Oral step-down for Staphylococcus aureus bacteraemia: an opportunity for antimicrobial stewardship?

Objectives: Long courses of intravenous antimicrobial therapy are traditionally recommended for the treatment of methicillin sensitive Staphylococcus aureus bacteraemia (MS-SAB), but are not always completed in clinical practice. Early intravenous to oral antibiotic switch is a key component of antimicrobial stewardship. This study aimed to identify whether intravenous antibiotic duration may be safely reduced in MS-SAB. Methods: We performed a single-centre retrospective study of MS-SAB management. Successful outcome was defined as 90-day recurrence-free survival. Effect of intravenous antibiotic duration on 90-day recurrence risk was examined. Results: 281 adult cases of MS-SAB were evaluated, of which 208 (74%) had a successful outcome. 176 cases (63%) received less than 14 days of intravenous antimicrobial therapy. Very short durations of intravenous therapy were associated with increased risk of recurrence (<7 days iv, 9.8% recurrence; 7-13 days, 1.4%; ≥14 days, 2.9%; p 0.005). This effect was robust to sensitivity analysis for total antimicrobial therapy duration of 14 days. CRP reduction of at least 37% from peak value at intravenous to oral antibiotic switch was associated with decreased risk of recurrence (<37% CRP reduction, 12% recurrence; >37%, 2.0%; p 0.001). Conclusions: Oral antimicrobial switch may allow safe reductions in duration of intravenous therapy in MS-SAB.

Care pathway and prioritization of rapid testing for COVID-19 in UK hospitals: a qualitative evaluation.

OBJECTIVES: The second wave of the coronavirus pandemic is now established, occurring at a time of winter pressure on acute care in the NHS. This is likely to be more challenging then the first wave for the diagnosis of COVID-19 because of the similar symptomology with other respiratory conditions highly prevalent in winter. This study sought to understand the care pathways in place in UK NHS hospitals during the first wave (March-July 2020) for identification of patients with COVID-19 and to learn lessons to inform optimal testing strategies within the COVID-19 National Diagnostic Research and Evaluation Platform (CONDOR). DESIGN, SETTING & PARTICIPANTS: Sixteen hospital-based clinicians from 12 UK NHS Trusts covering 10 different specialties were interviewed following a semi-structured topic guide. Data were coded soon after the interviews and analysed thematically. RESULTS: We developed a diagrammatic, high-level visualisation of the care pathway describing the main clinical decisions associated with the diagnosis and management of patients with suspected COVID-19. COVID-19 testing influenced infection control considerations more so than treatment decisions. Two main features of service provision influenced the patient management significantly: access to rapid laboratory testing and the number of single occupancy rooms. If time to return of result was greater than 24 h, patients with a presumptive diagnosis would often be cohorted based on clinical suspicion alone. Undetected COVID-19 during this time could therefore lead to an increased risk of viral transmission. CONCLUSIONS: During the winter months, priority for provision of rapid testing at admission should be given to hospitals with limited access to laboratory services and single room availability. Access to rapid testing is essential for urgent decisions related to emergency surgery, maternity services and organ transplant. The pathway and prioritization of need will inform the economic modelling, clinical evaluations, and implementation of new clinical tests in UK.

Utility of Routine Laboratory Biomarkers to Detect COVID-19: A Systematic Review and Meta-Analysis.

No routine laboratory biomarkers perform well enough in diagnosing COVID-19 in isolation for them to be used as a standalone diagnostic test or to help clinicians prioritize patients for treatment. Instead, other diagnostic tests are needed. The aim of this work was to statistically summarise routine laboratory biomarker measurements in COVID-19-positive and -negative patients to inform future work. A systematic literature review and meta-analysis were performed. The search included names of commonly used, routine laboratory tests in the UK NHS, and focused on research papers reporting laboratory results of patients diagnosed with COVID-19. A random effects meta-analysis of the standardized mean difference between COVID-19-positive and -negative groups was conducted for each biomarker. When comparing reported laboratory biomarker results, we identified decreased white blood cell, neutrophil, lymphocyte, eosinophil, and platelet counts; while lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase were elevated in COVID-19-positive compared to COVID-19-negative patients. Differences were identified across a number of routine laboratory biomarkers between COVID-19-positive and -negative patients. Further research is required to identify whether routine laboratory biomarkers can be used in the development of a clinical scoring system to aid with triage of patients.

