Prospective, randomised, parallel-group, open-label study to evaluate the effectiveness and safety of IMU-838, in combination with oseltamivir, in adults with COVID-19: the IONIC trial protocol.

BACKGROUND: Globally, there is a scarcity of effective treatments for SARS-CoV-2 infections (causing COVID-19). Repurposing existing medications may offer the best hope for treating patients with COVID-19 to curb the pandemic. IMU-838 is a dihydroorotate dehydrogenase inhibitor, which is an effective mechanism for antiviral effects against respiratory viruses. When used synergistically with oseltamivir, therapeutic effects have been observed against influenza and SARS-CoV-2 in rodents. The IMU-838 and Oseltamivir in the Treatment of COVID-19 (IONIC) trial is a randomised controlled trial that will investigate whether time to clinical improvement in patients with COVID-19 is improved following a 14-day course of IMU-838+oseltamivir versus oseltamivir alone. METHODS: IONIC trial is an open-label study in which participants will be randomised 1:1 in two parallel arms: the intervention arm (IMU-838+oseltamivir) and the control arm (oseltamivir only). The primary outcome is time to clinical improvement; defined as the time from randomisation to a two-point improvement on WHO ordinal scale; discharge from hospital, or death (whichever occurs first). The study is sponsored by the University Hospitals Coventry and Warwickshire NHS Trust and funded by LifeArc. DISCUSSION: The IONIC protocol describes an overarching trial design to provide reliable evidence on the effectiveness of IMU-838 (vidofludimus calcium) when delivered in combination with an antiviral therapy (oseltamivir) (IONIC intervention) for confirmed or suspected COVID-19 infection in adult patients receiving usual standard of care. ETHICS AND DISSEMINATION: This study has been independently reviewed and approved by Wales Research Ethics Committee. In addition, required regulatory approvals were received from Medicines and Healthcare products Regulatory Agency. TRIAL REGISTRATION NUMBER: EudraCT 2020-001805-21, ISRCTN53038326, NCT04516915.

Kikuchi-fujimoto disease: a rare cause of Fever in the returning traveller.

Background. Kikuchi-Fujimoto disease (KFD) is typically a self-limited, benign illness which presents with fever and lymphadenopathy. It is rare in Caucasians, normally occurring in those of Asian descent. The aetiology is poorly understood, but it appears to be an autoimmune disorder with a possible infectious trigger. The clinical features are such that it is often mistaken for infectious diseases or malignancy. Case Report. Here we describe a case of a 36-year-old Asian man who presented following a recent trip to Delhi, India. He described fever, neck swelling, and arthralgia. Given his travel history an infectious cause for his presentation was presumed but multiple investigations were negative. Persistence of his symptoms led to lymph node biopsy to investigate for malignancy; surprisingly this revealed a necrotizing lymphadenitis in keeping with KFD. The patient made a full recovery with supportive treatment only. Conclusion. This case presented an opportunity to reflect on two common presenting complaints-fever in the returning traveller and unexplained lymphadenopathy. Both presentations have a wide range of aetiologies to consider. Although KFD is rare, it is an important diagnosis to make as it can prevent further expensive and invasive investigations, as well as potentially harmful treatments and psychological stress to the patient.

Robust and sensitive high-performance liquid chromatographic-UV detection technique for the determination of tigecycline in rabbit plasma.

An isocratic HPLC method with detection at 248 nm was developed and fully validated for the determination of tigecycline in rabbit plasma. Minocycline was used as an internal standard. A Hypersil BDS RP-C18 column (250 x 4.6 mm, 5 microm particle size) was used with the mobile phase phosphate buffer (pH 7.10, 0.070 M)-acetonitrile (76 + 24, v/v) at a flow rate of 1.0 mL/min. The elution time of tigecycline and minocycline was approximately 8.1 and 9.9 min, respectively. Calibration curves of tigecycline were linear in the concentration range of 0.021-3.15 microg/mL in plasma. The LOD and LOQ in plasma were estimated as 7 and 21 ng/mL, respectively. The intraday and interday precision values of the method were in the range of 5.0-7.1 and 5.6-9.1%, while the corresponding accuracy values were in the ranges of 92.8-111.1 and 97.6-102.3%, respectively. At the LOQ, the intraday precision was 18.7%, while intraday and interday accuracy values were 97.3 and 98.0%, respectively. Robustness of the proposed method was studied using a Plackett-Burman experimental design. A pharmacokinetic profile is presented for confirmation of the applicability of the method to pharmacokinetic studies.

Risk factors for bloodstream infection with Klebsiella pneumoniae producing VIM-1 metallo-beta-lactamase.

