•Cytokine storms of different diseases including COVID-19 have shared abnormalities.•Elevated levels of TNF-α, IL-6, IL-1β, NFκB are common immune abnormalities.•Inflammasome activation and release ...of DAMPs is common to COVID-19, H1N1, and MAS.•Anakinra may adjust the biochemical and immune abnormalities reported in COVID-19.
An analysis of published data appertaining to the cytokine storms of COVID-19, H1N1 influenza, cytokine release syndrome (CRS), and macrophage activation syndrome (MAS) reveals many common immunological and biochemical abnormalities. These include evidence of a hyperactive coagulation system with elevated D-dimer and ferritin levels, disseminated intravascular coagulopathy (DIC) and microthrombi coupled with an activated and highly permeable vascular endothelium. Common immune abnormalities include progressive hypercytokinemia with elevated levels of TNF-α, interleukin (IL)-6, and IL-1β, proinflammatory chemokines, activated macrophages and increased levels of nuclear factor kappa beta (NFκB). Inflammasome activation and release of damage associated molecular patterns (DAMPs) is common to COVID-19, H1N1, and MAS but does not appear to be a feature of CRS. Elevated levels of IL-18 are detected in patients with COVID-19 and MAS but have not been reported in patients with H1N1 influenza and CRS. Elevated interferon-γ is common to H1N1, MAS, and CRS but levels of this molecule appear to be depressed in patients with COVID-19. CD4+ T, CD8+ and NK lymphocytes are involved in the pathophysiology of CRS, MAS, and possibly H1N1 but are reduced in number and dysfunctional in COVID-19. Additional elements underpinning the pathophysiology of cytokine storms include Inflammasome activity and DAMPs. Treatment with anakinra may theoretically offer an avenue to positively manipulate the range of biochemical and immune abnormalities reported in COVID-19 and thought to underpin the pathophysiology of cytokine storms beyond those manipulated via the use of, canakinumab, Jak inhibitors or tocilizumab. Thus, despite the relative success of tocilizumab in reducing mortality in COVID-19 patients already on dexamethasone and promising results with Baricitinib, the combination of anakinra in combination with dexamethasone offers the theoretical prospect of further improvements in patient survival. However, there is currently an absence of trial of evidence in favour or contravening this proposition. Accordingly, a large well powered blinded prospective randomised controlled trial (RCT) to test this hypothesis is recommended.
Background
Clostridium difficile
infection is the leading cause of hospital-acquired gastrointestinal infection and incidence rates continue to rise.
Clostridium difficile
infection is becoming ...increasingly complex to treat owing to the rise in treatment failures and recurrent infections. There is a clear need for new therapeutic options for the management of this disease.
Objective
This study aimed to assess auranofin, a drug approved for the treatment of arthritis, as a treatment for
C. difficile
infection. Previous investigations have demonstrated potential antimicrobial activity of auranofin against
C. difficile
and other organisms.
Methods
The activity of auranofin was assessed by in vitro investigations of its effect on
C. difficile
M7404 growth, vegetative cell viability, and spore viability. Activity of auranofin was also compared to that of the current treatments, metronidazole and vancomycin.
Results
Auranofin showed bactericidal activity at concentrations as low as 4.07 µg/mL, effectively reducing bacterial cell density by 50–70% and the viable vegetative cell and spore yields by 100%. The activity of auranofin was shown to be non-inferior to that of metronidazole and vancomycin.
Conclusions
Auranofin is highly efficacious against
C. difficile
M7404 in vitro and has the potential to be an ideal therapeutic option for the treatment of
C. difficile
infection.
Researchers have hypothesized that mosquitoes are vectors involved in Mycobacterium ulcerans transmission. Previous findings of a correlation between incidence of M. ulcerans, which causes Buruli ...ulcer, and locally acquired vectorborne diseases in southeastern Australia further strengthened this argument. However, our updated data indicate that this correlation has not continued beyond 2008.