Unmet clinical needs for COVID-19 tests in UK health and social care settings.

There is an urgent requirement to identify which clinical settings are in most need of COVID-19 tests and the priority role(s) for tests in these settings to accelerate the development of tests fit for purpose in health and social care across the UK. This study sought to identify and prioritize unmet clinical needs for COVID-19 tests across different settings within the UK health and social care sector via an online survey of health and social care professionals and policymakers. Four hundred and forty-seven responses were received between 22nd May and 15th June 2020. Hospitals and care homes were recognized as the settings with the greatest unmet clinical need for COVID-19 diagnostics, despite reporting more access to laboratory molecular testing than other settings. Hospital staff identified a need for diagnostic tests for symptomatic workers and patients. In contrast, care home staff expressed an urgency for screening at the front door to protect high-risk residents and limit transmission. The length of time to test result was considered a widespread problem with current testing across all settings. Rapid tests for staff were regarded as an area of need across general practice and dental settings alongside tests to limit antibiotics use.

The Clinical Need for New Diagnostics in the Identification and Management of Patients with Suspected Sepsis in UK NHS Hospitals: A Survey of Healthcare Professionals.

Development of a new diagnostic is ideally driven by an understanding of the clinical need that the test addresses and the optimal role the test will have within a care pathway. This survey aimed to understand the clinical need for new sepsis diagnostics and to identify specific clinical scenarios that could be improved by testing. An electronic, cross-sectional survey was circulated to UK National Health Service (NHS) doctors and nurses who care for patients with suspected sepsis in hospitals. Two hundred and sixty-five participants completed the survey, representing 64 NHS Trusts in England. Sixty-seven percent of respondents suggested that the major cause of delay was during the initial identification of sepsis and the subsequent recognition of patients who were deteriorating. Existing blood tests did not enhance the confidence of consultants making their diagnoses. Those surveyed identified a role for a near-patient test to "rule out" suspected sepsis and, thereby, stop or postpone use of antibiotics. Current diagnostic tests are slow, non-specific, and do not reliably identify patients with a high suspicion of sepsis. As a result, they have a limited use in patient management and antibiotic stewardship. Future development of sepsis diagnostics should focus on overcoming these limitations.

Cost Consequences for the NHS of Using a Two-Step Testing Method for the Detection of Clostridium difficile with a Point of Care, Polymerase Chain Reaction Test as the First Step.

Clostridium difficile infection (CDI) is a common healthcare-associated infection. Current practice for diagnosing CDI in the Newcastle upon Tyne Hospitals NHS Foundation Trust involves a three-step, laboratory testing strategy using glutamate dehydrogenase (GDH) enzyme immunoassay (EIA), followed by a polymerase chain reaction (PCR) test then a toxin EIA. However, a PCR point of care test (POCT) for the C. difficile tcdB gene for screening suspected CDI cases, may provide a more efficient way of facilitating an equally effective, two-step, testing strategy with a toxin EIA. This study evaluated the cost consequences of changing from the three-step to a two-step testing strategy. A cost-consequences model was developed to compare the costs and consequences of the two strategies. Uncertainties in the model inputs were investigated with one- and two-way sensitivity analysis. The two-step, POCT strategy was estimated to save £283,282 per 1000 hospitalized NHS patients with suspected infectious diarrhea. Sensitivity analysis indicated that the turnaround time for the POCT was the largest driver for cost savings. Providing the POCT has sufficiently high diagnostic accuracy for detecting C. difficile, the two-step, POCT strategy for CDI identification is likely to be cost saving for NHS hospitals with an offsite laboratory.

