Intranasal administration of DSM 32444 Bacillus subtilis spores: safety and tolerability.

Introduction. Administered nasally, spores of the Gram-positive bacterium Bacillus subtilis have been shown to be able to induce innate immunity sufficient to confer protection to influenza and respiratory syncytial virus.Hypothesis. Although members of the aerobiome, intranasal delivery of high numbers of live spores carries potential safety issues.Aim. To address the potential safety risk of using live spores, we assessed the safety of spores that had been completely inactivated using heat sterilization.Methodology. Using autoclaved, and therefore killed, spores of a generally recognized as safe-notified B. subtilis strain (DSM 32444), safety was assessed in vitro (biotype, genome and cell based cytoxicity) and in vivo, using intranasal administration in rodent models and lastly in human volunteers.Results. Using a 15-day, repeat-dose, regimen in a rodent model, no indication of toxicity was observed. In a registered human study (NCT05984004), a formulated preparation of inactivated DSM 32444 spores referred to as SPEROVID was developed, and tolerance in human volunteers was assessed following 7 days of nasal dosing (2-4 times/day).Conclusion. Our study demonstrated that in humans an intranasal dose of up to 3×108 killed spores was safe and well tolerated.

Diagnosis and management of obstructive sleep apnoea in adults.

Obstructive sleep apnoea is the most common form of sleep-disordered breathing. It is characterised by recurrent occlusion of the airway during sleep. Ensuing apnoeas terminate in arousal from sleep and lead to non-restorative sleep, excessive daytime sleepiness and adverse cardiovascular and neurocognitive effects. A sleep study should be offered to patients reporting witnessed apnoeas or symptoms related to non-restorative sleep. It should also be considered in the presence of predisposing factors for obstructive sleep apnoea (e.g. obesity, tonsillar hypertrophy, retrognathia, refractory hypertension). Treatment should aim to improve symptoms and reduce cardiovascular and neurocognitive risk. The treatment approach should consider the symptom burden, severity, anatomical factors, and patient preference. Positive airway pressure is the most effective treatment option, although intolerance and non-adherence are common. Other options include positional therapy, oral appliances and upper airway surgery. Weight loss and optimisation of cardiovascular disease risk should be considered in selected patients.

Intranasal Treatment of Ferrets with Inert Bacterial Spores Reduces Disease Caused by a Challenging H7N9 Avian Influenza Virus.

Background: Influenza is a respiratory infection that continues to present a major threat to human health, with ~500,000 deaths/year. Continued circulation of epidemic subtypes in humans and animals potentially increases the risk of future pandemics. Vaccination has failed to halt the evolution of this virus and next-generation prophylactic approaches are under development. Naked, "heat inactivated", or inert bacterial spores have been shown to protect against influenza in murine models. Methods: Ferrets were administered intranasal doses of inert bacterial spores (DSM 32444K) every 7 days for 4 weeks. Seven days after the last dose, the animals were challenged with avian H7N9 influenza A virus. Clinical signs of infection and viral shedding were monitored. Results: Clinical symptoms of infection were significantly reduced in animals dosed with DSM 32444K. The temporal kinetics of viral shedding was reduced but not prevented. Conclusion: Taken together, nasal dosing using heat-stable spores could provide a useful approach for influenza prophylaxis in both humans and animals.

Antibacterial and Antibiofilm Potency of XF Drugs, Impact of Photodynamic Activation and Synergy With Antibiotics.

With increasing incidence of antimicrobial resistance, there is an urgent need for novel and effective antibacterials. Destiny Pharma plc have developed a series of porphyrin-based XF drugs, some with dual mechanisms of antibacterial action. An innate mechanism acts through binding to the outer bacterial membrane and a separate, light-activated, photodynamic (PD) mechanism, acts via the generation of reactive oxygen species. This study aimed to assess the innate and PD associated antibacterial activity of XF drugs against planktonic bacteria, their biofilms and combinational effects with conventional antibiotics. Minimum inhibitory concentrations (MICs) were determined for 3 XF drugs against 114 bacterial isolates. MICs for XF-73 and XF-70 were determined (± PD). DPD-207 was designed to not exhibit PD action due to its structure. XF-drugs (± PD) were further assessed for synergy with conventional antibiotics (using a checkerboard assay) and antibiofilm activity against susceptible strains. XF drugs were innately active against all tested Gram-positive isolates. PD action significantly increased bacterial susceptibility to XF-73 and XF-70 for all Gram-positive isolates. Generally, the XF drugs exhibited higher MICs against Gram-negative isolates, however PD significantly enhanced potency, particularly for XF-70. XF-73 and XF-70 exhibited synergy with ertapenem against a methicillin resistant Staphylococcus aureus (MRSA) strain (± PD) and XF-73 with polymyxin B (± PD) against Pseudomonas aeruginosa. No antagonism was seen between the XF drugs and any of the 5 antibiotics tested. The antibiofilm effect of XF drugs was also observed for all Staphylococcus isolates tested. Generally, PD did not enhance activity for other bacterial isolates tested with the exception of XF-73 against Acinetobacter baumannii biofilms. XF drugs exhibited significant antimicrobial activity against Gram-positive bacteria, with PD enhancement of bacterial susceptibility. Additionally, XF drugs displayed synergy with conventional antibiotics and demonstrated antibiofilm effects.

Role of Interventional Radiology in the Management of Infection.

