The impact of immunosuppressive therapy on secondary infections and antimicrobial use in COVID-19 inpatients: a retrospective cohort study.

BACKGROUND: Immunosuppressive therapies have become a cornerstone of the management of severe COVID-19. The impact of these therapies on secondary infections and antimicrobial prescribing remains unclear. We sought to assess antimicrobial use and the incidence of bacterial and fungal infections in patients with severe COVID-19, and to explore their associations with receipt of immunosuppressive therapies. METHODS: Our retrospective cohort study included 715 hospitalised, adult patients with severe COVID-19 admitted to St George's Hospital, London, UK, during the first UK pandemic wave (1st March-10th June 2020). Co-infections (occurring within 48 h of admission) and secondary infections (≥ 48 h) were defined as a positive microbiological culture with supporting clinical, radiological or laboratory data to suggest true infection. Cox regression models with time-dependent covariates were used to explore the association between immunosuppressant use and secondary infection. RESULTS: Microbiologically confirmed co-infection occurred in 4.2% (n = 30) and secondary infection in 9.3% (n = 66) of the cohort (n = 715) and were associated with in-hospital mortality (48% vs 35%, OR 1.8, 95%CI 1.1-2.7, p = 0.01). Respiratory (n = 41, 39%) and bloodstream infections (n = 38, 36%) predominated, with primarily Gram-negative pathogens. 606 (84.7%) patients received an antimicrobial, amounting to 742 days of therapy per 1000 patient-days (DOTs). In multivariable models, receipt of high-dose steroids (≥ 30 mg prednisolone or equivalent) or tocilizumab was significantly associated with increased antimicrobial consumption (+ 5.5 DOTs, 95%CI 3.4-7.7 days) but not secondary infection (HR 0.56, 95%CI 0.26-1.18). CONCLUSIONS: Bacterial and fungal infections in severe COVID-19 were uncommon. Receipt of steroids or tocilizumab was independently associated with antimicrobial consumption despite its lack of association with secondary infection. These findings should galvanise efforts to promote antimicrobial stewardship in patients with COVID-19.

Clinical, microbiological characteristics and predictors of mortality in patients with carbapenemase-producing Enterobacterales bloodstream infections: a multicentre study.

Objectives: To investigate the clinical, microbiological characteristics and outcomes of patients with bloodstream infections (BSI) due to carbapenemase-producing Enterobacterales (CPE). Methods: A multicentre retrospective observational study of patients with BSIs due to CPE admitted to six UK hospitals was conducted between 2011 and 2021. Multivariate analysis was used to identify factors predicting 30-day case fatality rate (CFR). Results: There were 84 episodes of CPE-BSIs, 37 (44%) due to OXA-48, 35 (42%) to metallo-betalactamases (MBL) and 12 (14%) to KPC. 63% of patients were male with a median age of 64 years. Common organisms included Klebsiella spp. (61%), Escherichia coli (20%) and Enterobacter spp. (13%). Urinary devices were more often involved in OXA-48 BSIs (12/37; 32%) compared to infections caused by MBL and KPC (4/35; 11% and 1/12; 8%; P = 0.046). In contrast, central venous catheters were more frequently present in KPC-BSIs (10/12; 92%) compared with OXA-48 and MBL (11/37; 30% and 20/35; 57%; P = 0.002). Effective definitive antimicrobials were received by 72/84 (86%) patients, comprising monotherapy (32/72; 44%) or combination therapy (40/72; 56%). 30-day case fatality rate (CFR) was 38%. Sepsis or septic shock was associated with death [OR 3.81 (CI 1.19-12.14), P = 0.024]. Conclusion: Strategies targeting high-risk patients and adherence to infection prevention bundles for urinary devices and central venous catheters can reduce OXA-48 and KPC-BSIs. Early recognition and management of severe sepsis, prompt initiation of appropriate antimicrobial therapy and development of novel antimicrobials are crucial to mitigate the high CFR associated with CPE-BSIs.