The intestinal microbiome has been identified as a key modifier for a variety of health conditions. Fecal Microbiota Transplantation (FMT) has emerged as a fast, safe, and effective means by which to ...modify the intestinal microbiome and potentially treat a variety of health conditions. Despite extensive research of FMT for CDI, there is a lack of clarity informed by systematic synthesis of data regarding the safety and efficacy of FMT for other health conditions. This systematic review used PRISMA guidelines and was prospectively registered with PROSPERO (CRD42018104243). In March 2020, a search of MEDLINE, EMBASE, and PsycINFO was conducted. We identified 26 eligible studies. A meta-analysis of FMT for active Ulcerative Colitis (UC) showed that FMT significantly improved rates of clinical remission (OR = 3.634, 95% CI = 1.940 to 6.808, I
2
= 0%, p < .001), clinical response (OR = 2.634, 95% CI = 1.441 to 4.815, I
2
= 33%, p = .002) and endoscopic remission (OR = 4.431, 95% CI = 1.901 to 10.324, I
2
= 0%, p = .001). With respect to Irritable Bowel Syndrome, a meta-analysis showed no significant change in symptoms following FMT (p = .739). Hepatic disorders, metabolic syndrome, and antibiotic-resistant organisms were conditions with emerging data on FMT. Serious adverse events (AE) were more often reported in control group participants (n = 43) compared with FMT group participants (n = 26). There were similar rates of mild to moderate AE in both groups. Preliminary data suggest that FMT is a potentially safe, well-tolerated and efficacious treatment for certain conditions other than CDI, with evidence for active UC being the most compelling.
Mycobacterium ulcerans disease is a necrotising disease of the skin and subcutaneous tissue and is effectively treated with eight-weeks antibiotic therapy. Significant toxicities, however, are ...experienced under this prolonged regimen. Here, we investigated the length of antibiotic duration required to achieve negative cultures of M. ulcerans disease lesions and evaluated the influence of patient characteristics on this outcome. M. ulcerans cases from an observational cohort that underwent antibiotic treatment prior to surgery and had post-excision culture assessment at Barwon Health, Victoria, from May 25 1998 to June 30 2019, were included. Antibiotic duration before surgery was grouped as <2 weeks, ≥2-<4 weeks, ≥4-<6 weeks, ≥6-<8 weeks, ≥8-<10 weeks and ≥10-20 weeks. Cox regression analyses were performed to assess the association between variables and culture positive results. Ninety-two patients fitted the inclusion criteria. The median age was 60 years (IQR 28-74.5) and 51 (55.4%) were male. Rifampicin-based regimens were predominantly used in combination with clarithromycin (47.8%) and ciprofloxacin (46.7%), and the median duration of antibiotic treatment before surgery was 23 days (IQR, 8.0-45.5). There were no culture positive results after 19 days of antibiotic treatment and there was a significant association between antibiotic duration before surgery and a culture positive outcome (p<0.001). The World Health Organisation category of the lesion and the antibiotic regimen used had no association with the culture outcome. Antibiotics appear to be effective at achieving negative cultures of M. ulcerans disease lesions in less than the currently recommended eight-week duration.
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.
Objectives
Perturbations of the intestinal microbiota have been associated with mental health disorders, including major depressive disorder (MDD). Therefore, faecal microbiota transplantation (FMT) ...holds promise as a microbiota-modulating treatment for MDD. Yet, to date, there are no published controlled studies evaluating the use of FMT for MDD. This study aimed to address this gap by evaluating the feasibility, acceptability, and safety of FMT for MDD.
Methods
The study was an 8-week, double-blind, 2:1 parallel group, randomized controlled pilot trial (n = 15) of enema-delivered FMT (n = 10) compared with a placebo enema (n = 5) in adults with moderate-to-severe MDD.
