COVID-19-associated pulmonary aspergillosis in mechanically ventilated patients: a prospective, multicentre UK study.

BACKGROUND: Invasive pulmonary aspergillosis is a complication of severe COVID-19, with regional variation in reported incidence and mortality. We describe the incidence, risk factors and mortality associated with COVID-19-associated pulmonary aspergillosis (CAPA) in a prospective, multicentre UK cohort. METHODS: From March 2020 to March 2021, 266 mechanically ventilated adults with COVID-19 were enrolled across 5 UK hospital intensive care units (ICUs). CAPA was defined using European Confederation for Medical Mycology and the International Society for Human and Animal Mycology criteria and fungal diagnostics performed on respiratory and serum samples. RESULTS: Twenty-nine of 266 patients (10.9%) had probable CAPA, 14 (5.2%) possible CAPA and none proven CAPA. Probable CAPA was diagnosed a median of 9 (IQR 7-16) days after ICU admission. Factors associated with probable CAPA after multivariable logistic regression were cumulative steroid dose given within 28 days prior to ICU admission (adjusted OR (aOR) 1.16; 95% CI 1.01 to 1.43 per 100 mg prednisolone-equivalent), receipt of an interleukin (IL)-6 inhibitor (aOR 2.79; 95% CI 1.22 to 6.48) and chronic obstructive pulmonary disease (COPD) (aOR 4.78; 95% CI 1.13 to 18.13). Mortality in patients with probable CAPA was 55%, vs 46% in those without. After adjustment for immortal time bias, CAPA was associated with an increased risk of 90-day mortality (HR 1.85; 95% CI 1.07 to 3.19); however, this association did not remain statistically significant after further adjustment for confounders (adjusted HR 1.57; 95% CI 0.88 to 2.80). There was no difference in mortality between patients with CAPA prescribed antifungals (9 of 17; 53%) and those who were not (7 of 12; 58%) (p=0.77). INTERPRETATION: In this first prospective UK study, probable CAPA was associated with corticosteroid use, receipt of IL-6 inhibitors and pre-existing COPD. CAPA did not impact mortality following adjustment for prognostic variables.

Demographic and occupational determinants of anti-SARS-CoV-2 IgG seropositivity in hospital staff.

BACKGROUND: Although evidence suggests that demographic characteristics including minority ethnicity increase the risk of infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), it is unclear whether these characteristics, together with occupational factors, influence anti-SARS-CoV-2 IgG seroprevalence in hospital staff. METHODS: We conducted cross-sectional surveillance examining seroprevalence of anti-SARS-CoV-2 IgG amongst staff at University Hospitals of Leicester (UHL) NHS Trust. We quantified seroprevalence stratified by ethnicity, occupation and seniority of practitioner and used logistic regression to examine demographic and occupational factors associated with seropositivity. RESULTS: A total of 1148/10662 (10.8%) hospital staff members were seropositive. Compared to White staff (seroprevalence 9.1%), seroprevalence was higher in South Asian (12.3%) and Black (21.2%) staff. The occupations and department with the highest seroprevalence were nurses/healthcare assistants (13.7%) and the Emergency Department (ED)/Acute Medicine (17.5%), respectively. Seroprevalence decreased with seniority in medical/nursing practitioners. Minority ethnicity was associated with seropositivity on an adjusted analysis (South Asian: aOR 1.26; 95%CI: 1.07-1.49 and Black: 2.42; 1.90-3.09). Anaesthetics/ICU staff members were less likely to be seropositive than ED/Acute medicine staff (0.41; 0.27-0.61). CONCLUSIONS: Ethnicity and occupational factors, including specialty and seniority, are associated with seropositivity for anti-SARS-Cov-2 IgG. These findings could be used to inform occupational risk assessments for front-line healthcare workers.

No cases of asymptomatic SARS-CoV-2 infection among healthcare staff in a city under lockdown restrictions: lessons to inform 'Operation Moonshot'.

