Adjunctive intravenous then oral vitamin C for moderate and severe community-acquired pneumonia in hospitalized adults: feasibility of randomized controlled trial.

Patients hospitalised with community acquired pneumonia (CAP) have low peripheral blood vitamin C concentrations and limited antioxidant capacity. The feasibility of a trial of vitamin C supplementation to improve patient outcomes was assessed. Participants with moderate and severe CAP (CURB-65 ≥ 2) on intravenous antimicrobial treatment were randomised to either intravenous vitamin C (2.5 g 8 hourly) or placebo before switching to oral intervention (1 g tds) for 7 days when they were prescribed oral antimicrobial therapy. Of 344 patients screened 75 (22%) were randomised and analysed. The median age was 76 years, and 43 (57%) were male. In each group, one serious adverse event that was potentially intervention related occurred, and one subject discontinued treatment. Vitamin C concentrations were 226 µmol/L in the vitamin C group and 19 µmol/L in the placebo group (p < 0.001) after 3 intravneous doses. There were no signficant differences between the vitamin C and placebo groups for death within 28 days (0 vs. 2; p = 0.49), median length of stay (69 vs. 121 h; p = 0.07), time to clinical stability (22 vs. 49 h; p = 0.08), or readmission within 30 days (1 vs. 4; p = 0.22). The vitamin C doses given were safe, well tolerated and saturating. A randomised controlled trial to assess the efficacy of vitamin C in patients with CAP would require 932 participants (CURB-65 ≥ 2) to observe a difference in mortality and 200 participants to observe a difference with a composite endpoint such as mortality plus discharge after 7 days in hospital. These studies are feasible in a multicentre setting.

Radiometal chelators for infection diagnostics.

Infection of native tissues or implanted devices is common, but clinical diagnosis is frequently difficult and currently available noninvasive tests perform poorly. Immunocompromised individuals (for example transplant recipients, or those with cancer) are at increased risk. No imaging test in clinical use can specifically identify infection, or accurately differentiate bacterial from fungal infections. Commonly used [18F]fluorodeoxyglucose (18FDG) positron emission computed tomography (PET/CT) is sensitive for infection, but limited by poor specificity because increased glucose uptake may also indicate inflammation or malignancy. Furthermore, this tracer provides no indication of the type of infective agent (bacterial, fungal, or parasitic). Imaging tools that directly and specifically target microbial pathogens are highly desirable to improve noninvasive infection diagnosis and localization. A growing field of research is exploring the utility of radiometals and their chelators (siderophores), which are small molecules that bind radiometals and form a stable complex allowing sequestration by microbes. This radiometal-chelator complex can be directed to a specific microbial target in vivo, facilitating anatomical localization by PET or single photon emission computed tomography. Additionally, bifunctional chelators can further conjugate therapeutic molecules (e.g., peptides, antibiotics, antibodies) while still bound to desired radiometals, combining specific imaging with highly targeted antimicrobial therapy. These novel therapeutics may prove a useful complement to the armamentarium in the global fight against antimicrobial resistance. This review will highlight current state of infection imaging diagnostics and their limitations, strategies to develop infection-specific diagnostics, recent advances in radiometal-based chelators for microbial infection imaging, challenges, and future directions to improve targeted diagnostics and/or therapeutics.

Yersinia enterocolitica associated myopericarditis: case report and review of the literature.

We report a case of myopericarditis associated with Yersinia enterocolitica infection in an otherwise well 50-year-old man. We discuss the clinical features, microbiology and treatment of this rare cause of myopericarditis.

Oral amoxicillin challenge for low-risk penicillin allergic patients.

