WHY STOP? A prospective observational vignette-based study to determine the cognitive-behavioural effects of rapid diagnostic PCR-based point-of-care test results on antibiotic cessation in ICU infections.

OBJECTIVES: Point-of-care tests (POCTs) for infection offer accurate rapid diagnostics but do not consistently improve antibiotic stewardship (ASP) of suspected ventilator-associated pneumonia. We aimed to measure the effect of a negative PCR-POCT result on intensive care unit (ICU) clinicians' antibiotic decisions and the additional effects of patient trajectory and cognitive-behavioural factors (clinician intuition, dis/interest in POCT, risk averseness). DESIGN: Observational cohort simulation study. SETTING: ICU. PARTICIPANTS: 70 ICU consultants/trainees working in UK-based teaching hospitals. METHODS: Clinicians saw four case vignettes describing patients who had completed a course of antibiotics for respiratory infection. Vignettes comprised clinical and biological data (ie, white cell count, C reactive protein), varied to create four trajectories: clinico-biological improvement (the 'improvement' case), clinico-biological worsening ('worsening'), clinical improvement/biological worsening ('discordant clin better'), clinical worsening/biological improvement ('discordant clin worse'). Based on this, clinicians made an initial antibiotics decision (stop/continue) and rated confidence (6-point Likert scale). A PCR-based POCT was then offered, which clinicians could accept or decline. All clinicians (including those who declined) were shown the result, which was negative. Clinicians updated their antibiotics decision and confidence. MEASURES: Antibiotics decisions and confidence were compared pre-POCT versus post-POCT, per vignette. RESULTS: A negative POCT result increased the proportion of stop decisions (54% pre-POCT vs 70% post-POCT, χ2(1)=25.82, p<0.001, w=0.32) in all vignettes except improvement (already high), most notably in discordant clin worse (49% pre-POCT vs 74% post-POCT). In a linear regression, factors that significantly reduced clinicians' inclination to stop antibiotics were a worsening trajectory (b=-0.73 (-1.33, -0.14), p=0.015), initial confidence in continuing (b=0.66 (0.56, 0.76), p<0.001) and involuntary receipt of POCT results (clinicians who accepted the POCT were more inclined to stop than clinicians who declined it, b=1.30 (0.58, 2.02), p<0.001). Clinician risk averseness was not found to influence antibiotic decisions (b=-0.01 (-0.12, 0.10), p=0.872). CONCLUSIONS: A negative PCR-POCT result can encourage antibiotic cessation in ICU, notably in cases of clinical worsening (where the inclination might otherwise be to continue). This effect may be reduced by high clinician confidence to continue and/or disinterest in POCT, perhaps due to low trust/perceived utility. Such cognitive-behavioural and trajectorial factors warrant greater consideration in future ASP study design.

National action plans for antimicrobial resistance and variations in surveillance data platforms.

Objective: To assess how national antimicrobial susceptibility data used to inform national action plans vary across surveillance platforms. Methods: We identified available open-access, supranational, interactive surveillance platforms and cross-checked their data in accordance with the World Health Organization's (WHO's) Data Quality Assurance: module 1. We compared platform usability and completeness of time-matched data on the antimicrobial susceptibilities of four blood isolate species: Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and Streptococcus pneumoniae from WHO's Global Antimicrobial Resistance and Use Surveillance System, European Centre for Disease Control's (ECDC's) network and Pfizer's Antimicrobial Testing Leadership and Surveillance database. Using Bland-Altman analysis, paired t-tests, and Wilcoxon signed-rank tests, we assessed susceptibility data and number of isolate concordances between platforms. Findings: Of 71 countries actively submitting data to WHO, 28 also submit to Pfizer's database; 19 to ECDC; and 16 to all three platforms. Limits of agreement between WHO's and Pfizer's platforms for organism-country susceptibility data ranged from -26% to 35%. While mean susceptibilities of WHO's and ECDC's platforms did not differ (bias: 0%, 95% confidence interval: -2 to 2), concordance between organism-country susceptibility was low (limits of agreement -18% to 18%). Significant differences exist in isolate numbers reported between WHO-Pfizer (mean of difference: 674, P-value: < 0.001, and WHO-ECDC (mean of difference: 192, P-value: 0.04) platforms. Conclusion: The considerable heterogeneity of nationally submitted data to commonly used antimicrobial resistance surveillance platforms compromises their validity, thus undermining local and global antimicrobial resistance strategies. Hence, we need to understand and address surveillance platform variability and its underlying mechanisms.