Real-World Budget Impact of Fidaxomicin versus Vancomycin or Metronidazole for In-Hospital Treatment of Clostridioides difficile Infection

Fidaxomicin, a macrocyclic antibiotic, selectively kills Clostridioides difficile and reduces C. difficile infection (CDI) recurrence compared with vancomycin, but some studies and guidelines report fidaxomicin as being less cost-effective. The aim of this study was to compare the cost-effectiveness and budget impact of fidaxomicin versus vancomycin or metronidazole for treating CDI in a real-world UK setting. Data were retrospectively collected from medical records of 86 patients with CDI treated with vancomycin or metronidazole at a single UK hospital between April 2011 and March 2012, and prospectively from 62 patients with CDI treated with fidaxomicin between August 2012 and July 2013. CDI cases were matched by age, financial year, and healthcare resource use to control cases. CDI recurrence rates were lower with fidaxomicin (6.5%) than vancomycin/metronidazole (19.8%). An estimated 12 additional recurrent CDIs were prevented with fidaxomicin treatment. Patients with CDI had significantly higher healthcare costs than those without CDI, with a mean excess spend of GBP 10,748 and GBP 17,451 per patient in the fidaxomicin (p = 0.015) and vancomycin/metronidazole cohorts (p < 0.001), respectively. A second CDI was associated with mean excess costs of GBP 8373 and GBP 20,249 per patient in the fidaxomicin and vancomycin/metronidazole cohorts, respectively. Despite higher fidaxomicin drug costs, overall cost savings were estimated at GBP 140,292 (GBP 2125 per CDI). In this real-world study, first-line CDI treatment with fidaxomicin reduced healthcare costs versus vancomycin/metronidazole, consistent with previous studies.

Sensitivity and specificity of monocyte distribution width (MDW) in detecting patients with infection and sepsis in patients on sepsis pathway in the emergency department.

PURPOSE: Monocyte distribution width (MDW) is a biomarker for the early identification of sepsis. We assessed its accuracy in patients presenting with suspected sepsis in the emergency department (ED). METHODS: This was a single gate, single centre study in consecutive adults (≥ 18 years) admitted to the ED with suspected sepsis and clinical history compatible with infection, between 01 January and 31 December 2020 (n = 2570). RESULTS: The overall median MDW was 22.0 (IQR 19.3, 25.6). Using Sepsis-3 (qSOFA) to define sepsis, the Area Under Curve (AUC) for a receiver operator characteristic (ROC) relationship was 0.59 (95% CI 0.56, 0.61). Discrimination was similar using other clinical scores, and to that of C-reactive protein. At an MDW cutoff of 20.0, sensitivity was 0.76 (95% CI 0.73, 0.80) and specificity 0.35 (95% CI 0.33, 0.37) for Sepsis-3. MDW showed better performance to discriminate infection, with AUC 0.72 (95% CI 0.69, 0.75). At MDW 20.0, sensitivity for infection was 0.72 (95% CI 0.70, 0.74) and specificity 0.64 (95% CI 0.59, 0.70). A sensitivity analysis excluding coronavirus disease (COVID-19) admissions (n = 552) had no impact on the AUC. MDW distribution at admission was similar for bacteraemia and COVID-19. CONCLUSIONS: In this population of ED admissions with a strong clinical suspicion of sepsis, MDW had a performance to identify sepsis comparable to that of other commonly used biomarkers. In this setting, MDW could be a useful additional marker of infection.

SARS-CoV-2 Vaccine Immunogenicity in Patients with Gastrointestinal Cancer Receiving Systemic Anti-Cancer Therapy.

INTRODUCTION: Patients with gastrointestinal (GI) cancers have an increased risk of serious complications and death from SARS-CoV-2 infection. The immunogenicity of vaccines in patients with GI cancers receiving anti-cancer therapies is unclear. We conducted a prospective study to evaluate the prevalence of neutralizing antibodies in a cohort of GI cancer patients receiving chemotherapy following SARS-CoV-2 vaccination. MATERIALS AND METHODS: Between September 2020 and April 2021, patients with cancer undergoing chemotherapy were enrolled. At baseline (day 0), days 28, 56, and 84, we assessed serum antibodies to SARS-CoV-2 spike (anti-S) and anti-nucleocapsid (anti-NP) and concomitantly assessed virus neutralization using a pseudovirus neutralization assay. Patients received either the Pfizer/BioNTech BNT162b2, or the Oxford/AstraZeneca ChAdOx1 vaccine. RESULTS: All 152 patients enrolled had a prior diagnosis of cancer; colorectal (n = 80, 52.6%), oesophagogastric (n = 38, 25.0%), and hepato pancreatic biliary (n = 22, 12.5%). Nearly all were receiving systemic anti-cancer therapy (99.3%). Of the 51 patients who did not receive a vaccination prior to, or during the study, 5 patients had detectable anti-NP antibodies. Ninety-nine patients received at least one dose of vaccine prior to, or during the study. Within 19 days following the first dose of vaccine, 30.0% had anti-S detected in serum which increased to 70.2% at days 20-39. In the 19 days following a second dose, anti-S positivity was 84.2% (32/38). However, pseudovirus neutralization titers (pVNT80) decreased from days 20 to 39. CONCLUSION: Despite the immunosuppressive effects of chemotherapy, 2 doses of SARS-CoV-2 vaccines are able to elicit a protective immune response in patients' ongoing treatment for gastrointestinal cancers. Decreases in pseudoviral neutralization were observed after 20-39 days, re-affirming the current recommendation for vaccine booster doses. CLINICAL TRIAL REGISTRATION NUMBER: NCT04427280.