BACKGROUND: Leicester was the first city in the UK to have 'local lockdown' measures imposed in response to high community rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. As part of this response, a directive was issued by NHS England to offer testing of asymptomatic healthcare workers (HCWs) at University Hospitals of Leicester NHS Trust (UHL) for SARS-CoV-2 infection. METHODS: Between 20 July and 14 August 2020, we invited all HCWs at UHL to attend for SARS-CoV-2 testing by nucleic acid amplification (NAAT). We combined the result of this assay with demographic information from the electronic staff record. RESULTS: A total of 1150 staff (~8% of the workforce) volunteered. The median age was 46 years (IQR 34-55), 972 (84.5%) were female; 234 (20.4%) were of South Asian and 58 (5.0%) of Black ethnicity; 564 (49.0%) were nurses/healthcare assistants. We found no cases of asymptomatic infection. In comparison, average community test positivity rate in Leicester city was 2.6%. CONCLUSIONS: Within the context of local lockdowns due to high community transmission rates, voluntary testing of asymptomatic staff has low uptake and low yield and thus its premise and cost-effectiveness should be re-considered.

SARS-CoV-2 vaccine uptake in a multi-ethnic UK healthcare workforce: A cross-sectional study.

BACKGROUND: Healthcare workers (HCWs) and ethnic minority groups are at increased risk of COVID-19 infection and adverse outcomes. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is now available for frontline UK HCWs; however, demographic/occupational associations with vaccine uptake in this cohort are unknown. We sought to establish these associations in a large UK hospital workforce. METHODS AND FINDINGS: We conducted cross-sectional surveillance examining vaccine uptake amongst all staff at University Hospitals of Leicester NHS Trust. We examined proportions of vaccinated staff stratified by demographic factors, occupation, and previous COVID-19 test results (serology/PCR) and used logistic regression to identify predictors of vaccination status after adjustment for confounders. We included 19,044 HCWs; 12,278 (64.5%) had received SARS-CoV-2 vaccination. Compared to White HCWs (70.9% vaccinated), a significantly smaller proportion of ethnic minority HCWs were vaccinated (South Asian, 58.5%; Black, 36.8%; p < 0.001 for both). After adjustment for age, sex, ethnicity, deprivation, occupation, SARS-CoV-2 serology/PCR results, and COVID-19-related work absences, factors found to be negatively associated with vaccine uptake were younger age, female sex, increased deprivation, pregnancy, and belonging to any non-White ethnic group (Black: adjusted odds ratio [aOR] 0.30, 95% CI 0.26-0.34, p < 0.001; South Asian: aOR 0.67, 95% CI 0.62-0.72, p < 0.001). Those who had previously had confirmed COVID-19 (by PCR) were less likely to be vaccinated than those who had tested negative. Limitations include data being from a single centre, lack of data on staff vaccinated outside the hospital system, and that staff may have taken up vaccination following data extraction. CONCLUSIONS: Ethnic minority HCWs and those from more deprived areas as well as younger staff and female staff are less likely to take up SARS-CoV-2 vaccination. These findings have major implications for the delivery of SARS-CoV-2 vaccination programmes, in HCWs and the wider population, and should inform the national vaccination programme to prevent the disparities of the pandemic from widening.

Personalised dosing of vancomycin: A prospective and retrospective comparative quasi-experimental study.

AIMS: The 2019 update to the US consensus guideline for vancomycin therapeutic monitoring advocates using Bayesian-guided personalised dosing to maximise efficacy and minimise toxicity of vancomycin. We conducted an observational cohort study of the implementation of bed-side Bayesian-guided vancomycin dosing in vascular surgery patients. METHODS: Over a 9-month prospective study period, vascular surgery patients were dosed vancomycin using Bayesian-guided dosing decision tool (DoseMeRx) and compared retrospectively with a control group admitted to the same ward in the 14 months prior to the study and dosed using a standard algorithmic approach. Primary endpoints were proportion of patients achieving mean area under the curve in 24 hours (AUC24 ) in the acceptable range 350-450 mg/L• h and percentage time in acceptable range (%TTR). Secondary endpoints focused on clinical outcomes including incidence of acute kidney injury. RESULTS: A significantly higher proportion of DoseMeRx patients achieved mean AUC24 values in the acceptable range compared to the control group; 71/104 (68.3%) vs 58/139 (41.7%), P < .005. The median %TTR was also greater in DoseMeRx patients compared to the control group (57.1 vs 30.0%, P < .00001). Patients in the DoseMeRx group missed an average of 0.23 doses per course compared to 1.04 doses in the control group (P < .00001). No difference was observed in secondary (clinical) outcomes between the 2 groups. CONCLUSION: Bedside Bayesian-guided personalised dosing of vancomycin increases the proportion of patients achieving target AUC24 and the %TTR.