Hybrid immunity in older adults is associated with reduced SARS-CoV-2 infections following BNT162b2 COVID-19 immunisation.

BACKGROUND: Older adults, particularly in long-term care facilities (LTCF), remain at considerable risk from SARS-CoV-2. Data on the protective effect and mechanisms of hybrid immunity are skewed towards young adults precluding targeted vaccination strategies. METHODS: A single-centre longitudinal seroprevalence vaccine response study was conducted with 280 LCTF participants (median 82 yrs, IQR 76-88 yrs; 95.4% male). Screening by SARS-CoV-2 polymerase chain reaction with weekly asymptomatic/symptomatic testing (March 2020-October 2021) and serology pre-/post-two-dose Pfizer-BioNTech BNT162b2 vaccination for (i) anti-nucleocapsid, (ii) quantified anti-receptor binding domain (RBD) antibodies at three time-intervals, (iii) pseudovirus neutralisation, and (iv) inhibition by anti-RBD competitive ELISA were conducted. Neutralisation activity: antibody titre relationship was assessed via beta linear-log regression and RBD antibody-binding inhibition: post-vaccine infection relationship by Wilcoxon rank sum test. RESULTS: Here we show neutralising antibody titres are 9.2-fold (95% CI 5.8-14.5) higher associated with hybrid immunity (p < 0.00001); +7.5-fold (95% CI 4.6-12.1) with asymptomatic infection; +20.3-fold, 95% (CI 9.7-42.5) with symptomatic infection. A strong association is observed between antibody titre: neutralising activity (p < 0.00001) and rising anti-RBD antibody titre: RBD antibody-binding inhibition (p < 0.001), although 18/169 (10.7%) participants with high anti-RBD titre (>100BAU/ml), show inhibition <75%. Higher RBD antibody-binding inhibition values are associated with hybrid immunity and reduced likelihood of infection (p = 0.003). CONCLUSIONS: Hybrid immunity in older adults was associated with considerably higher antibody titres, neutralisation and inhibition capacity. Instances of high anti-RBD titre with lower inhibition suggests antibody quantity and quality as independent potential correlates of protection, highlighting added value of measuring inhibition over antibody titre alone to inform vaccine strategy.

Older adults continue to be at risk of COVID-19, particularly in residential care home settings. We investigated the effect of infection and vaccination on antibody development and subsequent SARS-CoV-2 infection in older adults. Antibodies are proteins that the immune system produces on infection or vaccination that can help respond to subsequent infection with SARS-CoV-2. We found that older adults produce antibodies to SARS-CoV-2 after 2-doses of Pfizer BioNTech BNT162b2 vaccine. The strongest immune responses were seen among those older adults who also had prior history of infection. The results highlight the importance of both antibody quality and quantity when considering possible indicators of protection against COVID-19 and supports the need for a third, booster, vaccination in this age group..

Haematological and hepatic adverse effects of ceftriaxone in ambulatory care: a dual-centre retrospective observational analysis of standard vs high dose.