Increased monocyte distribution width in COVID-19 and sepsis arises from a complex interplay of altered monocyte cellular size and subset frequency.

INTRODUCTION: Monocyte distribution width (MDW), a parameter generated alongside full blood counts (FBC) in new-generation haematology analysers, has been proposed as a diagnostic test for severe infection/sepsis. It represents the standard deviation (SD) of the monocyte mean volume (MMV). METHODS: This study aimed to compare monocyte volumetric parameters retrieved by the UniCel DxH 900 haematology analyser (MMV and MDW) against corresponding parameters from the same sample measured using flow cytometry (forward scatter [FSC] mean and SD) in combination with phenotypic characterization of monocyte subtypes. We analysed blood samples from healthy individuals (n = 11) and patients with conditions associated with elevated MDW: sepsis (n = 26) and COVID-19 (n = 15). RESULTS: Between-instrument comparisons of monocyte volume parameters (MMV vs. FSC-mean) showed relatively good levels of correlation, but comparisons across volume variability parameters (MDW vs. FSC-SD) were poor. Stratification on sample type revealed this lack of correlation only within the sepsis group. Flow cytometry analysis revealed that in healthy controls intermediate monocytes are the largest and non-classical the smallest cells. In each disease state, however, each monocyte subset undergoes different changes in volume and frequency that together determine the overall configuration of the monocyte population. Increased MDW was associated with reduced classical monocyte frequency and increased intermediate monocyte size. In COVID-19, the range of monocyte sizes (smallest to largest) reduced, whereas in sepsis it increased. CONCLUSION: Increased MDW in COVID-19 and sepsis has no single flow cytometric phenotypic correlate. It represents-within a single value-the delicate equipoise between monocyte subset frequency and size.

Increased risk of death in COVID-19 hospital admissions during the second wave as compared to the first epidemic wave: a prospective, single-centre cohort study in London, UK.

BACKGROUND: The second coronavirus disease (COVID-19) epidemic wave in the UK progressed aggressively and was characterised by the emergence and circulation of variant of concern alpha (VOC 202012/01). The impact of this variant on in-hospital COVID-19-specific mortality has not been widely studied. We aimed to compare mortality, clinical characteristics, and management of COVID-19 patients across epidemic waves to better understand the progression of the epidemic at a hospital level and support resource planning. METHODS: We conducted an analytical, dynamic cohort study in a large hospital in South London. We included all adults (≥ 18 years) with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who required hospital admission to COVID-19-specific wards between January 2020 and March 2021 (n = 2701). Outcome was COVID-19-specific in-hospital mortality ascertained through Medical Certificate Cause of Death. RESULTS: In the second wave, the number of COVID-19 admissions doubled, and the crude mortality rate dropped 25% (1.66 versus 2.23 per 100 person-days in second and first wave, respectively). After accounting for age, sex, dexamethasone, oxygen requirements, symptoms at admission and Charlson Comorbidity Index, mortality hazard ratio associated with COVID-19 admissions was 1.62 (95% CI 1.26, 2.08) times higher in the second wave. CONCLUSIONS: Although crude mortality rates dropped during the second wave, the multivariable analysis suggests a higher underlying risk of death for COVID-19 admissions in the second wave. These findings are ecologically correlated with an increased circulation of SARS-CoV-2 variant of concern 202012/1 (alpha). Availability of improved management, particularly dexamethasone, was important in reducing risk of death.