BACKGROUND: Penicillin allergy is the most reported adverse drug reaction (ADR). Being labelled with 'penicillin allergy' is associated with suboptimal antibiotic therapy and poor patient outcomes. Most labelled with 'penicillin allergy' are at low risk of harm from penicillins and guidelines recommend testing for accurate diagnosis. Although skin testing is recommended to exclude immunoglobulin E (IgE)-mediated reactions, there is limited access in most settings. AIMS: To evaluate oral amoxicillin challenge without prior skin testing for patients labelled with 'penicillin allergy' assessed as low risk during hospital admission. METHODS: General Medical inpatients with a 'penicillin allergy' label were assessed. For those who had tolerated a penicillin since the index event, the ADR label was removed. Those assessed as 'low risk' were administered 250 mg amoxicillin orally without prior skin testing. The durability of de-labelling was subsequently assessed by review of clinical records. RESULTS: Of 224 patients with a history of a penicillin ADR, 162 (72%) were low risk. A further 12 were excluded and of the remaining 150, 56 (37%) had tolerated penicillins since their index reaction and were de-labelled without challenge, 15 (10%) with a non-allergic history were de-labelled. The remaining 79 were offered an oral amoxicillin challenge; 38 declined and 41 tolerated amoxicillin. Overall, 112 of the 224 (50%) patients had their ADR label removed. CONCLUSIONS: A careful ADR history enables de-labelling of many patients. An oral amoxicillin challenge without prior skin testing is safe and feasible for low-risk penicillin allergic patients while in hospital.

Urinalysis orders and yield among General Medicine patients: a single-centre's experience in New Zealand.

BACKGROUND: Urinalysis performed by dipstick testing is an aid to diagnosing urinary tract infections (UTI), and a tool in selecting patients who require urine culture and antibiotic treatment. Previous studies have demonstrated that UTI, especially in the elderly, are over-diagnosed and over-treated. We sought to study the pattern and yield of urinalysis and urine culture at our service in a tertiary institution. METHODS: A convenience sampling method was utilised to prospectively collect clinical data, through a pre-designed pro forma, from patients admitted to the General Medicine service at Christchurch Hospital between March and June 2016. RESULTS: The study included 395 patients, with a median age of 76 (range 15-100 years). The presence of urinary tract symptoms was documented in 94 patients (24%) and a non-specific syndrome of elevated temperature, confusion or subjective feverishness in 69 (17%). In symptomatic patients, 121 (74%) had a dipstick performed and 104 (86%) urine samples cultured. In the remaining patients, 181 (78%) had a dipstick performed and 81 (35%) had a urine sample sent for culture. CONCLUSIONS: We found a large number of urine dipsticks is being ordered unnecessarily in asymptomatic patients. A more useful test is urine microscopy and culture that is done on symptomatic patients only following careful clinical evaluation. Performing 'routine' urinalysis in patients presenting a wide variety of symptoms may lead to unnecessary urine cultures and treatment of asymptomatic bacteriuria. Efforts to reduce unnecessary tests and antibiotic treatment are a vital component of diagnostic stewardship programmes.

Outpatient parenteral antimicrobial therapy (OPAT) in Christchurch: 18 years on.

AIM: Outpatient parenteral antimicrobial therapy (OPAT) has become an established option for management infections requiring intravenous therapy. As the uptake of OPAT has increased, the clinical governance has changed and is now managed via virtual clinics and increased use of district nurses in addition to specialist outpatient review. The aim of this study was to report the characteristics, diagnoses, treatment and outcomes of patients managed by the service over 12 months in 2015/6 and compared these features with those of patients treated with OPAT in 1999. METHODS: Cases for 2015/6 were identified from the OPAT service database which records prospectively all information on diagnosis, antibiotic choice and duration of treatment, complications and requirement for review by the ID physicians and OPAT nurses prospectively. The outcomes, complications and readmissions were found by reviewing computerised records of Christchurch Hospital. All results were entered into a Microsoft® Excel database for analysis. Statistical analyses were performed using OpenEpi software. Data for 1999 was taken from an earlier publication. RESULTS: OPAT treatment in 12 months from 1 July 2015 was administered 407 times to 385 patients, which represented a 2.7 times increase in treatment courses than in 1999. The median age was 55 years in 1999 and 61 in 2015/6. There was a substantial increase in the proportion of bone and joint, abdominal and urinary tract infections but a fall in cellulitis and soft tissue infection. The number and proportion of patients treated with broad spectrum agents including piperacillin + tazobactam, ceftriaxone and carbapenems increased from 1% in 1999 to 20% in 2015/6. Unplanned readmission to hospital increased from 15 (10%) in 1999 to 62 patients (15%) in 2015/6. The most common reason for readmission in 2015/6 was for ongoing symptoms or progression of the infection requiring OPAT. Eight patients (2%) required readmission from adverse reactions to antimicrobial therapy. Two patients on palliative care died while on OPAT and 35 (9%) within 12 months of the index admission. CONCLUSION: OPAT use has increased and is used to treat patients with comorbidities, who are older, and with a different case-mix than 1999. Safety has not been compromised but the risk of treatment failure has increased. A better understanding of the reasons for treatment failure would improve patient selection and management with OPAT.