BACKGROUND: European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint criteria for methicillin-susceptible Staphylococcus aureus (MSSA) treatment with ceftriaxone are based upon high dose (4 g/day) rather than standard dose (2 g/day) posology. This is particularly relevant for invasive infections, and for patients managed via Outpatient Parenteral Antimicrobial Therapy (OPAT), but may result in increased drug toxicity. We quantified the incidence of neutropenia, thrombocytopenia and raised liver enzymes between standard and high dose ceftriaxone in adult patients. METHOD: Adult outpatients prescribed ≥ 7 days of ceftriaxone therapy were identified, and clinical, pharmacological, and laboratory parameters extracted from electronic health records between May 2021 and December 2021. Incidence and median time to haematological and hepto-toxicity were analysed. Univariate odds ratios were calculated for neutrophil count and ALT levels with 95% confidence level and Chi squared/Fisher's exact test used to identify statistical significance. RESULTS: Incidence of neutropenia was comparable between both groups; 8/47 (17%) in the 2 g group vs 6/39 (15.4%) in the 4 g group (OR 0.89 (95% CI 0.26-2.63), p > 0.999). Median time to neutropenia was 12 and 17 days in the 2 g and 4 g groups respectively. Thrombocytopenia was observed in 0/47 in the 2 g group compared with 3/39 (7.7%) in the 4 g group (p 0.089). Median time to thrombocytopenia was 7 days in the 4 g group. Elevated liver enzymes did not clearly correlate with ceftriaxone dosing; present in 5/47 (10.6%) and 2/39 (5.1%) for 2 g and 4 g respectively (OR 0.45 (95% CI 0.87-2.36), p 0.448). Treatment cessation due to any adverse effect was similar between both groups 2/47 (4.3%) for 2 g and 3/39 (7.7%) for 4 g (OR 1.86 (95% CI 0.36-10.92), p 0.655). CONCLUSIONS: Increased adverse effects with 4 g (over 2 g) daily dosing of ceftriaxone was not observed in an OPAT population. However absolute development of haematological and liver dyscrasias was appreciable-monitoring of liver function and full blood count in patients receiving prolonged ceftriaxone is indicated irrespective of dosing.

Evaluating the long-term impact of an antimicrobial stewardship programme in a Central London mixed medical and surgical intensive care unit.

Background: Antimicrobial overuse causes increased antimicrobial resistance in ICUs; antimicrobial stewardship programmes (ASPs) aim to optimize usage. Following an MDR Acinetobacter baumannii (MRAb) outbreak in 2008, an ASP was implemented at a London ICU, and then continued as a long-term programme. This study aimed to determine long-term changes in antimicrobial prescribing 9 years on. Methods: Data were collected from ICU patients in 2008 immediately before ASP implementation, and thereafter for 6 month cohort periods in 2010-2011, 2012 and 2017. Antimicrobial usage in DDD per 1000 occupied bed days (OBD) were compared. Multivariate linear regression models for antimicrobial days were fitted, adjusting for APACHE II score and patient days. Antimicrobial resistance in Pseudomonas aeruginosa (as an indicator organism) was compared across cohort periods. Findings: Across 400 patients over 9 years, antimicrobial use changed significantly (P < 0.011) and remained lower in all post-ASP cohorts compared with pre-ASP [(2008; 1827 DDD/1000 OBD), (2010; 1264 DDD/1000 OBD), (2012; 1270 DDD/1000 OBD) and (2017; 1566 DDD/1000 OBD)]. There was reduction in usage of all antimicrobial classes except ß-lactams (where there was no significant increase nor decrease, P = 0.178) and aminoglycosides (where there was a significant increase in usage, P < 0.0001). The latter was temporally associated with restrictions on specific carbapenems. There was an increase in carbapenem-resistant P. aeruginosa in 2012 only (P = 0.028) but not subsequently. Conclusions: Following ASP implementation after an outbreak of MRAb, reduced antimicrobial prescribing was maintained 9 years on. We identify several factors influencing successful long-term maintenance of ASPs in ICUs.

Early identification of high-risk individuals for monoclonal antibody therapy and prophylaxis is feasible by SARS-CoV-2 anti-spike antibody specific lateral flow assay.

Monoclonal antibody therapy has been approved for prophylaxis and treatment of severe COVID-19 infection. Greatest benefit appears limited to those yet to mount an effective immune response from natural infection or vaccination, but concern exists around ability to make timely assessment of immune status of community-based patients where laboratory-based serodiagnostics predominate. Participants were invited to undergo paired laboratory-based (Abbott Architect SARS-CoV-2 IgG Quant II chemiluminescent microparticle immunoassay) and lateral flow assays (LFA; a split SARS-CoV-2 IgM/IgG and total antibody test) able to detect SARS-CoV-2 anti-spike antibodies. LFA band strength was compared with CMIA titer by log-linear regression. Two hundred individuals (median age 43.5 years, IQR 30-59; 60.5% female) underwent testing, with a further 100 control sera tested. Both LFA band strengths correlated strongly with CMIA antibody titers (P < 0.001). LFAs have the potential to assist in early identification of seronegative patients who may demonstrate the greatest benefit from monoclonal antibody treatment.