Impact of rapid susceptibility testing on antimicrobial therapy and clinical outcomes in Gram-negative bloodstream infections.

BACKGROUND: Rapid antimicrobial susceptibility testing (rAST) has the potential to improve care of bloodstream infections. OBJECTIVES: The aim of this service evaluation was to assess the impact of rAST on antimicrobial therapy and clinical outcomes in patients with Gram-negative bloodstream infection. METHODS: A prospective service evaluation was conducted from March 2018 to December 2018. A rAST system (Alfred 60AST) was run Monday-Friday before midday and results were communicated to clinicians on the same day as positive blood culture, with subsequent conventional AST performed. Times to antibiotic therapy and clinical outcomes were compared between rAST and conventional AST. RESULTS: One hundred and ninety-one patients with Gram-negative bacteraemia were included (93 in the rapid group and 98 in the conventional group). Aminoglycoside combination therapy was stopped earlier in the rapid group [32 h (0-795) versus 54 h (4-216), P = 0.002]. The median time to optimal antibiotic based on AST results was significantly shorter than that in the conventional group [50 h (10-339) versus 69.5 h (20-872), P = 0.034]. In the subgroup of patients on ineffective empirical antibiotic, time to effective antibiotic was shorter in the rapid group [39.5 h (32-97) versus 57 h (49-83), P = 0.036]. No differences were found in 28 day mortality or length of stay. CONCLUSIONS: Rapid susceptibility testing resulted in faster discontinuation of aminoglycosides and a shorter time to starting effective and optimal antibiotic when compared with conventional AST results. rAST has potential clinical benefits and points to the need for larger future studies in areas of high antibiotic resistance.

Prevalence of neutralising antibodies against SARS-CoV-2 in acute infection and convalescence: A systematic review and meta-analysis.

BACKGROUND: Individuals infected with SARS-CoV-2 develop neutralising antibodies. We investigated the proportion of individuals with SARS-CoV-2 neutralising antibodies after infection and how this proportion varies with selected covariates. METHODOLOGY/PRINCIPAL FINDINGS: This systematic review and meta-analysis examined the proportion of individuals with SARS-CoV-2 neutralising antibodies after infection and how these proportions vary with selected covariates. Three models using the maximum likelihood method assessed these proportions by study group, covariates and individually extracted data (protocol CRD42020208913). A total of 983 reports were identified and 27 were included. The pooled (95%CI) proportion of individuals with neutralising antibodies was 85.3% (83.5-86.9) using the titre cut off >1:20 and 83.9% (82.2-85.6), 70.2% (68.1-72.5) and 54.2% (52.0-56.5) with titres >1:40, >1:80 and >1:160, respectively. These proportions were higher among patients with severe COVID-19 (e.g., titres >1:80, 84.8% [80.0-89.2], >1:160, 74.4% [67.5-79.7]) than those with mild presentation (56.7% [49.9-62.9] and 44.1% [37.3-50.6], respectively) and lowest among asymptomatic infections (28.6% [17.9-39.2] and 10.0% [3.7-20.1], respectively). IgG and neutralising antibody levels correlated poorly. CONCLUSIONS/SIGNIFICANCE: 85% of individuals with proven SARS-CoV-2 infection had detectable neutralising antibodies. This proportion varied with disease severity, study setting, time since infection and the method used to measure antibodies.

Rapid versus standard antimicrobial susceptibility testing to guide treatment of bloodstream infection.