Human-to-Human Transmission of Monkeypox Virus, United Kingdom, October 2018.

In September 2018, monkeypox virus was transmitted from a patient to a healthcare worker in the United Kingdom. Transmission was probably through contact with contaminated bedding. Infection control precautions for contacts (vaccination, daily monitoring, staying home from work) were implemented. Of 134 potential contacts, 4 became ill; all patients survived.

Pyogenic Spondylodiscitis: Risk Factors for Adverse Clinical Outcome in Routine Clinical Practice.

We aimed to describe the clinical features and outcomes of pyogenic spondylodiscitis and to identify factors associated with an unfavourable clinical outcome (defined as death, permanent disability, spinal instability or persistent pain). In our tertiary centre, 91 cases were identified prospectively and a retrospective descriptive analysis of clinical records was performed prior to binary regression analysis of factors associated with an unfavourable outcome. A median 26 days elapsed from the onset of symptoms to diagnosis and 51% of patients had neurological impairment at presentation. A microbiological diagnosis was reached in 81%, with Staphylococcus aureus most commonly isolated. Treatment involved prolonged hospitalisation (median stay 40.5 days), long courses of antibiotics (>6 weeks in 98%) and surgery in 42%. While this was successful in eradicating infection, only 32% of patients had a favourable clinical outcome and six patients (7%) died. Diabetes mellitus, clinical evidence of neurological impairment at presentation, a longer duration of symptoms and radiological evidence of spinal cord or cauda equina compression were independent factors associated with an unfavourable outcome. Our data indicate that spondylodiscitis is associated with significant morbidity and suggest that adverse outcomes may be predicted to an extent by factors present at the time of diagnosis.

Pyogenic brain abscess and subdural empyema: presentation, management, and factors predicting outcome.

PURPOSE: To describe the presentation and management of bacterial brain abscess and subdural empyema in adults treated at two tertiary centers. In addition, to identify factors that may predict a poor clinical outcome. METHODS: A retrospective analysis of data obtained from clinical records was performed, followed by multivariate regression analysis of patient and treatment-related factors. RESULTS: 113 patients were included with a median age of 53 years and a male preponderance. At presentation symptoms were variable, 28% had a focal neurological deficit, and 39% had a reduced Glasgow coma scale (GCS). Brain abscesses most frequently affected the frontal, temporal, and parietal lobes while 36% had a subdural empyema. An underlying cause was identified in 76%; a contiguous ear or sinus infection (43%), recent surgery or trauma (18%) and haematogenous spread (15%). A microbiological diagnosis was confirmed in 86%, with streptococci, staphylococci, and anaerobes most frequently isolated. Treatment involved complex, prolonged antibiotic therapy (> 6 weeks in 84%) combined with neurosurgical drainage (91%) and source control surgery (34%). Mortality was 5% with 31% suffering long-term disability and 64% achieving a good clinical outcome. A reduced GCS, focal neurological deficit, and seizures at presentation were independently associated with an unfavorable clinical outcome (death or disability). CONCLUSIONS: Complex surgical and antimicrobial treatment achieves a good outcome in the majority of patients with bacterial brain abscess and subdural empyema. Factors present at diagnosis can help to predict those likely to suffer adverse outcomes. Research to determine optimal surgical and antibiotic management would be valuable.

Tenofovir disoproxil fumarate-associated renal tubular dysfunction: noninvasive assessment of mitochondrial injury.