Accreditation of antimicrobial stewardship programmes: addressing a global need to tackle antimicrobial resistance.

Accreditation of healthcare services provides quality assurance of hospital practice to support safe and effective care for patients. Accreditation programmes focused on antimicrobial stewardship (AMS) have been developed in high-income countries (HIC) and recently the WHO has developed a toolkit to support AMS practice in low and middle-income (LMIC) countries. BSAC has developed their Global Antimicrobial Stewardship Accreditation Scheme (GAMSAS) for hospitals based on globally applicable standards. GAMSAS aims to support healthcare organizations to build measurable AMS programmes and to support spread of best practice. GAMSAS involves a desktop assessment by BSAC experts followed by a hospital visit to gather further insight into how a hospital's AMS programme operates. A final report of compliance with the GAMSAS standards and a recommendation about accreditation at one of three levels is formally approved at a GAMSAS panel meeting involving well-established global experts in AMS. The BSAC GAMSAS team reflect on progress during the first year and ambitions for future spread.

Predictors of adverse outcome in the first and second waves of the COVID-19 pandemic: results from a UK centre.

BACKGROUND/AIMS: Data concerning differences in demographics/disease severity between the first and second waves of COVID-19 are limited. We aimed to examine prognosis in patients presenting to hospital with COVID-19 amongst different ethnic groups between the first and second waves in the UK. METHODS: In this retrospective cohort study, we included 1763 patients presenting to a regional hospital centre in Leicester (UK) and compared those in the first (n = 956) and second (n = 807) waves. Admission National Early Warning Scores, mechanical ventilation and mortality rate were lower in the second wave compared with the first. RESULTS: Thirty-day mortality risk in second wave patients was approximately half that of first wave patients [adjusted hazard ratio (aHR) 0.55, 95% confidence interval (CI) 0.40-0.75]. In the second wave, Black patients were at higher risk of 30-day mortality than White patients (4.73, 1.56-14.3). CONCLUSION: We found that disporportionately higher risks of death in patients from ethnic minority groups were not equivalent across consecutive waves of the pandemic. This suggests that risk factors for death in those from ethnic minority groups are malleable and potentially reversible. Our findings need urgent investigation in larger studies.

Drivers of Broad-Spectrum Antibiotic Overuse across Diverse Hospital Contexts-A Qualitative Study of Prescribers in the UK, Sri Lanka and South Africa.

Antimicrobial stewardship programs focus on reducing overuse of broad-spectrum antibiotics (BSAs), primarily through interventions to change prescribing behavior. This study aims to identify multi-level influences on BSA overuse across diverse high and low income, and public and private, healthcare contexts. Semi-structured interviews were conducted with 46 prescribers from hospitals in the UK, Sri Lanka, and South Africa, including public and private providers. Interviews explored decision making about prescribing BSAs, drivers of the use of BSAs, and benefits of BSAs to various stakeholders, and were analyzed using a constant comparative approach. Analysis identified drivers of BSA overuse at the individual, social and structural levels. Structural drivers of overuse varied significantly across contexts and included: system-level factors generating tensions with stewardship goals; limited material resources within hospitals; and patient poverty, lack of infrastructure and resources in local communities. Antimicrobial stewardship needs to encompass efforts to reduce the reliance on BSAs as a solution to context-specific structural conditions.

Development of Loop-Mediated Isothermal Amplification Rapid Diagnostic Assays for the Detection of Klebsiella pneumoniae and Carbapenemase Genes in Clinical Samples.