Results
Recruitment was completed within 2 months, with 0% attrition and 100% attendance at key study appointments. There were no major protocol deviations. The placebo and blinding strategies were considered successful; nurses and participants correctly guessing their treatment allocation at a rate similar to that anticipated by chance. No serious or severe adverse events were reported in either group, and there were no significant differences in mild-to-moderate adverse events between groups (median of 2 adverse events per participant reported in both groups). Furthermore, the 12/15 participants who completed the Week 2 participant satisfaction survey agreed or strongly agreed that the enema delivery was tolerable and that they would have the treatment again if required. Whilst the study was not designed to measure clinical outcomes, exploratory data also suggested that the active FMT treatment may lead to improvements in gastrointestinal symptoms and quality of life in this population, noting that irritable bowel syndrome is commonly comorbid with MDD.
Conclusions
All feasibility targets were met or exceeded. This study found that enema-delivered FMT is feasible, acceptable, well-tolerated, and safe in patients with MDD. The findings of this study support further research to evaluate clinical efficacy, and the use of this protocol is supported.
Staphylococcus aureus (S. aureus) bacteraemia is increasingly acquired from community settings and is associated with a mortality rate of up to 40% following complications. Identifying risk factors ...for complicated S. aureus bacteraemia would aid clinicians in targeting patients that benefit from expedited investigations and escalated care.
In this prospective observational cohort study, we aimed to identify risk factors associated with a complicated infection in community-onset S. aureus bacteraemia. Potential risk factors were collected from electronic medical records and included: - patient demographics, symptomology, portal of entry, and laboratory results.
We identified several potential risk factors using univariate analysis. In a multiple logistic regression model, age, haemodialysis, and entry point from a diabetic foot ulcer were all significantly protective against complications. Conversely, an unknown entry point of infection, an entry point from an indwelling medical device, and a C-reactive protein concentration of over 161 mg/L on the day of admission were all significantly associated with complications.
We conclude that several factors are associated with complications including already conducted laboratory investigations and portal of entry of infection. These factors could aid the triage of at-risk patients for complications of S. aureus bacteraemia.
•Secondary infections in 6.9% (194,660) of COVID-19 admissions in Victoria, 2020-2023.•Prevalence was highest in the pre-Delta (10.4%) and Omicron BA2 (8.1%) periods.•Escherichia coli, Haemophilus ...influenzae, and Staphylococcus spp. caused most secondary infections.•Over time, the sepsis incidence declined and secondary infections in post–COVID-19 cases grew.•Being unvaccinated and low socioeconomic status increased the risk for secondary infections.
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.
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.
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.
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.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are novel hypoglycemic agents which reduce reabsorption of glucose at the renal proximal tubule, resulting in significant glycosuria and increased ...risk of genital mycotic infections (GMI). These infections are typically not severe as reported in large systematic reviews and meta-analyses of the medications. These reviews have also demonstrated significant cardiovascular benefits through other mechanisms of action, making them attractive options for the management of Type 2 diabetes mellitus (T2DM). We present two cases with underlying abnormalities of the urogenital tract in which the GMI were complicated and necessitated cessation of the SGLT2 inhibitor.
Both cases are patients with T2DM on empagliflozin, an SGLT2 inhibitor. The first case is a 64 year old man with Candida albicans balanitis and candidemia who was found to have an obstructing renal calculus and prostatic abscess requiring operative management. The second case describes a 72 year old man with Candida glabrata candidemia who was found to have prostatomegaly, balanitis xerotica obliterans with significant urethral stricture and bladder diverticulae. His treatment was more complex due to fluconazole resistance and concerns about urinary tract penetration of other antifungals. Both patients recovered following prolonged courses of antifungal therapy and in both cases the SGLT2 inhibitor was ceased.
Despite their cardiovascular benefits, SGLT2 inhibitors can be associated with complicated fungal infections including candidemia and patients with anatomical abnormalities of the urogenital tract may be more susceptible to these infections as demonstrated in these cases. Clinicians should be aware of their mechanism of action and associated risk of infection and prior to prescription, assessment of urogenital anatomical abnormalities should be performed to identify patients who may be at risk of complicated infection.
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