OBJECTIVE: To determine whether tenofovir disoproxil fumarate (TDF)-associated renal tubular dysfunction is associated with evidence of mitochondrial injury in urine. DESIGN: Single-centre cross-sectional observational study of HIV-positive outpatients. METHODS: Biochemistry was performed on paired serum and urine samples. Mitochondrial DNA (mtDNA) was studied by real-time PCR and long-range PCR on cellular fractions of urine. RESULTS: In total, 48 study participants were enrolled of whom half were TDF treated. Mean age was 43 years. 58% had estimated glomerular filtration rate at least 90, with no differences between ART treatment groups. Urinary phosphate wasting was common and independently associated with TDF exposure (P = 0.02). No study participants had low molecular weight proteinuria. Cellular mtDNA content in urine was heavily influenced by the cellularity of the sample. The mtDNA 'common deletion' mutation was detectable significantly more commonly in the urine of TDF exposed study participants compared with unexposed (13/22 TDF study participants (59%), 4/21 TDF (19%), P = 0.01). Common deletion levels were not associated with age, estimated glomerular filtration rate, or urinary phosphate wasting. No mtDNA measures were associated with current or nadir CD4 lymphocyte counts, duration of disease or antiretroviral therapy, or historical exposure to nucleoside analogue reverse transcriptase inhibitors with systemic mitochondrial toxicity. CONCLUSION: The presence of mtDNA mutations in the context of TDF exposure adds weight to the hypothesis that TDF-associated renal damage is at least in part mitochondrially mediated. The assessment of mtDNA markers in urine may be a feasible noninvasive investigation for TDF-treated patients.

In vivo mitochondrial function in HIV-infected persons treated with contemporary anti-retroviral therapy: a magnetic resonance spectroscopy study.

Modern anti-retroviral therapy is highly effective at suppressing viral replication and restoring immune function in HIV-infected persons. However, such individuals show reduced physiological performance and increased frailty compared with age-matched uninfected persons. Contemporary anti-retroviral therapy is thought to be largely free from neuromuscular complications, whereas several anti-retroviral drugs previously in common usage have been associated with mitochondrial toxicity. It has recently been established that patients with prior exposure to such drugs exhibit irreversible cellular and molecular mitochondrial defects. However the functional significance of such damage remains unknown. Here we use phosphorus magnetic resonance spectroscopy ((31)P-MRS) to measure in vivo muscle mitochondrial oxidative function, in patients treated with contemporary anti-retroviral therapy, and compare with biopsy findings (cytochrome c oxidase (COX) histochemistry). We show that dynamic oxidative function (post-exertional ATP (adenosine triphosphate) resynthesis) was largely maintained in the face of mild to moderate COX defects (affecting up to ∼10% of fibers): τ½ ADP (half-life of adenosine diphosphate clearance), HIV-infected 22.1±9.9 s, HIV-uninfected 18.8±4.4 s, p = 0.09. In contrast, HIV-infected patients had a significant derangement of resting state ATP metabolism compared with controls: ADP/ATP ratio, HIV-infected 1.24±0.08×10(-3), HIV-uninfected 1.16±0.05×10(-3), p = 0.001. These observations are broadly reassuring in that they suggest that in vivo mitochondrial function in patients on contemporary anti-retroviral therapy is largely maintained at the whole organ level, despite histochemical (COX) defects within individual cells. Basal energy requirements may nevertheless be increased.

Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations.

There is emerging evidence that people with successfully treated HIV infection age prematurely, leading to progressive multi-organ disease, but the reasons for this are not known. Here we show that patients treated with commonly used nucleoside analog anti-retroviral drugs progressively accumulate somatic mitochondrial DNA (mtDNA) mutations, mirroring those seen much later in life caused by normal aging. Ultra-deep re-sequencing by synthesis, combined with single-cell analyses, suggests that the increase in somatic mutation is not caused by increased mutagenesis but might instead be caused by accelerated mtDNA turnover. This leads to the clonal expansion of preexisting age-related somatic mtDNA mutations and a biochemical defect that can affect up to 10% of cells. These observations add weight to the role of somatic mtDNA mutations in the aging process and raise the specter of progressive iatrogenic mitochondrial genetic disease emerging over the next decade.