Are medical procedures that induce coughing or involve respiratory suctioning associated with increased generation of aerosols and risk of SARS-CoV-2 infection? A rapid systematic review.

BACKGROUND: The risk of transmission of SARS-CoV-2 from aerosols generated by medical procedures is a cause for concern. AIM: To evaluate the evidence for aerosol production and transmission of respiratory infection associated with procedures that involve airway suctioning or induce coughing/sneezing. METHODS: The review was informed by PRISMA guidelines. Searches were conducted in PubMed for studies published between January 1st, 2003 and October 6th, 2020. Included studies examined whether nasogastric tube insertion, lung function tests, nasendoscopy, dysphagia assessment, or suctioning for airway clearance result in aerosol generation or transmission of SARS-CoV-2, SARS-CoV, MERS, or influenza. Risk of bias assessment focused on robustness of measurement, control for confounding, and applicability to clinical practice. FINDINGS: Eighteen primary studies and two systematic reviews were included. Three epidemiological studies found no association between nasogastric tube insertion and acquisition of respiratory infections. One simulation study found low/very low production of aerosols associated with pulmonary lung function tests. Seven simulation studies of endoscopic sinus surgery suggested significant increases in aerosols but findings were inconsistent; two clinical studies found airborne particles associated with the use of microdebriders/drills. Some simulation studies did not use robust measures to detect particles and are difficult to equate to clinical conditions. CONCLUSION: There was an absence of evidence to suggest that the procedures included in the review were associated with an increased risk of transmission of respiratory infection. In order to better target precautions to mitigate risk, more research is required to determine the characteristics of medical procedures and patients that increase the risk of transmission of SARS-CoV-2.

Optimizing design of research to evaluate antibiotic stewardship interventions: consensus recommendations of a multinational working group.

BACKGROUND: Antimicrobial stewardship interventions and programmes aim to ensure effective treatment while minimizing antimicrobial-associated harms including resistance. Practice in this vital area is undermined by the poor quality of research addressing both what specific antimicrobial use interventions are effective and how antimicrobial use improvement strategies can be implemented into practice. In 2016 we established a working party to identify the key design features that limit translation of existing research into practice and then to make recommendations for how future studies in this field should be optimally designed. The first part of this work has been published as a systematic review. Here we present the working group's final recommendations. METHODS: An international working group for design of antimicrobial stewardship intervention evaluations was convened in response to the fourth call for leading expert network proposals by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR). The group comprised clinical and academic specialists in antimicrobial stewardship and clinical trial design from six European countries. Group members completed a structured questionnaire to establish the scope of work and key issues to develop ahead of a first face-to-face meeting that (a) identified the need for a comprehensive systematic review of study designs in the literature and (b) prioritized key areas where research design considerations restrict translation of findings into practice. The working group's initial outputs were reviewed by independent advisors and additional expertise was sought in specific clinical areas. At a second face-to-face meeting the working group developed a theoretical framework and specific recommendations to support optimal study design. These were finalized by the working group co-ordinators and agreed by all working group members. RESULTS: We propose a theoretical framework in which consideration of the intervention rationale the intervention setting, intervention features and the intervention aims inform selection and prioritization of outcome measures, whether the research sets out to determine superiority or non-inferiority of the intervention measured by its primary outcome(s), the most appropriate study design (e.g. experimental or quasi- experimental) and the detailed design features. We make 18 specific recommendation in three domains: outcomes, objectives and study design. CONCLUSIONS: Researchers, funders and practitioners will be able to draw on our recommendations to most efficiently evaluate antimicrobial stewardship interventions.

Adaptation and implementation of the ARK (Antibiotic Review Kit) intervention to safely and substantially reduce antibiotic use in hospitals: a feasibility study.