Klebsiella pneumoniae is an important pathogenic bacterium commonly associated with human healthcare and community-acquired infections. In recent years, K. pneumoniae has become a significant threat to global public and veterinary health, because of its high rates of antimicrobial resistance (AMR). Early diagnosis of K. pneumoniae infection and detection of any associated AMR would help to accelerate directed therapy and reduce the risk of the emergence of multidrug-resistant isolates. In this study, we identified three target genes (yhaI, epsL, and xcpW) common to K. pneumoniae isolates from both China and Europe and designed loop-mediated isothermal amplification (LAMP) assays for the detection of K. pneumoniae in clinical samples. We also designed LAMP assays for the detection of five AMR genes commonly associated with K. pneumoniae. The LAMP assays were validated on a total of 319 type reference strains and clinical isolates of diverse genetic backgrounds, in addition to 40 clinical human sputum samples, and were shown to be reliable, highly specific, and sensitive. For the K. pneumoniae-specific LAMP assay, the calculated sensitivity, specificity, and positive and negative predictive values (comparison with culture and matrix-assisted laser desorption/ionization-time of flight mass spectrometry) were all 100% on clinical isolates and, respectively, of 100%, 91%, and 90%, and 100% when tested on clinical sputum samples, while being significantly faster than the reference methods. For the bla KPC and other carbapenemases' LAMP assays, the concordance between the LAMP results and the references methods (susceptibility tests) was 100%, on both pure cultures (n = 125) and clinical samples (n = 18). In conclusion, we developed highly sensitive and specific LAMP assays for the clinical identification of K. pneumoniae and detection of carbapenem resistance.

Whole-genome analysis uncovers loss of blaZ associated with carriage isolates belonging to methicillin-resistant Staphylococcus aureus (MRSA) clone ST5-VI in Cape Verde.

OBJECTIVES: Surveillance studies for Staphylococcus aureus carriage are a primary tool to survey the prevalence of methicillin-resistant S. aureus (MRSA) in the general population, patients and healthcare workers. We have previously reported S. aureus carriage in various African countries, including Cape Verde. METHODS: Whole-genome sequences of 106 S. aureus isolates from Cape Verde were determined. RESULTS: Staphylococcus aureus carriage isolates in Cape Verde show high genetic variability, with the detection of 27 sequence types (STs) and three primary genetic clusters associated with ST152, ST15 and ST5. One transmission event with less than eight core-genome single nucleotide polymorphisms (cgSNP) differences was detected among the ST5-VI MRSA lineage. Genetic analysis confirmed the phenotypic resistance and allowed the identification of six independent events of plasmid or transposon loss associated with the deletion of blaZ in nine isolates. In the four ST5 MRSA isolates, loss of the blaZ plasmid coincided with the acquisition of SCCmec type VI and an unusual penicillin phenotype with a minimum inhibitory concentration (MIC) at the breakpoint, indicating an adaptation trend in this endemic lineage. Similar events of blaZ plasmid loss, with concomitant acquisition SCCmec elements, were detected among ST5 isolates from different geographical origins. CONCLUSION: Overall, the genome data allowed to place isolates in a phylogenetic context and to identify different blaZ gene deletions associated with plasmid or transposon loss. Genomic analysis unveiled adaptation and evolution trends, namely among emerging MRSA lineages in the country, which deserve additional consideration in the design of future infection control protocols.

Panton-Valentine leukocidin expressing Staphylococcus aureus pneumonia managed with extracorporeal membrane oxygenation: experience and outcome.

OBJECTIVE: Panton-Valentine leukocidin expressing Staphylococcus aureus pneumonia, an infection that affects predominantly young people, has a mortality rate of > 70% despite aggressive conventional management. Little information is available on the management of patients with Panton-Valentine leukocidin expressing S. aureus pneumonia with extracorporeal membrane oxygenation support. As a large extracorporeal membrane oxygenation center, we reviewed our experience and outcomes with Panton-Valentine Leukocidin expressing S. aureus pneumonia. DATA SOURCES: Locally held register of all extracorporeal membrane oxygenation patients at Glenfield Hospital. STUDY SELECTION: Retrospective study including all patients with sputum-positive Panton-Valentine leukocidin expressing S. aureus pneumonia managed with extracorporeal membrane oxygenation support at a single extracorporeal membrane oxygenation center. DATA SYNTHESIS: On review of our database held from September 1989 until date, there were four patients with sputum-confirmed Panton-Valentine leukocidin expressing S. aureus pneumonia managed with extracorporeal membrane oxygenation. Refractory hypoxemia and/or uncompensated hypercapnia despite optimal conventional management were the indications for extracorporeal membrane oxygenation. After varying periods on extracorporeal membrane oxygenation with appropriate antibiotic and ancillary care, all four patients were discharged home. CONCLUSIONS: Panton-Valentine leukocidin expressing S. aureus pneumonia can cause severe, necrotizing pneumonia associated with acute respiratory distress syndrome, which can be particularly challenging to manage. Extracorporeal membrane oxygenation support permits low pressure lung ventilation, avoiding barotrauma to lungs made friable by Panton-Valentine leukocidin expressing S. aureus infection. Although this is a small number of patients, the results are encouraging.