In healthy volunteers, taking flucloxacillin with food does not compromise effective plasma concentrations in most circumstances.

It is usually recommended that flucloxacillin is given on an empty stomach. The aim of this study was to compare total and free flucloxacillin concentrations after oral flucloxacillin, given with and without food, based on contemporary pharmacokinetic and pharmacodynamic targets. Flucloxacillin 1000 mg orally was given to 12 volunteers, after a standardised breakfast and while fasting, on two separate occasions. Flucloxacillin concentrations over 12 hours were measured by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, and pharmacodynamic endpoints related to target concentration achievement, were compared in the fed and fasting states. For free flucloxacillin, the fed/fasting area under the concentration-time curve from zero to infinity (AUC0-∞) ratio was 0.80 (p<0.01, 90% CI 0.70-0.92), the peak concentraton (Cmax) ratio 0.51 (p<0.001, 0.42-0.62) and the time to peak concentration (Tmax) ratio 2.2 (p<0.001, 1.87-2.55). The ratios for total flucloxacillin concentrations were similar. The mean (90% CI) fed/fasting ratios of free concentrations exceeded for 30%, 50% and 70% of the first 6 hours post-dose were 0.74 (0.63-0.87, fed inferior p<0.01), 0.95 (0.81-1.11, bioequivalent) and 1.15 (0.97-1.36, fed non-inferior), respectively. Results for 8 hours post-dose and those predicted for steady state were similar. Comparison of probability of target attainments for fed versus fasting across a range of minimum inhibitory concentrations (MICs) were in line with these results. Overall, this study shows that food reduced the AUC0-∞ and Cmax, and prolonged the Tmax of both free and total flucloxacillin concentrations compared with the fasting state, but achievement of free concentration targets associated with efficacy was in most circumstances equivalent. These results suggest that taking flucloxacillin with food is unlikely to compromise efficacy in most circumstances.

Advances in prevention and treatment of vancomycin-resistant Enterococcus infection.

PURPOSE OF REVIEW: This article reviews data, particularly from the last 2 years, addressing the prevention and treatment of vancomycin-resistant Enterococcus (VRE). We focus on infection control, particularly active screening, use of contact precautions as well as pharmacologic options for therapy. This is timely given the evolving priorities in efforts towards the prevention and treatment of multidrug-resistant organisms globally. RECENT FINDINGS: Key findings include new data regarding the impact of contact precautions on the incidence of VRE colonization and bloodstream infection, new laboratory screening methods, and novel decolonization strategies and treatments. SUMMARY: Additional and specific measures beyond standard precautions for infection prevention of VRE remain controversial. Horizontal measures such as chlorhexidine bathing appear beneficial, as are nontouch environmental cleaning methods. Treatment options for invasive disease have improved considerably in the last decade. Decolonization strategies require further research. Overall, the threat of VRE seems exaggerated.

Human T cell responses to Japanese encephalitis virus in health and disease.