OBJECTIVES: To identify risk factors for bloodstream infections (BSIs) caused by VIM-1-producing Klebsiella pneumoniae (VPKP). METHODS: Consecutive patients with K. pneumoniae BSIs were identified in three tertiary care hospitals between February 2004 and March 2006. Patients infected with VPKP were designated as cases and those infected with non-VPKP as controls. Potential risk factors for VPKP BSIs were examined by univariate and multivariate analysis. RESULTS: A total of 178 patients with K. pneumoniae BSIs were identified; 67 (37.6%) were infected with VPKP (cases) and 111 with non-VPKP (controls). In multivariate analysis, cases were more likely to have been in an intensive care unit (ICU) [odds ratio (OR), 6.78; 95% confidence interval (CI), 2.69-17.06; P < 0.001], have had prior exposure to >3 different classes of antibiotics (OR, 12.6; 95% CI, 2.17-73.27; P = 0.01) and have had prior use of carbapenems (OR, 2.83; 95% CI, 1.07-7.49; P = 0.03). CONCLUSIONS: Stay in an ICU, prior use of carbapenems and prior exposure to >3 different classes of antibiotics were independent predictors for VPKP BSIs. These findings provide guidance for antibiotic policies and infection control strategies to contain the spread of VPKP.

Gastric syphilis: a systematic review of published cases of the last 50 years.

The authors conducted a systematic review of the English literature for cases of Gastric Syphilis (GS) in the last 50 years. The 34 studies which met selection criteria included 52 patients with GS. Of the reviewed patients, only 13% had a history of syphilis diagnosis and 46% had prior or concurrent clinical manifestations of the disease. Epigastric pain/fullness was the most common presenting symptom (92%) and epigastric tenderness being the most common sign. Gastric bleeding of variable intensity was documented in 35% of the cases. In the radiologic examinations, fibrotic narrowing and rigidity of the gastric wall was the most common finding (43%), followed by hypertrophic and irregular folds, while in endoscopy the most common lesion types were multiple ulcerations (48%), nodular mucosa, and erosions. The antrum was the most commonly affected area (56%). The majority of the patients received penicillin (83%) with a rapid resolution of their symptoms. Seventeen percent of the patients were treated surgically either due to a complication or due to strong suspicion of infiltrating tumor or lymphoma. The nonspecific clinical, radiologic, and pathologic characteristics of GS can establish it as a great imitator of other gastric diseases. GS should be considered in the differential diagnosis in patients at risk for sexually transmitted diseases who present with abdominal complaints and unusual endoscopic lesions and no other diagnosis is made, irrespective of the presence of H. pylori. The absence of primary or secondary luetic lesions should not deter one from considering GS.

Prospective observational study of the impact of VIM-1 metallo-beta-lactamase on the outcome of patients with Klebsiella pneumoniae bloodstream infections.

VIM-1-producing Klebsiella pneumoniae (VPKP) is an emerging pathogen. A prospective observational study was conducted to evaluate the importance of VIM production on outcome of patients with K. pneumoniae bloodstream infections (BSIs). Consecutive patients with K. pneumoniae BSIs were identified and followed up until patient discharge or death. A total of 162 patients were included in the analysis; 67 (41.4%) were infected with VPKP, and 95 were infected with non-VPKP. Fourteen of the patients infected with VPKP were carbapenem resistant (Carb(r)) (MIC > 4 mug/ml), whereas none of the non-VPKP exhibited carbapenem resistance. The patients infected with a Carb(r) organism were more likely (odds ratio, 4.08; 95% confidence interval [CI], 1.29 to 12.85; P = 0.02) to receive inappropriate empirical therapy. The all-cause 14-day mortality rates were 15.8% (15 of 95) for patients infected with VIM-negative organisms, 18.9% (10 of 53) for those infected with VIM-positive carbapenem-susceptible organisms, and 42.9% (6 of 14) for those infected with VIM-positive Carb(r) organisms (P = 0.044). In Cox regression analysis, age (hazard ratio [HR], 1.03; 95% CI, 1.01 to 1.06; P = 0.021), rapidly fatal underlying disease (HR, 2.84; 95% CI, 1.26 to 6.39; P = 0.012), and carbapenem resistance (HR, 2.83; 95% CI, 1.08 to 7.41; P = 0.035) were independent predictors of death. After adjustment for inappropriate empirical or definitive therapy, the effect of carbapenem resistance on outcome was reduced to a level of nonsignificance. In patients with K. pneumoniae BSIs, carbapenem resistance, advanced, age, and severity of underlying disease were independent predictors of outcome, whereas VIM production had no effect on mortality. The higher mortality associated with carbapenem resistance was probably mediated by the failure to provide effective therapy.

Factors associated with non-bacterial thrombotic endocarditis: case report and literature review.

The case is reported of non-bacterial thrombotic endocarditis (NBTE) in a patient with giant cell arteritis and prostate cancer, and the relevant literature reviewed. To the present authors' knowledge, this is the first case to be reported where NBTE coexists with both arteritis and cancer. NBTE is difficult to diagnose if the underlying disease is accompanied by fever. If a diagnosis of probable infective endocarditis is established, the cultures and serology are negative, and there is no response to antibiotic treatment, then NBTE should be considered.