unstructured treatment interruptions and association with survival in low to middle income countries.

BACKGROUND: Antiretroviral therapy (ART) treatment interruptions lead to poor clinical outcomes with unplanned or unstructured TIs (uTIs) likely to be underreported. This study describes; uTIs, their risk factors and association with survival. METHODS: Analysis of ART programmatic data from 11 countries across Asia and Africa between 2003 and 2013 where an uTI was defined as a ≥90-day patient initiated break from ART calculated from the last day the previous ART prescription would have run out until the date of the next ART prescription. Factors predicting uTI were assessed with a conditional risk-set multiple failure time-to-event model to account for repeated events per subject. Association between uTI and mortality was assessed using Cox proportional hazards, with a competing risks extension to test for the influence of lost to follow-up (LTFU). RESULTS: 40,632 patients were included from 11 countries across 33 sites (17 Africa, 16 Asia). Median duration of follow-up was 1.61 years (IQR 0.54-3.31 years), 3386 (8.3 %) patients died, and 3453 (8.5 %) were LTFU. There were 14,817 uTIs, with 10,162 (25 %) patients having more than one uTI. In the adjusted model males were at lower risk of uTI (aHR 0.94, p < 0.01, and age 20-59 was protective compared to <20 years (20-39 years aHR 0.87, p < 0.01; 40-59 years aHR 0.86, p < 0.01). Preserved immune function, as measured by higher CD4 cell count, was associated with a reduced rate of uTI compared to CD4 <200 cells/µL (CD4 200-350 cells/µL aHR 0.89, p < 0.01; CD4 >350 cells/µL aHR 0.87, p < 0.01), whereas advanced clinical disease was associated with increased uTI rate (WHO stage 3 aHR 1.10, p < 0.01; WHO stage 4 aHR 1.21, p < 0.01). There was no relationship between uTI and mortality after adjusting for disease status and considering LTFU as a competing risk. CONCLUSIONS: uTIs were frequent in people in ART programs in low-middle income countries and associated with younger age, female gender and advanced HIV. uTI did not predict survival when loss to follow-up was considered a competing risk. Further evaluation of uTI predictors and interventions to reduce their occurrence is warranted.

Clinical features and management of a severe paradoxical reaction associated with combined treatment of Buruli ulcer and HIV co-infection.

BACKGROUND: In West and Central Africa Buruli ulcer (BU) and HIV co-infection is increasingly recognised and management of these two diseases combined is an emerging challenge for which there is little published information. In this case we present a severe paradoxical reaction occurring after commencing antibiotic treatment for BU combined with antiretroviral therapy for HIV, and describe its clinical features and management. This includes to our knowledge the first reported use of prednisolone in Africa to manage a severe paradoxical reaction related to BU treatment. CASE PRESENTATION: A 30 year old immunosuppressed HIV positive man from Cameroon developed a severe paradoxical reaction 24 days after commencing antibiotic treatment for BU and 14 days after commencing antiretroviral therapy for HIV. Oral prednisolone was successfully used to settle the reaction and prevent further tissue loss. The antiretroviral regimen was continued unchanged and the BU antibiotic treatment not prolonged beyond the recommended duration of 8 weeks. A second small local paradoxical lesion developed 8 months after starting antibiotics and settled with conservative treatment only. Complete healing of lesions occurred and there was no disease recurrence 12 months after commencement of treatment. CONCLUSIONS: Clinicians should be aware that severe paradoxical reactions can occur during the treatment of BU/HIV co-infected patients. Prednisolone was effectively and safely used to settle the reaction and minimize the secondary tissue damage.

Treatment and prevention of Mycobacterium ulcerans infection (Buruli ulcer) in Australia: guideline update.

• 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.

Use of Ultrasound-Assisted, Catheter-Directed Thrombolysis in a Patient With High-Risk Pulmonary Embolism.

High-risk pulmonary embolism (PE) is a complex clinical entity associated with high mortality rates. Ultrasound-assisted, catheter-directed thrombolysis, typically used for intermediate-risk PE, may be a viable treatment approach for high-risk PE, particularly in patients at increased risk for major bleeding. This report describes a case in which ultrasound-assisted, catheter-directed thrombolysis was successfully used to treat high-risk PE in a female patient with extensive peritoneal metastases from gastric adenocarcinoma. Other examples from the literature, in which ultrasound-assisted, catheter-directed thrombolysis was used to treat high-risk PE, are also provided.

A lesion in two: Buruli ulcer and squamous cell carcinoma coexistence.

The concurrent diagnoses of Buruli ulcer (BU) and cutaneous squamous cell carcinoma (SCC) is a phenomenon not previously described, despite the fact that both conditions are highly prevalent in Australia. This report presents an intriguing case of concurrent diagnoses, with clues alluding to more than one skin condition being present. The case involves a 73-year-old man with BU diagnosed on the scalp, an atypical location, which led to the consideration of malignancy, ultimately revealing concurrent SCC. This case highlights the importance of considering both conditions in patients with epidemiological risk factors, necessitating multiple lines of investigation for accurate diagnosis. Medical practitioners must remain vigilant and incorporate this possibility into their diagnostic algorithms for suspicious skin lesions to optimize treatment and outcomes. This is the first recorded instance of simultaneous diagnosis, underlining the need for enhanced awareness and attention to these unique cases.

Use of targeted SMS messaging to encourage COVID-19 oral antiviral uptake in South West Victoria.