Panton-Valentine leucocidin-producing Staphylococcus aureus: a clinical review.

Panton-Valentine leucocidin (PVL) is a virulence factor produced by certain strains of Staphylococcus aureus (SA). Through its cytolytic action on the cell membranes of human polymorphonuclear neutrophils, PVL causes a range of pathologies collectively known as PVL-SA disease. The hallmark clinical signs of PVL-SA are recurrent boils and necrotizing skin and soft tissue infections (SSTIs) in otherwise healthy patients; however, it can lead to more severe and invasive presentations, including necrotizing haemorrhagic pneumonia, necrotizing fasciitis and purpura fulminans. Young adults with minimal previous exposure to healthcare settings tend to be at highest risk for acquiring PVL-SA disease, with close physical contact playing a central role in disease transmission. The prevalence of PVL-SA varies globally; however, this is often underestimated owing to a lack of routine PVL testing. In the UK, PVL-positive SA isolates have been rising over the past decade alongside an increasing prevalence of multidrug resistance in larger cities. This review article aims to raise awareness of the PVL toxin, to aid clinicians with diagnostic pointers and to provide guidance with treatment, with an emphasis on the need for further population-based studies.

Optimization of antimicrobial dosing in patients with acute kidney injury: a single-centre observational study.

Background: Acute kidney injury (AKI) is a potential complication of systemic infection. Optimizing antimicrobial dosing in this dynamic state can be challenging with sub- or supra-therapeutic dosing risking treatment failure or toxicity, respectively. Locally, unadjusted renal dosing for the first 48 h of infection is recommended. Objectives: To determine the outcomes associated with this dosing strategy. Methods: A retrospective cohort analysis was undertaken in patients treated for Gram-negative bacteraemia with concurrent non-filtration dependent AKI from a single-centre NHS acute hospital (April 2016-March 2020). Patient demographics, microbiology data, antimicrobial treatment and patient outcome (in-hospital mortality and kidney function) were analysed. Results: In total, 647 episodes of Gram-negative bacteraemia (608 patients) were included; 305/608 (50.2%) were male with median age 71 years (range 18-100). AKI was present in 235/647 (36.3%); 78/647 (12.1%) and 45/647 (7.0%) having Kidney Disease Improving Global Outcomes-defined injury (stage 2) or failure (stage 3), respectively. In-hospital 30 day mortality was 25/352 (7.1%), 14/112 (12.5%), 26/123 (21.1%) and 11/60(18.3%) in patients with normal renal function, AKI stage 1, AKI stage ≥2 and established chronic kidney disease, respectively. Recovery of renal function at Day 21 or discharge was present in 105/106 surviving patients presenting with AKI stage ≥2. Time to recovery of AKI was similar in patients receiving full, low or no aminoglycoside (3 versus 4 versus 3 days, P = 0.612) and those receiving full- and low-dose ß-lactam (3 versus 5 days, P = 0.077). Conclusions: There is a high burden of AKI in patients with Gram-negative bacteraemia. Dose adjustments of ß-lactams may not be necessary in the first 48 h of infection-induced AKI and single-dose aminoglycosides may be considered for early empirical coverage.

Demographic and clinical characteristics of confirmed human monkeypox virus cases in individuals attending a sexual health centre in London, UK: an observational analysis.