BACKGROUND: Antimicrobial stewardship initiatives in secondary care depend on clinicians undertaking antibiotic prescription reviews but decisions to limit antibiotic treatment at review are complex. AIM: To assess the feasibility and acceptability of implementing ARK (Antibiotic Review Kit), a behaviour change intervention made up of four components (brief online tool, prescribing decision aid, regular data collection and feedback process, and patient leaflet) to support stopping antibiotic treatment when it is safe to do so among hospitalized patients; before definitive evaluation through a stepped-wedge cluster-randomized controlled trial. METHODS: Acceptability of the different intervention elements was assessed for a period of 12 weeks by uptake of the online tool, adoption of the decision aid into prescribing practice, and rates of decisions to stop antibiotics at review (assessed through repeated point-prevalence surveys). Patient perceptions of the information leaflet were assessed through a brief questionnaire. FINDINGS: All elements of the intervention were successfully introduced into practice. A total of 132 staff encompassing a broad range of prescribers and non-prescribers completed the online tool (19.4 per 100 acute beds), including 97% (32/33) of the pre-specified essential clinical staff. Among 588 prescription charts evaluated in seven point-prevalence surveys over the 12-week implementation period, 82% overall (76-90% at each survey) used the decision aid. The median antibiotic stop rate post implementation was 36% (range: 29-40% at each survey) compared with 9% pre implementation (P < 0.001). CONCLUSION: ARK provides a feasible and acceptable mechanism to support stopping antibiotics safely at post-prescription reviews in an acute hospital setting.

Intervention planning for Antibiotic Review Kit (ARK): a digital and behavioural intervention to safely review and reduce antibiotic prescriptions in acute and general medicine.

BACKGROUND: Hospital antimicrobial stewardship strategies, such as 'Start Smart, Then Focus' in the UK, balance the need for prompt, effective antibiotic treatment with the need to limit antibiotic overuse using 'review and revise'. However, only a minority of review decisions are to stop antibiotics. Research suggests that this is due to both behavioural and organizational factors. OBJECTIVES: To develop and optimize the Antibiotic Review Kit (ARK) intervention. ARK is a complex digital, organizational and behavioural intervention that supports implementation of 'review and revise' to help healthcare professionals safely stop unnecessary antibiotics. METHODS: A theory-, evidence- and person-based approach was used to develop and optimize ARK and its implementation. This was done through iterative stakeholder consultation and in-depth qualitative research with doctors, nurses and pharmacists in UK hospitals. Barriers to and facilitators of the intervention and its implementation, and ways to address them, were identified and then used to inform the intervention's development. RESULTS: A key barrier to stopping antibiotics was reportedly a lack of information about the original prescriber's rationale for and their degree of certainty about the need for antibiotics. An integral component of ARK was the development and optimization of a Decision Aid and its implementation to increase transparency around initial prescribing decisions. CONCLUSIONS: The key output of this research is a digital and behavioural intervention targeting important barriers to stopping antibiotics at review (see http://bsac-vle.com/ark-the-antibiotic-review-kit/ and http://antibioticreviewkit.org.uk/). ARK will be evaluated in a feasibility study and, if successful, a stepped-wedge cluster-randomized controlled trial at acute hospitals across the NHS.

The quality of studies evaluating antimicrobial stewardship interventions: a systematic review.

BACKGROUND: Antimicrobial stewardship aims to optimize antibiotic use and minimize selection of antimicrobial resistance. The methodological quality of published studies in this field is unknown. AIMS: Our objective was to perform a comprehensive systematic review of antimicrobial stewardship research design and identify features which limit validity and translation of research findings into clinical practice. SOURCES: The following online database was searched: PubMed. STUDY ELIGIBILITY CRITERIA: Studies published between January 1950 and January 2017, evaluating any antimicrobial stewardship intervention in the community or hospital setting, without restriction on study design or outcome. CONTENT: We extracted data on pre-specified design quality features and factors that may influence design choices including (1) clinical setting, (2) age group studied, (3) when the study was conducted, (4) geographical region, and (5) financial support received. The initial search yielded 17 382 articles; 1008 were selected for full-text screening, of which 825 were included. Most studies (675/825, 82%) were non-experimental; 104 (15%) used interrupted time series analysis, 41 (6%) used external controls, and 19 (3%) used both. Studies in the community setting fulfilled a median of five out of 10 quality features (IQR 3-7) and 3 (IQR 2-4) in the hospital setting. Community setting studies (25%, 205/825) were significantly more likely to use randomization (OR 5.9; 95% CI 3.8-9.2), external controls (OR 5.6; 95% CI 3.6-8.5), and multiple centres (OR 10.5; 95% CI 7.1-15.7). From all studies, only 48% (398/825) reported clinical and 23% (190/825) reported microbiological outcomes. Quality did not improve over time. IMPLICATIONS: Overall quality of antimicrobial stewardship studies is low and has not improved over time. Most studies do not report clinical and microbiological outcome data. Studies conducted in the community setting were associated with better quality. These limitations should inform the design of future stewardship evaluations so that a robust evidence base can be built to guide clinical practice.

A national quality incentive scheme to reduce antibiotic overuse in hospitals: evaluation of perceptions and impact.