OBJECTIVES: During winter 2022, as part of a multifaceted approach to optimise oral antiviral uptake in the Barwon South West region in Victoria, Australia, the Barwon South West Public Health Unit (BSWPHU) implemented an innovative, targeted SMS messaging program that encouraged people with coronavirus disease 2019 (COVID-19) to be assessed for antiviral treatment. In this study, we investigated patterns of antiviral uptake, identified barriers and facilitators to accessing antivirals, and examined the potential impact of targeted SMS messaging on oral antiviral uptake. METHODS: We conducted a cross-sectional study of notified COVID-19 cases aged 50 years and older, and Aboriginal and Torres Strait Islander people aged 30-49 years, in the BSWPHU catchment area over a 6-week period commencing 21 July 2022. We analysed survey data using descriptive statistics and generalised linear models. RESULTS: Of the 3829 survey respondents, 36.7% (95% confidence interval (CI) 35.2, 38.2) reported being prescribed oral antivirals, with 75.4% (95% CI 72.8, 77.9) of these aged ≥70. Antiviral prescriptions increased significantly over the 6-week survey period. Most prescriptions (87.5%; 95% CI 85.7, 89.2) were provided by the respondents' usual general practitioners (GPs). Barriers to receiving antivirals included respondents being unable to get a medical appointment in time (3.7%; 95% CI 3.1, 4.2), testing too late in their illness (2.3%; 95% CI 1.8, 2.8) and being unable to access medications in time after receiving a prescription (0.2%; 95% CI 0.1, 0.6). Facilitators to receiving antivirals included respondents first hearing about antivirals from a trusted source such as a family member, friend or usual doctor. Nearly one in eight people who were prescribed antivirals reported first hearing about them from the SMS message sent by BSWPHU. CONCLUSIONS: Oral antiviral treatment uptake in south-west Victoria in July-August 2022 was high among survey respondents and increased over time. GPs were the key prescribers in the community. Targeted SMS messaging to COVID-19 cases is a simple, low-cost intervention that potentially increases antiviral uptake.

Prevalence, risk factors, and outcomes of secondary infections among hospitalized patients with COVID-19 or post-COVID-19 conditions in Victoria, 2020-2023.

OBJECTIVES: Estimates of secondary infections are variedly reported, with few studies done in Australia. We investigated the occurrence and impact of secondary infections complicating COVID-19 and post-COVID-19 admissions in Victoria, Australia, 2020-2023. METHODS: We used linked population-wide data sets and specific International Classification of Disease, 10th Revision codes to identify and estimate the occurrence of secondary infections. Using hospital/intensive care unit length of stay in negative binomial regression and mortality, we examined the impact of secondary infections. RESULTS: Secondary infections were identified in 6.9% (13,467 of 194,660) of COVID-19 and post-COVID-19 admissions: 6.0% (11,651 of 194,660) bacterial, 0.9% (1691 of 194,660) viral, and 0.2% (385 of 194,660) fungal. Prevalence was highest during the pre-Delta (10.4%) and Omicron-BA2 (8.1%) periods. Sepsis and pneumonia were the most reported syndromes; the occurrence of sepsis declined gradually over time. The odds of secondary infections were higher among the ≥70-year-olds (adjusted odds ratio (aOR) 3.76, 95% confidence interval [CI] 3.43-4.14, vs 20-29-year-olds), individuals with chronic conditions (aOR 3.15, 95% CI 2.88-3.45, vs those without), the unvaccinated (aOR 1.59, 95% CI 1.45-1.75), and the lowest socioeconomic group (aOR 1.12, 95% CI 1.05-1.19). Patients with secondary infections had 2.43 times longer hospital length of stay and 9.60 times longer intensive care unit length of stay than those without secondary infections. The mortality risk was 2.17 times higher in those with secondary infections. CONCLUSIONS: Secondary infections occurred in 69 per 1000 COVID-19-associated hospital admissions in Victoria, mostly in high-risk groups, and were associated with severe outcomes.

A human model of Buruli ulcer: Provisional protocol for a Mycobacterium ulcerans controlled human infection study.

Critical knowledge gaps have impeded progress towards reducing the global burden of disease due to Mycobacterium ulcerans, the cause of the neglected tropical disease Buruli ulcer (BU). Development of a controlled human infection model of BU has been proposed as an experimental platform to explore host-pathogen interactions and evaluate tools for prevention, diagnosis, and treatment. We have previously introduced the use case for a new human model and identified M. ulcerans JKD8049 as a suitable challenge strain. Here, we present a provisional protocol for an initial study, for transparent peer review during the earliest stages of protocol development. Following simultaneous scientific peer review and community/stakeholder consultation of this provisional protocol, we aim to present a refined protocol for institutional review board (IRB) evaluation.

This paper describes a provisional clinical protocol for the pilot human challenge model of Mycobacterium ulcerans infection, which causes the skin disease 'Buruli ulcer' (BU). BU is typically painless and begins as a small area of redness or swelling, and is curable with antibiotics. If the diagnosis is delayed, it can result in large ulceration and disability. Side effects from antibiotics are common but rarely severe; nevertheless, preventative strategies, such as vaccination, are urgently needed. The overarching project, known as 'MuCHIM', aims to establish a safe and acceptable controlled human challenge model (CHIM) of this disease in healthy volunteers in Melbourne, Australia. This pilot protocol primarily aims to establish that it is safe and acceptable to participants, and secondarily to confirm successful establishment of infection and the infection rate amongst participants. We also aim to test less invasive diagnostic tests, assess immune responses to infection, to understand changes in the human microbiome during the trial, and explore microbiological characteristics of M. ulcerans infection. If this pilot is successful, we hope to test vaccines and other therapeutics using this model, which could blunt or reduce the rising incidence of this disease in Australia, while further informing vaccine development research.