BACKGROUND: Rapid antimicrobial susceptibility tests are expected to reduce the time to clinically important results of a blood culture. This might enable clinicians to better target therapy to a person's needs, and thereby, improve health outcomes (mortality, length of hospital stay), and reduce unnecessary prescribing of broad-spectrum antibiotics; thereby reducing antimicrobial resistance rates. OBJECTIVES: To assess the effects of rapid susceptibility testing versus standard susceptibility testing for bloodstream infections (BSIs). SEARCH METHODS: To identify studies with selected outcomes, we searched the Cochrane Infectious Diseases Group Specialised Register, CENTRAL, MEDLINE, LILACS, and two trials registries, between 1987 and October 2020. We used 'bloodstream infection' and 'antimicrobial susceptibility tests' as search terms. We had no language or publication status limitations. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing rapid antimicrobial susceptibility testing (with a time-to-result of ≤ 8 hours) versus conventional antimicrobial susceptibility testing in people with a BSI caused by any bacteria, as identified by a positive blood culture. DATA COLLECTION AND ANALYSIS: Two review authors independently screened references, full-text reports of potentially relevant studies, extracted data from the studies, and assessed risk of bias. Any disagreement was discussed and resolved with a third review author. For mortality, a dichotomous outcome, we extracted the number of events in each arm, and presented a risk ratio (RR) with 95% confidence interval (CI) to compare rapid susceptibility testing to conventional methods. We used Review Manager 5.4 to meta-analyse the data. For other outcomes, which are time-to-event outcomes (time-to-discharge from hospital, time-to-first appropriate antibiotic change), we conducted qualitative narrative synthesis, due to heterogeneity of outcome measures.  MAIN RESULTS: We included six trials, with 1638 participants. For rapid antimicrobial susceptibility testing compared to conventional methods, there was little or no difference in mortality between groups (RR 1.10, 95% CI 0.82 to 1.46; 6 RCTs, 1638 participants; low-certainty evidence). In subgroup analysis, for rapid genotypic or molecular antimicrobial susceptibility testing compared to conventional methods, there was little or no difference in mortality between groups (RR 1.02, 95% CI 0.69 to 1.49; 4 RCTs, 1074 participants; low-certainty evidence). For phenotypic rapid susceptibility testing compared to conventional methods, there was little or no difference in mortality between groups  (RR 1.37, 95% CI 0.80 to 2.35; 2 RCTs, 564 participants; low-certainty evidence). In qualitative analysis, rapid susceptibility testing may make little or no difference in time-to-discharge (4 RCTs, 1165 participants; low-certainty evidence). In qualitative analysis, rapid genotypic susceptibility testing compared to conventional testing may make little or no difference in time-to-appropriate antibiotic (3 RCTs, 929 participants; low-certainty evidence). In subgroup analysis, rapid phenotypic susceptibility testing compared to conventional testing may improve time-to-appropriate antibiotic (RR -17.29, CI -45.05 to 10.47; 2 RCTs, 564 participants; low-certainty evidence).  AUTHORS' CONCLUSIONS: The theoretical benefits of rapid susceptibility testing have not been demonstrated to directly improve mortality, time-to-discharge, or time-to-appropriate antibiotic in these randomized studies. Future large prospective studies should be designed to focus on the most clinically meaningful outcomes, and aim to optimize blood culture pathways.

Persistence of SARS-CoV-2 N-Antibody Response in Healthcare Workers, London, UK.

Prospective serosurveillance of severe acute respiratory syndrome coronavirus 2 in 1,069 healthcare workers in London, UK, demonstrated that nucleocapsid antibody titers were stable and sustained for <12 weeks in 312 seropositive participants. This finding was consistent across demographic and clinical variables and contrasts with reports of short-term antibody waning.

An Analysis of Clostridium difficile Environmental Contamination During and After Treatment for C difficile Infection.

BACKGROUND: Lower Clostridium difficile spore counts in feces from C difficile infection (CDI) patients treated with fidaxomicin versus vancomycin have been observed. We aimed to determine whether environmental contamination is lower in patients treated with fidaxomicin compared with those treated with vancomycin/metronidazole. METHODS: The CDI cases were recruited at 4 UK hospitals (Leeds, Bradford, and London [2 centers]). Environmental samples (5 room sites) were taken pretreatment and at 2-3, 4-5, 6-8, and 9-12 days of treatment, end of treatment (EOT), and post-EOT. Fecal samples were collected at diagnosis and as often as produced thereafter. Swabs/feces were cultured for C difficile; percentage of C difficile-positive samples and C difficile bioburden were compared between different treatment arms at each time point. RESULTS: Pre-EOT (n = 244), there was a significant reduction in environmental contamination (≥1 site positive) around fidaxomicin versus vancomycin/metronidazole recipients at days 4-5 (30% vs 50% recipients, P = .04) and at days 9-12 (22% vs 49%, P = .005). This trend was consistently seen at all other timepoints, but it was not statistically significant. No differences were seen between treatment groups post-EOT (n = 76). Fidaxomicin-associated fecal positivity rates and colony counts were consistently lower than those for vancomycin/metronidazole from days 4 to 5 of treatment (including post-EOT); however, the only significant difference was in positivity rate at days 9-12 (15% vs 55%, P = .03). CONCLUSIONS: There were significant reductions in C difficile recovery from both feces and the environment around fidaxomicin versus vancomycin/metronidazole recipients. Therefore, fidaxomicin treatment may lower the C difficile transmission risk by reducing excretion and environmental contamination.