Background: In 2016/2017, a financially linked antibiotic prescribing quality improvement initiative Commissioning for Quality and Innovation (AMR-CQUIN) was introduced across acute hospitals in England. This aimed for >1% reductions in DDDs/1000 admissions of total antibiotics, piperacillin/tazobactam and carbapenems compared with 2013/2014 and improved review of empirical antibiotic prescriptions. Objectives: To assess perceptions of staff leading antimicrobial stewardship activity regarding the AMR-CQUIN, the investments made by hospitals to achieve it and how these related to achieving reductions in antibiotic use. Methods: We invited antimicrobial stewardship leads at acute hospitals across England to complete a web-based survey. Antibiotic prescribing data were downloaded from the PHE Antimicrobial Resistance Local Indicators resource. Results: Responses were received from 116/155 (75%) acute hospitals. Owing to yearly increases in antibiotic use, most trusts needed to make >5% reductions in antibiotic consumption to achieve the AMR-CQUIN goal of 1% reduction. Additional funding was made available at 23/113 (20%) trusts and, in 18 (78%), this was <10% of the AMR-CQUIN value. Nationally, the annual trend for increased antibiotic use reversed in 2016/2017. In 2014/2015, year-on-year changes were +3.7% (IQR -0.8%, +8.4%), +9.4% (+0.2%, +19.5%) and +5.8% (-6.2%, +18.2%) for total antibiotics, piperacillin/tazobactam and carbapenems, respectively, and +0.1% (-5.4%, +4.0%), -4.8% (-16.9%, +3.2%) and -8.0% (-20.2%, +4.0%) in 2016/2017. Hospitals where staff believed they could reduce antibiotic use were more likely to do so (P < 0.001). Conclusions: Introducing the AMR-CQUIN was associated with a reduction in antibiotic use. For individual hospitals, achieving the AMR-CQUIN was associated with favourable perceptions of staff and not availability of funding.

Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition.

OBJECTIVES: To define standardized endpoints to aid the design of trials that compare antibiotic therapies for bloodstream infections (BSI). METHODS: Prospective studies, randomized trials or registered protocols comparing antibiotic therapies for BSI, published from 2005 to 2016, were reviewed. Consensus endpoints for BSI studies were defined using a modified Delphi process. RESULTS: Different primary and secondary endpoints were defined for pilot (small-scale studies designed to evaluate protocol design, feasibility and implementation) and definitive trials (larger-scale studies designed to test hypotheses and influence clinical practice), as well as for Staphylococcus aureus and Gram-negative BSI. For pilot studies of S. aureus BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever, stable/improved Sequential Organ Failure Assessment (SOFA) score and clearance of blood cultures, with no microbiologically confirmed failure up to 90 days. For definitive S. aureus BSI studies, a primary outcome of success at 90 days was defined by survival and no microbiologically confirmed failure. For pilot studies of Gram-negative BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever and symptoms related to BSI source, stable or improved SOFA score and negative blood cultures. For definitive Gram-negative BSI studies, a primary outcome of survival at 90 days supported by a secondary outcome of success at day 7 (as previously defined) was agreed. CONCLUSIONS: These endpoints provide a framework to aid future trial design. Further work will be required to validate these endpoints with respect to patient-centred clinical outcomes.

Gram-negative bacteraemia; a multi-centre prospective evaluation of empiric antibiotic therapy and outcome in English acute hospitals.

Increasing antibiotic resistance makes choosing antibiotics for suspected Gram-negative infection challenging. This study set out to identify key determinants of mortality among patients with Gram-negative bacteraemia, focusing particularly on the importance of appropriate empiric antibiotic treatment. We conducted a prospective observational study of 679 unselected adults with Gram-negative bacteraemia at ten acute english hospitals between October 2013 and March 2014. Appropriate empiric antibiotic treatment was defined as intravenous treatment on the day of blood culture collection with an antibiotic to which the cultured organism was sensitive in vitro. Mortality analyses were adjusted for patient demographics, co-morbidities and illness severity. The majority of bacteraemias were community-onset (70%); most were caused by Escherichia coli (65%), Klebsiella spp. (15%) or Pseudomonas spp. (7%). Main foci of infection were urinary tract (51%), abdomen/biliary tract (20%) and lower respiratory tract (14%). The main antibiotics used were co-amoxiclav (32%) and piperacillin-tazobactam (30%) with 34% receiving combination therapy (predominantly aminoglycosides). Empiric treatment was inappropriate in 34%. All-cause mortality was 8% at 7 days and 15% at 30 days. Independent predictors of mortality (p <0.05) included older age, greater burden of co-morbid disease, severity of illness at presentation and inflammatory response. Inappropriate empiric antibiotic therapy was not associated with mortality at either time-point (adjusted OR 0.82; 95% CI 0.35-1.94 and adjusted OR 0.92; 95% CI 0.50-1.66, respectively). Although our study does not exclude an impact of empiric antibiotic choice on survival in Gram-negative bacteraemia, outcome is determined primarily by patient and disease factors.