Japanese encephalitis (JE) virus (JEV) is an important cause of encephalitis in children of South and Southeast Asia. However, the majority of individuals exposed to JEV only develop mild symptoms associated with long-lasting adaptive immunity. The related flavivirus dengue virus (DENV) cocirculates in many JEV-endemic areas, and clinical data suggest cross-protection between DENV and JEV. To address the role of T cell responses in protection against JEV, we conducted the first full-breadth analysis of the human memory T cell response using a synthetic peptide library. Ex vivo interferon-γ (IFN-γ) responses to JEV in healthy JEV-exposed donors were mostly CD8(+) and targeted nonstructural (NS) proteins, whereas IFN-γ responses in recovered JE patients were mostly CD4(+) and targeted structural proteins and the secreted protein NS1. Among patients, a high quality, polyfunctional CD4(+) T cell response was associated with complete recovery from JE. T cell responses from healthy donors showed a high degree of cross-reactivity to DENV that was less apparent in recovered JE patients despite equal exposure. These data reveal divergent functional CD4(+) and CD8(+) T cell responses linked to different clinical outcomes of JEV infection, associated with distinct targeting and broad flavivirus cross-reactivity including epitopes from DENV, West Nile, and Zika virus.

Legionnaires' disease caused by Legionella longbeachae: Clinical features and outcomes of 107 cases from an endemic area.

BACKGROUND AND OBJECTIVE: Legionella longbeachae is a predominant cause of Legionnaires' disease in some parts of the world, particularly in Australasia. Clinical reports of L. longbeachae infection are limited to case reports or small case series, and culture-confirmed cases. METHODS: We reviewed the clinical characteristics and outcomes of L. longbeachae pneumonia in a large case series from Christchurch, New Zealand during a 4-year period when both PCR and cultures were used as routine diagnostic tools for Legionnaires' disease. Cases of Legionella pneumophila pneumonia were reviewed for comparison. RESULTS: A total of 107 cases of L. longbeachae infection were identified by PCR and/or culture. The median age was 65 years (range 25-90 years), 63% were male, and most became unwell during spring or summer. Presenting clinical features were similar to those reported for community-acquired pneumonia, with headache, myalgia and diarrhoea being common. Elevated C-reactive protein, hyponatraemia and abnormal liver function tests were also common. History of productive cough, involvement of both lungs, and high bacterial load were independently associated with culture of Legionella from lower respiratory samples. One quarter required intensive care unit admission, and 5% died. Among patients given antimicrobial therapy before admission, those given agents without anti-Legionella activity were more likely to be admitted to the intensive care unit. Limited comparisons were made with the 19 L. pneumophila cases over the same time period. CONCLUSION: Characteristics of L. longbeachae pneumonia are broadly similar to those reported for community-acquired pneumonia from a variety of other populations, except for the spring/summer seasonality.

Which visual pathways cause fixation-related inhibition?

Visual stimuli can both inhibit and activate motor mechanisms. In one well-known example, the latency of saccadic eye movements is prolonged in the presence of a fixation stimulus, relative to the case in which the fixation stimulus disappears before the target appears. This automatic sensory-motor effect, known as the gap effect or fixation-offset effect, has been associated with inhibitory connections within the superior colliculus (SC). Visual information is provided to the SC and other oculomotor areas, such as the frontal eye fields (FEF), mainly by the magnocellular geniculostriate pathway, and also by the retinotectal pathway. We tested whether signals in these pathways are necessary to create fixation-related inhibition, by using stimuli invisible to them. We found that such stimuli, visible only to short-wave-sensitive cones (S cones), do produce fixation-related inhibition (including when warning effects were equated). We also demonstrate that this fixation-related inhibition cannot be explained by residual activation of luminance pathways and must be caused by a route separate from that of luminance fixation signals. Thus there are at least two routes that cause fixation-related inhibition, and direct sensory input to the SC or FEF by the magnocellular or retinotectal pathways is not required. We discuss the implications that there may be both cortical and collicular mechanisms.