Interventional radiology (IR) is plays a crucial role in the management of localized infections, utilizing percutaneous access to loculated fluid collections for drainage and source control. Interventions have been developed in multiple organs and systems and used over decades, allowing the IR physician to provide patient care in many cases where surgical options are not optimal. In this review, we will examine the emergent, urgent, and routine nature of various IR procedures in the infectious context and timelines for each in regards to the decision making process. An algorithmic approach should guide the clinician's decision making for IR procedures in both large academic centers and smaller community hospitals. This approach and the pertinent procedural technique are described for multiple systems and organs including the biliary tree, gallbladder, genitourinary tract, and thoracic, abdominal, and pelvic abscesses. Increased awareness of the abilities and limitations of IR physicians in clinical scenarios needs to be implemented, to allow multispecialty input in efforts to decrease morbidity and mortality.

Infections of the Hepatobiliary System.

Hepatobiliary infections account for a small but clinically important proportion of emergency department presentations. They present a clinical challenge due to the broad range of imaging characteristics on presentation. Recognition of complications is imperative to drive appropriate patient care and resource utilization to avoid diagnostic pitfalls and avert adverse patient outcomes. A thorough understanding of anatomy infectious pathology of hepatobiliary system is essential in the emergency setting to confidently diagnose and guide medical intervention. Many presentations of hepatobiliary infection have characteristic imaging features on individual imaging modalities with others requiring the assimilation of findings of multiple imaging modalities along with incorporating the clinical context and multispecialist consultation. Familiarity with the strengths of individual imaging modalities in the radiologists' arsenal is imperative to guide the appropriate utilization of resources, particularly in the emergent time sensitive setting. Accurate identification and diagnosis of hepatobiliary infections is vital for appropriate patient care and management stratification.

Nonhemorrhagic Adrenal Infarction in Pregnancy: Magnetic Resonance Imaging and Computed Tomography Evaluation.

We present the case of unilateral nonhemorrhagic adrenal infarct in a 29-week pregnant 21-year-old woman. The patient presented with right upper quadrant pain, nausea, and vomiting. Ultrasonography of the right upper quadrant and appendix was negative for pathology. Magnetic resonance imaging of the abdomen demonstrated a right nonhemorrhagic adrenal infarct, subsequently confirmed with limited computed tomography of the upper abdomen. This case discusses the clinical presentation and pertinent imaging findings of adrenal infarction in pregnancy.

Arteriovenous blood gas agreement in intensive care patients with varying levels of circulatory compromise: a pilot study.

OBJECTIVE: Venous blood gas (VBG) analysis is suggested as an alternative to arterial blood gas (ABG) analysis. In haemodynamically stable patients, there is clinically acceptable arteriovenous (AV) agreement for pH and bicarbonate (HCO3-) concentration, but in haemodynamically unstable patients, evidence is conflicting. We aimed to evaluate the level of AV agreement for the values of pH, PCO2, base excess, HCO3- and lactate between ABGs and VBGs in critically ill patients with varying degrees of hypotension. DESIGN AND SETTING: A prospective cohort study of a convenience sample of patients in an intensive care unit of a metropolitan teaching hospital. INTERVENTION: Paired ABG and central VBG samples were drawn within 5 minutes of each other from existing arterial lines and central venous lines, and analysed for AV agreement of pH, PCO2, base excess, HCO3- and lactate. The outcome of interest was AV agreement with varying levels of blood pressure (BP). Analysis was by descriptive statistics, box whisker plot and Bland-Altman bias plot analysis. RESULTS: We studied 50 patients with 117 paired ABG and VBG samples. The AV differences (venous-arterial) were: pH, -0.04; HCO3-, -0.37 mmmol/L; base excess, 0.08 mEq/ L; and lactate, 0.16 mmol/L. There was not a clinically relevant deterioration in agreement for these parameters with falling BP. CONCLUSION: In critically ill patients with varying degrees of hypotension in the ICU, there is clinically acceptable AV agreement for the values of pH, HCO3-, base excess and lactate, an agreement that does not deteriorate significantly with falling blood pressure.

Delayed association of the NADPH oxidase complex with macrophage vacuoles containing the opportunistic pathogen Burkholderia cenocepacia.

Burkholderia cenocepacia causes chronic lung infections in patients suffering from cystic fibrosis and chronic granulomatous disease. We have previously shown that B. cenocepacia survives intracellularly in macrophages within a membrane vacuole (BcCV) that delays acidification. Here, we report that after macrophage infection with live B. cenocepacia there is a approximately 6 h delay in the association of NADPH oxidase with BcCVs, while heat-inactivated bacteria are normally trafficked into NADPH oxidase-positive vacuoles. BcCVs in macrophages treated with a functional inhibitor of the cystic fibrosis transmembrane conductance regulator exhibited a further delay in the assembly of the NADPH oxidase complex at the BcCV membrane, but the inhibitor did not affect NADPH oxidase complex assembly onto vacuoles containing heat-inactivated B. cenocepacia or live Escherichia coli. Macrophages produced less superoxide following B. cenocepacia infection as compared to heat-inactivated B. cenocepacia and E. coli controls. Reduced superoxide production was associated with delayed deposition of cerium perhydroxide precipitates around BcCVs of macrophages infected with live B. cenocepacia, as visualized by transmission electron microscopy. Together, our results demonstrate that intracellular B. cenocepacia resides in macrophage vacuoles displaying an altered recruitment of the NADPH oxidase complex at the phagosomal membrane. This phenomenon may contribute to preventing the efficient clearance of this opportunistic pathogen from the infected airways of susceptible patients.