The role of the humoral immune response to Clostridium difficile toxins A and B in susceptibility to C. difficile infection: a case-control study.

Antibody levels to Clostridium difficile toxin A (TcdA), but not toxin B (TcdB), have been found to determine risk of C. difficile infection (CDI). Historically, TcdA was thought to be the key virulence factor; however the importance of TcdB in disease is now established. We re-evaluated the role of antibodies to TcdA and TcdB in determining patient susceptibility to CDI in two separate patient cohorts. In contrast to earlier studies, we find that CDI patients have lower pre-existing IgA titres to TcdB, but not TcdA, when compared to control patients. Our findings suggest that mucosal immunity to TcdB may be important in the early stages of infection and identifies a possible target for preventing CDI progression.

Prediction of Staphylococcus aureus antimicrobial resistance by whole-genome sequencing.

Whole-genome sequencing (WGS) could potentially provide a single platform for extracting all the information required to predict an organism's phenotype. However, its ability to provide accurate predictions has not yet been demonstrated in large independent studies of specific organisms. In this study, we aimed to develop a genotypic prediction method for antimicrobial susceptibilities. The whole genomes of 501 unrelated Staphylococcus aureus isolates were sequenced, and the assembled genomes were interrogated using BLASTn for a panel of known resistance determinants (chromosomal mutations and genes carried on plasmids). Results were compared with phenotypic susceptibility testing for 12 commonly used antimicrobial agents (penicillin, methicillin, erythromycin, clindamycin, tetracycline, ciprofloxacin, vancomycin, trimethoprim, gentamicin, fusidic acid, rifampin, and mupirocin) performed by the routine clinical laboratory. We investigated discrepancies by repeat susceptibility testing and manual inspection of the sequences and used this information to optimize the resistance determinant panel and BLASTn algorithm. We then tested performance of the optimized tool in an independent validation set of 491 unrelated isolates, with phenotypic results obtained in duplicate by automated broth dilution (BD Phoenix) and disc diffusion. In the validation set, the overall sensitivity and specificity of the genomic prediction method were 0.97 (95% confidence interval [95% CI], 0.95 to 0.98) and 0.99 (95% CI, 0.99 to 1), respectively, compared to standard susceptibility testing methods. The very major error rate was 0.5%, and the major error rate was 0.7%. WGS was as sensitive and specific as routine antimicrobial susceptibility testing methods. WGS is a promising alternative to culture methods for resistance prediction in S. aureus and ultimately other major bacterial pathogens.

Healthcare-associated outbreak of meticillin-resistant Staphylococcus aureus bacteraemia: role of a cryptic variant of an epidemic clone.

BACKGROUND: New strains of meticillin-resistant Staphylococcus aureus (MRSA) may be associated with changes in rates of disease or clinical presentation. Conventional typing techniques may not detect new clonal variants that underlie changes in epidemiology or clinical phenotype. AIM: To investigate the role of clonal variants of MRSA in an outbreak of MRSA bacteraemia at a hospital in England. METHODS: Bacteraemia isolates of the major UK lineages (EMRSA-15 and -16) from before and after the outbreak were analysed by whole-genome sequencing in the context of epidemiological and clinical data. For comparison, EMRSA-15 and -16 isolates from another hospital in England were sequenced. A clonal variant of EMRSA-16 was identified at the outbreak hospital and a molecular signature test designed to distinguish variant isolates among further EMRSA-16 strains. FINDINGS: By whole-genome sequencing, EMRSA-16 isolates during the outbreak showed strikingly low genetic diversity (P < 1 × 10(-6), Monte Carlo test), compared with EMRSA-15 and EMRSA-16 isolates from before the outbreak or the comparator hospital, demonstrating the emergence of a clonal variant. The variant was indistinguishable from the ancestral strain by conventional typing. This clonal variant accounted for 64/72 (89%) of EMRSA-16 bacteraemia isolates at the outbreak hospital from 2006. CONCLUSIONS: Evolutionary changes in epidemic MRSA strains not detected by conventional typing may be associated with changes in disease epidemiology. Rapid and affordable technologies for whole-genome sequencing are becoming available with the potential to identify and track the emergence of variants of highly clonal organisms.