BACKGROUND: Historically, human monkeypox virus cases in the UK have been limited to imported infections from west Africa. Currently, the UK and several other countries are reporting a rapid increase in monkeypox cases among individuals attending sexual health clinics, with no apparent epidemiological links to endemic areas. We describe demographic and clinical characteristics of patients diagnosed with human monkeypox virus attending a sexual health centre. METHODS: In this observational analysis, we considered patients with confirmed monkeypox virus infection via PCR detection attending open-access sexual health clinics in London, UK, between May 14 and May 25, 2022. We report hospital admissions and concurrent sexually transmitted infection (STI) proportions, and describe our local response within the first 2 weeks of the outbreak. FINDINGS: Monkeypox virus infection was confirmed in 54 individuals, all identifying as men who have sex with men (MSM), with a median age of 41 years (IQR 34-45). 38 (70%) of 54 individuals were White, 26 (48%) were born in the UK, and 13 (24%) were living with HIV. 36 (67%) of 54 individuals reported fatigue or lethargy, 31 (57%) reported fever, and ten (18%) had no prodromal symptoms. All patients presented with skin lesions, of which 51 (94%) were anogenital. 37 (89%) of 54 individuals had skin lesions affecting more than one anatomical site and four (7%) had oropharyngeal lesions. 30 (55%) of 54 individuals had lymphadenopathy. One in four patients had a concurrent STI. Five (9%) of 54 individuals required admission to hospital, mainly due to pain or localised bacterial cellulitis requiring antibiotic intervention or analgesia. We recorded no fatal outcomes. INTERPRETATION: Autochthonous community monkeypox virus transmission is currently observed among MSM in the UK. We found a high proportion of concomitant STIs and frequent anogenital symptoms, suggesting transmissibility through local inoculation during close skin-to-skin or mucosal contact, during sexual activity. Additional resources are required to support sexual health and other specialist services in managing this condition. A review of the case definition and better understanding of viral transmission routes are needed to shape infection control policies, education and prevention strategies, and contact tracing. FUNDING: None.

Variability in detection of SARS-CoV-2-specific antibody responses following mild infection: a prospective multicentre cross-sectional study, London, United Kingdom, 17 April to 17 July 2020.

IntroductionImmunoassays targeting different SARS-CoV-2-specific antibodies are employed for seroprevalence studies. The degree of variability between immunoassays targeting anti-nucleocapsid (anti-NP; the majority) vs the potentially neutralising anti-spike antibodies (including anti-receptor-binding domain; anti-RBD), particularly in mild or asymptomatic disease, remains unclear.AimsWe aimed to explore variability in anti-NP and anti-RBD antibody detectability following mild symptomatic or asymptomatic SARS-CoV-2 infection and analyse antibody response for correlation with symptomatology.MethodsA multicentre prospective cross-sectional study was undertaken (April-July 2020). Paired serum samples were tested for anti-NP and anti-RBD IgG antibodies and reactivity expressed as binding ratios (BR). Multivariate linear regression was performed analysing age, sex, time since onset, symptomatology, anti-NP and anti-RBD antibody BR.ResultsWe included 906 adults. Antibody results (793/906; 87.5%; 95% confidence interval: 85.2-89.6) and BR strongly correlated (ρ = 0.75). PCR-confirmed cases were more frequently identified by anti-RBD (129/130) than anti-NP (123/130). Anti-RBD testing identified 83 of 325 (25.5%) cases otherwise reported as negative for anti-NP. Anti-NP presence (+1.75/unit increase; p < 0.001), fever (≥ 38°C; +1.81; p < 0.001) or anosmia (+1.91; p < 0.001) were significantly associated with increased anti-RBD BR. Age (p = 0.85), sex (p = 0.28) and cough (p = 0.35) were not. When time since symptom onset was considered, we did not observe a significant change in anti-RBD BR (p = 0.95) but did note decreasing anti-NP BR (p < 0.001).ConclusionSARS-CoV-2 anti-RBD IgG showed significant correlation with anti-NP IgG for absolute seroconversion and BR. Higher BR were seen in symptomatic individuals, particularly those with fever. Inter-assay variability (12.5%) was evident and raises considerations for optimising seroprevalence testing strategies/studies.

Burden of enteral supplement interactions with common antimicrobial agents: a single-centre observational analysis.

INTRODUCTION: Oral antimicrobials, including ciprofloxacin, levofloxacin and doxycycline, are susceptible to binding with enteral therapies such as calcium and iron therapies. Administered together, the bioavailability of these antimicrobials is expected to be reduced. METHODS: A retrospective case series of patients receiving oral antimicrobials (ciprofloxacin, levofloxacin and doxycycline) was analysed at a single-centre NHS acute hospital (April 2016-September 2019). Patient demographics, including concurrent enteral therapies, were recorded using medical records. Clinically important interactions were defined as doses administered within 2 hours of antimicrobial therapy. RESULTS: A total of 4067 prescriptions for the study antimicrobials (ciprofloxacin, n=1905; levofloxacin, n=538; and doxycycline, n=1624) were prescribed for 3584 patients. 1918/3583 (53.5%) of the patients were female, and the median age was 67 years (range 0.5-105.0 years). 810/4067 (19.3%) prescriptions reviewed had an interacting enteral therapy (calcium or iron salt) administered within 2 hours of the study medication. CONCLUSION: The concomitant administration of enteral calcium and iron with oral antimicrobials is common within the acute care hospital setting. Approximately one in five patients has a clinically important interaction which may impair oral bioavailability and limit treatment efficacy. As antimicrobial stewardship teams strive for increased intravenous-to-oral de-escalation, it is important that optimum dosing administration is followed to optimise patient outcomes.