Moral and Contextual Dimensions of "Inappropriate" Antibiotic Prescribing in Secondary Care: A Three-Country Interview Study.

Overuse of broad-spectrum antibiotics in secondary care is a key contributor to the emergence and spread of antimicrobial resistance (AMR); efforts are focused on minimizing antibiotic overuse as a crucial step toward containing the global threat of AMR. The concept of overtreatment has, however, been difficult to define. Efforts to address the overuse of medicine need to be informed by an understanding of how prescribers themselves understand the problem. We report findings from a qualitative interview study of 46 acute care hospital prescribers differing in seniority from three countries: United Kingdom, Sri Lanka and South Africa. Prescribers were asked about their understanding of inappropriate use of antibiotics. Prescriber definitions of inappropriate use included relatively clear-cut and unambiguous cases of antibiotics being used "incorrectly" (e.g., in the case of viral infections). In many cases, however, antibiotic prescribing decisions were seen as involving uncertainty, with prescribers having to make decisions about the threshold for appropriate use. Decisions about thresholds were commonly framed in moral terms. Some prescribers drew on arguments about their duty to protect public health through having a high threshold for prescribing, while others made strong arguments for prioritizing risk avoidance for the patients in front of them, even at a cost of increased resistance. Notions of whether prescribing was inappropriate were also contextually dependent: high levels of antibiotic prescribing could be seen as a rational response when prescribers were working in challenging contexts, and could be justified in relation to financial and social considerations. Inappropriate antibiotic use is framed by prescribers not just in clinical, but also in moral and contextual terms; this has implications for the design and implementation of antibiotic stewardship interventions aiming to reduce inappropriate use of antibiotics globally.

Socio-demographic heterogeneity in the prevalence of COVID-19 during lockdown is associated with ethnicity and household size: Results from an observational cohort study.

BACKGROUND: Accumulating evidence indicates that COVID-19 causes adverse outcomes in ethnic minority groups. However, little is known about the impact of ethnicity and household size on acquiring infection with SARS-CoV-2. METHODS: We undertook a retrospective cohort study, in Leicester (UK), of all individuals assessed for COVID-19 with polymerase chain reaction (PCR) testing at University Hospitals of Leicester NHS Trust between 1st March and 28th April 2020. We used logistic regression to identify sociodemographic, clinical and temporal factors associated with SARS-CoV-2 PCR positivity before/after lockdown. FINDINGS: 971/4051 (24.0%) patients with suspected COVID-19 were found to be PCR positive for SARS-CoV-2. PCR positivity was more common amongst individuals from ethnic minortiy backgrounds than their White counterparts (White 20.0%, South Asian 37.5%, Black 36.1%, Other 32.2%; p<0.001 for all ethnic minority groups vs White). After adjustment, compared to White ethnicity, South Asian (aOR 2.44 95%CI 2.01, 2.97), Black (aOR 2.56 95%CI 1.71, 3.84) and Other (aOR 2.53 95%CI 1.74, 3.70) ethnicities were more likely to test positive, as were those with a larger estimated household size (aOR 1.06 95%CI 1.02, 1.11). We saw increasing proportions of positive tests in the three weeks post-lockdown amongst the ethnic minority , but not the White, cohort. Estimated household size was associated with PCR positivity after, but not before, lockdown (aOR 1.10 95%CI 1.03, 1.16). INTERPRETATION: In individuals presenting with suspected COVID-19, those from ethnic minority communities and larger households had an increased likelihood of SARS-CoV-2 PCR positivity. Pandemic control measures may have more rapid impact on slowing viral transmission amongst those of White ethnicity compared to ethnic minority groups, Research is urgently required to understand the mechanisms underlying these disparities and whether public health interventions have differential effects on individuals from ethnic minority groups. FUNDING: 10.13039/100006662 NIHR.