Anti-bacterial antibodies in multiple myeloma patients at disease presentation, in response to therapy and in remission: implications for patient management.

Multiple myeloma (MM) is associated with increased risk of infection, but little is known regarding antibody levels against specific bacteria. We assessed levels of polyclonal immunoglobulin and antibacterial antibodies in patients recruited to the TEAMM trial, a randomised trial of antibiotic prophylaxis at the start of anti-myeloma treatment. Polyclonal IgG, IgA and IgM levels were below the reference range in 71%, 83% and 90% of 838 MM patients at diagnosis. Anti-vaccine targeted tetanus toxoid antibodies were protective in 95% of 193 healthy controls but only 41% of myeloma patients. In healthy controls, protective antibodies against 6/12 pneumococcal serotypes, haemophilus and meningococcus A were present in 67%, 41% and 56% compared to just 15%, 21% and 17% of myeloma patients. By 1 year, myeloma patients IgG levels had recovered for 57% of patients whilst the proportion with protective levels of IgG against thymus-dependent protein antigen tetanus toxoid had changed little. In contrast the proportions of patients with protective levels against thymus independent polysaccharide antigens pneumococcus, haemophilus and meningococcus had fallen from 15 to 7%, 21 to 0% and 17 to 11%. Findings highlight the need for strategies to protect patients against bacterial infections during therapy and vaccination programmes during remission.

PCR for the detection of pathogens in neonatal early onset sepsis.

BACKGROUND: A large proportion of neonates are treated for presumed bacterial sepsis with broad spectrum antibiotics even though their blood cultures subsequently show no growth. This study aimed to investigate PCR-based methods to identify pathogens not detected by conventional culture. METHODS: Whole blood samples of 208 neonates with suspected early onset sepsis were tested using a panel of multiplexed bacterial PCRs targeting Streptococcus pneumoniae, Streptococcus agalactiae (GBS), Staphylococcus aureus, Streptococcus pyogenes (GAS), Enterobacteriaceae, Enterococcus faecalis, Enterococcus faecium, Ureaplasma parvum, Ureaplasma urealyticum, Mycoplasma hominis and Mycoplasma genitalium, a 16S rRNA gene broad-range PCR and a multiplexed PCR for Candida spp. RESULTS: Two-hundred and eight samples were processed. In five of those samples, organisms were detected by conventional culture; all of those were also identified by PCR. PCR detected bacteria in 91 (45%) of the 203 samples that did not show bacterial growth in culture. S. aureus, Enterobacteriaceae and S. pneumoniae were the most frequently detected pathogens. A higher bacterial load detected by PCR was correlated positively with the number of clinical signs at presentation. CONCLUSION: Real-time PCR has the potential to be a valuable additional tool for the diagnosis of neonatal sepsis.

Evaluation of a new Rapid Antimicrobial Susceptibility system for Gram-negative and Gram-positive bloodstream infections: speed and accuracy of Alfred 60AST.

BACKGROUND: Blood stream infections (BSIs) are a major cause of morbidity and mortality. The time from taking blood cultures to obtain results of antibiotic sensitivity can be up to five days which impacts patient care. The Alfred 60 AST™ can reduce laboratory time from positive culture bottle to susceptibility results from 16 to 25 h to 5-6 h, transforming patient care. To evaluate the diagnostic accuracy of a rapid antimicrobial susceptibility system, the Alfred 60 AST™, in clinical isolates from patients with BSIs and confirm time to results. 301 Gram-negative and 86 Gram-positive isolates were analysed directly from positive blood culture bottles following Gram staining. Antimicrobial susceptibility results and time-to-results obtained by rapid Alfred 60 AST system and BD Phoenix were compared . RESULTS: A total of 2196 antimicrobial susceptibility test results (AST) were performed: 1863 Gram-negative and 333 Gram-positive. AST categorical agreement (CA) for Alfred 60 AST™ was 95% (1772/1863) for Gram-negative and 89% (295/333) for Gram-positive isolates. Gram-negative CA: ampicillin 96% (290/301); ciprofloxacin 95% (283/297); ceftriaxone 96% (75/78); meropenem 97% (288/297); piperacillin-tazobactam 95% (280/295); gentamicin 94% (279/297) and amikacin 93% (277/298). The median time to susceptibility results from blood culture flagging positive was 6.3 h vs 20 h (p < 0.01) for Alfred system vs BD Phoenix™. CONCLUSION: Alfred 60 AST system greatly reduced time to antimicrobial susceptibility results in Gram-negative and Gram-positive BSIs with good performance and cost, particularly for Gram-negative bacteraemia.