Near-fatal Panton-Valentine leukocidin-positive Staphylococcus aureus pneumonia, shock and complicated extracorporeal membrane oxygenation cannulation: A case report.

BACKGROUND: Panton-Valentine leukocidin (PVL) is an exotoxin secreted by Staphylococcus aureus (S. aureus), responsible for skin and soft tissue infections. As a cause of severe necrotising pneumonia, it is associated with a high mortality rate. A rare entity, the epidemiology of PVL S. aureus (PVL-SA) pneumonia as a complication of influenza coinfection, particularly in young adults, is incompletely understood. CASE SUMMARY: An adolescent girl presented with haemoptysis and respiratory distress, deteriorated rapidly, with acute respiratory distress syndrome (ARDS) and profound shock requiring extensive, prolonged resuscitation, emergency critical care and venovenous extracorporeal membrane oxygenation (ECMO). Cardiac arrest and a rare complication of ECMO cannulation necessitated intra-procedure extracorporeal cardiopulmonary resuscitation, i.e., venoarterial ECMO. Coordinated infectious disease, microbiology and Public Health England engagement identified causative agents as PVL-SA and influenza A/H3N2 from bronchial aspirates within hours. Despite further complications of critical illness, the patient made an excellent recovery with normal cognitive function. The coordinated approach of numerous multidisciplinary specialists, nursing staff, infection control, specialist cardiorespiratory support, hospital services, both adult and paediatric and Public Health are testimony to what can be achieved to save life against expectation, against the odds. The case serves as a reminder of the deadly nature of PVL-SA when associated with influenza and describes a rare complication of ECMO cannulation. CONCLUSION: PVL-SA can cause severe ARDS and profound shock, with influenza infection. A timely coordinated multispecialty approach can be lifesaving.

Procalcitonin to Guide Antibacterial Prescribing in Patients Hospitalised with COVID-19.

Antibacterial prescribing in patients presenting with COVID-19 remains discordant to rates of bacterial co-infection. Implementing diagnostic tests to exclude bacterial infection may aid reduction in antibacterial prescribing. (1) Method: A retrospective observational analysis was undertaken of all hospitalised patients with COVID-19 across a single-site NHS acute Trust (London, UK) from 1 December 2020 to 28 February 2021. Electronic patient records were used to identify patients, clinical data, and outcomes. Procalcitonin (PCT) serum assays, where available on admission, were analysed against electronic prescribing records for antibacterial prescribing to determine relationships with a negative PCT result (<25 mg/L) and antibacterial course length. (2) Results: Antibacterial agents were initiated on admission in 310/624 (49.7%) of patients presenting with COVID-19. A total of 33/74 (44.5%) patients with a negative PCT on admission had their treatment stopped within 24 h. A total of 6/49 (12.2%) patients were started on antibacterials, but a positive PCT saw their treatment stopped. Microbiologically confirmed bacterial infection was low (19/594; 3.2%) and no correlation was seen between PCT and culture positivity (p = 1). Lower mortality (15.6% vs. 31.4%; p = 0.049), length of hospital stay (7.9 days vs. 10.1 days; p = 0.044), and intensive care unit (ICU) admission (13.9% vs. 40.8%; p = 0.001) was noted among patients with low PCT. (3) Conclusions: This retrospective analysis of community acquired COVID-19 patients demonstrates the potential role of PCT in excluding bacterial co-infection. A negative PCT on admission correlates with shorter antimicrobial courses, early cessation of therapy, and predicts lower frequency of ICU admission. Low PCT may support decision making in cessation of antibacterials at the 48-72 h review.