A five-year retrospective study shows increasing rates of antimicrobial drug resistance in Cabo Verde for both Staphylococcus aureus and Escherichia coli.

OBJECTIVES: Data on baseline drug resistance important in informing future antimicrobial stewardship programs. So far, no data on the antimicrobial drug resistance of clinical isolates available for the African archipelago of Cabo Verde. METHODS: We performed a retrospective analysis over years (2013-17) of the drug susceptibility profiles of clinical isolates in the two main hospitals of Cabo Verde. For Escherichia coli and Staphylococcus aureus, representing 47% and 26% of all clinical isolates, the antimicrobial drug resistance profile was reported for six representative drugs. RESULTS: For E. coli we detected an increase in resistance to ampicillin, amoxicillin/clavulanic acid, ceftriaxone, ciprofloxacin and trimethoprim-and for S. aureus to methicillin, erythromycin and trimethoprim-sulfamethoxazole. This increase in both the most commonly isolated bacterial pathogens is alarm as it might compromise empirical treatment in a setting with limited access to laboratory testing. CONCLUSIONS: When compared to the published low resistance rates in carriage isolates, the more alarming situation in clinical isolates for S. aureus might encourage antimicrobial stewardship programs to reduce in hospital settings, possibly as part of the Cabo Verdean national plan against antimicrobial drug resistance.

Native valve endocarditis caused by Lactococcus garvieae: an emerging human pathogen.

A 57-year-old man presented with native mitral valve endocarditis caused by Lactococcus garvieae, a known animal pathogen that is increasingly being reported as a cause of human infections. The organism was cultured in four sets of blood cultures and identification was initially made by matrix-assisted laser desorption/ionisation-time of flight mass spectrometry and confirmed by 16S rDNA PCR of the blood culture isolate. He was successfully treated with 6 weeks of both amoxicillin and gentamicin and underwent valve replacement surgery after 4 weeks of antimicrobial treatment. The removed valve was sterile but L. garvieae DNA was detected on the valve using 16S rDNA PCR. The cause of the L. garvieae infection could not be ascertained but flexible sigmoidoscopy demonstrated colonic polyps, which have been linked to infection with this organism.

Extracorporeal life support in pertussis.

Severe B. pertussis infection in infants is characterized by severe respiratory failure, pulmonary hypertension, leukocytosis, and death. This retrospective case analysis highlights the course and outcome of severe B. pertussis infection treated with extracorporeal membrane oxygenation (ECMO) at a single center. Over the last decade, out of a total caseload of nearly 800 infants and children, 12 infants with severe B. pertussis have been referred for ECMO therapy to our center. All infants with pertussis infection who received ECMO therapy were less than 3 months of age at presentation and unvaccinated. There was a high mortality rate (7 of 12 infants died), which was associated with an elevated neutrophil count at presentation and multiorgan dysfunction characterized by intractable pulmonary hypertension, persistent systemic hypotension, renal insufficiency, and fits. ECMO should be offered to children with pertussis infection and respiratory failure refractory to mechanical ventilation. However, further research is required to determine the optimal management for infants receiving ECMO therapy with this disease.

On computational control of flow in airblast atomisers for pulmonary drug delivery.

Among different approaches to successful pharmacotherapy the pulmonary drug delivery (PDD) mode plays an increasingly important role. In this paper PDD systems based on air-blast atomisation have been analysed mathematically. In order to allow the bioengineer to estimate the degree of effectiveness of a specific system prototype and to lay the basic principles for design, a conservation-law-based mathematical model is discussed. Key control parameters that allow improvement in the efficiency of the system have been identified and main characteristics of the system have been analysed numerically as functions of these parameters.