Influence of cohorting patients with Clostridium difficile infection on risk of symptomatic recurrence.

BACKGROUND: Cohorting of patients with Clostridium difficile infection (CDI) is recommended when single side-rooms are unavailable. Although patients may remain infectious after cessation of diarrhoea, continued cohorting may place them at increased risk of reinfection. AIM: To identify risk factors for CDI recurrence and to determine whether cohorting of patients is associated with increased risk of recurrence. METHODS: Data describing patient demographics, comorbidity, CDI severity and treatment were collected for 248 CDI patients at our hospital between October 2008 and June 2011. The primary outcome was symptomatic recurrence within 30 days of diagnosis. FINDINGS: One hundred and thirty-eight (55.6%) CDI patients were admitted to the cohort ward. These patients were more likely to have severe CDI (odds ratio: 1.95; 95% confidence interval: 1.10-3.46; P = 0.022) and receive vancomycin (1.59; 0.94-2.68; P = 0.083) than patients who were not cohorted. Twenty-six patients (10.5%) suffered recurrence (21 cohorted and five not cohorted). Urinary infection on admission (5.16; 2.10-12.64; P < 0.001), cohorting (3.77; 1.37-10.35; P = 0.01) and concomitant antibiotics (2.07; 0.91-4.72; P = 0.083) were associated with increased risk of recurrence. On multivariate analysis, cohorting (3.94; 1.23-12.65; P = 0.021) and urinary infection (4.27; 1.62-11.24; P = 0.003) were significant predictors of recurrence. CONCLUSION: Patients admitted to a C. difficile cohort ward may be at increased risk of recurrence because they are at increased risk of reinfection. Hospitals using cohort wards to control C. difficile should manage patient flow through the cohort to minimize this risk.

Whole genome sequencing in the prevention and control of Staphylococcus aureus infection.

BACKGROUND: Staphylococcus aureus remains a leading cause of hospital-acquired infection but weaknesses inherent in currently available typing methods impede effective infection prevention and control. The high resolution offered by whole genome sequencing has the potential to revolutionise our understanding and management of S. aureus infection. AIM: To outline the practicalities of whole genome sequencing and discuss how it might shape future infection control practice. METHODS: We review conventional typing methods and compare these with the potential offered by whole genome sequencing. FINDINGS: In contrast with conventional methods, whole genome sequencing discriminates down to single nucleotide differences and allows accurate characterisation of transmission events and outbreaks and additionally provides information about the genetic basis of phenotypic characteristics, including antibiotic susceptibility and virulence. However, translating its potential into routine practice will depend on affordability, acceptable turnaround times and on creating a reliable standardised bioinformatic infrastructure. CONCLUSION: Whole genome sequencing has the potential to provide a universal test that facilitates outbreak investigation, enables the detection of emerging strains and predicts their clinical importance.

Diagnostic utility of bone marrow sampling in HIV-infected patients since the advent of highly active antiretroviral therapy.

We investigated the diagnostic value of bone marrow (BM) sampling in investigation of HIV-infected patients presenting to a major London HIV treatment centre between 1999 and 2004. One hundred and fourteen consecutive patients underwent 130 BM samplings. The majority of BM aspirates were normal or showed non-diagnostic changes; microscopy revealed lymphoma in one and mycobacterial infection in two. Subsequent culture identified mycobacterial infection in nine samples. BM trephine had a diagnostic yield of 26% in patients with fever and cytopaenia (including mycobacteriosis in 14%, lymphoma in 6%, Castleman disease in 3% and "drug effect" in 3%), a yield of 20% in patients with fever, but no cytopaenia (mycobacteriosis in each case), and a yield of 19% in patients with cytopaenia in the absence of fever (lymphoma in 5% and "drug effect" in 14%). In investigation/staging of lymphoma, the diagnostic yield was 36%. The overall yield from BM sampling was 30% in patients receiving highly active antiretroviral therapy (HAART) and 23% in those not receiving HAART. In this study, BM sampling was of most diagnostic value in HIV-infected patients where fever and cytopaenia coexisted in the absence of localizing signs of infection, and in the staging/investigation of lymphoma. BM sampling had less diagnostic value in the investigation of fever without cytopaenia or cytopaenia without fever.