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT.

BACKGROUND: Staphylococcus aureus bacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance early S. aureus killing, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death. OBJECTIVES: To determine whether or not adjunctive rifampicin reduces bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Secondary objectives included evaluating the impact of rifampicin on all-cause mortality, clinically defined failure/recurrence or death, toxicity, resistance emergence, and duration of bacteraemia; and assessing the cost-effectiveness of rifampicin. DESIGN: Parallel-group, randomised (1 : 1), blinded, placebo-controlled multicentre trial. SETTING: UK NHS trust hospitals. PARTICIPANTS: Adult inpatients (≥ 18 years) with meticillin-resistant or susceptible S. aureus grown from one or more blood cultures, who had received < 96 hours of antibiotic therapy for the current infection, and without contraindications to rifampicin. INTERVENTIONS: Adjunctive rifampicin (600-900 mg/day, oral or intravenous) or placebo for 14 days in addition to standard antibiotic therapy. Investigators and patients were blinded to trial treatment. Follow-up was for 12 weeks (assessments at 3, 7, 10 and 14 days, weekly until discharge and final assessment at 12 weeks post randomisation). MAIN OUTCOME MEASURES: The primary outcome was all-cause bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. RESULTS: Between December 2012 and October 2016, 758 eligible participants from 29 UK hospitals were randomised: 370 to rifampicin and 388 to placebo. The median age was 65 years [interquartile range (IQR) 50-76 years]. A total of 485 (64.0%) infections were community acquired and 132 (17.4%) were nosocomial; 47 (6.2%) were caused by meticillin-resistant S. aureus. A total of 301 (39.7%) participants had an initial deep infection focus. Standard antibiotics were given for a median of 29 days (IQR 18-45 days) and 619 (81.7%) participants received flucloxacillin. By 12 weeks, 62 out of 370 (16.8%) patients taking rifampicin versus 71 out of 388 (18.3%) participants taking the placebo experienced bacteriological (microbiologically confirmed) failure/recurrence or died [absolute risk difference -1.4%, 95% confidence interval (CI) -7.0% to 4.3%; hazard ratio 0.96, 95% CI 0.68 to 1.35; p = 0.81]. There were 4 (1.1%) and 5 (1.3%) bacteriological failures (p = 0.82) in the rifampicin and placebo groups, respectively. There were 3 (0.8%) versus 16 (4.1%) bacteriological recurrences (p = 0.01), and 55 (14.9%) versus 50 (12.9%) deaths without bacteriological failure/recurrence (p = 0.30) in the rifampicin and placebo groups, respectively. Over 12 weeks, there was no evidence of differences in clinically defined failure/recurrence/death (p = 0.84), all-cause mortality (p = 0.60), serious (p = 0.17) or grade 3/4 (p = 0.36) adverse events (AEs). However, 63 (17.0%) participants in the rifampicin group versus 39 (10.1%) participants in the placebo group experienced antibiotic or trial drug-modifying AEs (p = 0.004), and 24 (6.5%) participants in the rifampicin group versus 6 (1.5%) participants in the placebo group experienced drug-interactions (p = 0.0005). Evaluation of the costs and health-related quality-of-life impacts revealed that an episode of S. aureus bacteraemia costs an average of £12,197 over 12 weeks. Rifampicin was estimated to save 10% of episode costs (p = 0.14). After adjustment, the effect of rifampicin on total quality-adjusted life-years (QALYs) was positive (0.004 QALYs), but not statistically significant (standard error 0.004 QALYs). CONCLUSIONS: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S. aureus bacteraemia. FUTURE WORK: Given the substantial mortality, other antibiotic combinations or improved source management should be investigated. TRIAL REGISTRATIONS: Current Controlled Trials ISRCTN37666216, EudraCT 2012-000344-10 and Clinical Trials Authorisation 00316/0243/001. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 59. See the NIHR Journals Library website for further project information.